SECTION 18 Respiratory disorders Section editor Pa

18.1 Structure and function 3933 18.1.1 The upper

18.1 Structure and function 3933 18.1.1 The upper respiratory tract 3933 Pallav L. Shah, J.R. Stradling, and S.E. Craig

CONTENTS 18.1.1 The upper respiratory tract  3933 Pallav L. Shah, J.R. Stradling, and S.E. Craig 18.1.2 Airways and alveoli  3937 Peter D. Wagner and Pallav L. Shah 18.1.1  The upper respiratory tract Pallav L. Shah, J.R. Stradling, and S.E. Craig ESSENTIALS The upper respiratory tract extends from the anterior nares to the larynx and comprises (1) the nose—​with the main function as first-​ line defence against problems with incoming air, acting as a coarse particle filter and a conditioner (temperature and humidity) of the air, and with the sense of smell helping to detect noxious substances that are best avoided. (2) The pharynx—​this has to act as a rigid tube when used for breathing, but during swallowing it has to be a col- lapsible tube capable of peristalsis, a combination of functions which is achieved by complex innervation and musculature. Subepithelial collections of lymphoid tissue in the pharynx are ideally suited to process inhaled and swallowed antigens. (3)  The larynx—​this has three important functions: communication, protection of the airway, and dynamic control of lung volume. The nose Anterior nares The anterior nares, which include the nasal valve just inside the nose, are usually the narrowest part of the respiratory tract and account for about 40–​50% of the total respiratory resistance. In normal subjects the resistance in the lower airways is small (<25%) compared with the larynx and nose. This anterior nasal resistance is actively con- trolled by the levator alae nasi and procerus muscles, which flare the nostrils, and the compressor naris muscle, which narrows the nasal valve further. During mild exercise, these muscles (combined with sympathetic nasal mucosal vasoconstriction) can halve the nasal resistance and allow minute ventilations up to 30 litres/​min before conversion to oral breathing is necessary. These muscles receive a phasic inspiratory signal, to brace open the nares with each breath, just in advance of diaphragmatic activity. Occasionally, owing to deformity of the anterior nasal cartilages, the anterior nares are very narrow and limit inspiration, particularly during sleep when the dilator muscle activity is reduced. This is one of the rarer causes of snoring that is amenable to treatment. Turbinates The main function of the nose is as first-​line defence against prob- lems with the incoming air. In this respect it acts as a coarse particle filter and a conditioner (temperature and humidity) of the air, and helps the sense of smell to detect noxious substances that are best avoided. The turbinates in the nose present a surface on to which large inhaled particles, such as pollen grains and house dust mite faecal particles, will be retained, with the potential for an allergic response producing allergic rhinitis. Debris arriving on the mucosal surfaces is wafted backwards to be swallowed eventually. Without this so-​called mucociliary carpet there is decreased resistance to infections (usually a generalized respiratory problem and not just in the nose), with pooling of mucopurulent material and recurrent sinus infections. This mucociliary function can be tested by placing a saccharine tablet on the anterior floor of the nasal cavity and timing the period that elapses before it can be tasted in the oral cavity. The normal interval is about 15–​20 min, but with ciliary defects this can extend to an hour or more. Vascular supply The turbinates fill such a large proportion of the nasal cavity that minor swelling produces large changes in nasal airflow resistance (Fig. 18.1.1.1). There are several rich vascular beds at different depths in the nasal mucosa, providing a large surface area to warm and humidify incoming air. These are supplied by the sphenopalatine branch of the maxillary artery, with venous drainage passing back into the cavernous sinus around the carotid artery. The volume of fluid in these vascular beds is controlled via the vidian nerve, which contains sympathetic vasoconstrictor and parasympathetic vaso- dilator fibres acting on both arterioles and venules. The overall blood flow and total volume of blood in the sinusoids determine the degree 18.1 Structure and function

Section 18  Respiratory disorders 3934 of mucosal congestion, which undergoes a cyclical reciprocal change across the two sides of the nose over 2–​4 h, hence as the mucosa on one side is congesting that on the other side is shrinking. This cycle, usually only obvious to individuals with already narrowed nasal pas- sages (when blockage can occur intermittently), can be interrupted by a reflex mediated by pressure on the side of the thorax or in the axilla. Thus, in the decubitus position, the upper nostril becomes clearer and the lower more congested, with the two sides swapping within a minute or two of turning on to the other side. The pur- pose of this nasal cycle is not known, but using the upper rather than the lower nostril when lying on one’s side may lessen the chance of inhaling particulate matter. In addition to this effect there is a gen- eral increase in nasal congestion on lying down, due to a hydrostatic rise in capillary pressure. The volume of fluid needed to humidify the incoming air is con- siderable, but is reduced by condensation of some of this moisture back on to the cooler nasal mucosa during exhalation. Of course, this conditioning is lost during oral breathing, which has important im- plications for exercise-​induced asthma, which is due to the cooling and drying of intrathoracic airways. Secretory function and sensory innervation Nasal secretions come mainly from submucosal glands that are stimulated by parasympathetic (cholinergic) fibres. There is some evidence that sympathetic activity can also stimulate secretions, but of higher viscosity. The sensory fibres from the nose travel in the maxillary nerve (mainly the ophthalmic branch) and are the afferent limb of some interesting reflexes. Airflow is sensed and can itself influence breathing pattern. Nerves containing substance P in the epithelium seem to be responsible for sensations leading to sneezing. Sneezing is like coughing, in that an explosive expiration is generated in an attempt to expel foreign matter. Coughing involves closure of the larynx until pressure builds up, whereas sneezing involves closure of the pharynx. Unlike coughing, sneezing is never voluntary. Sensory fibres from much of the upper airway, nose, and face are also involved in the diving reflex. This reflex is of great importance to diving mammals, when the combination of facial stimulation by cold water, apnoea, and hypoxaemia produce intense peripheral, splanchnic, renal, and muscular vasoconstriction. This diverts blood to the brain and conserves oxygen (producing a heart–​lung–​brain circulation that prolongs diving time), with the rise in blood pres- sure limited by a marked vagally induced bradycardia. This vestigial reflex in humans can be utilized in the control of some cardiac ar- rhythmias, when a brisk increase in vagal tone can be produced by applying ice-​cold water to the face. Nasal irritation can lead to either bronchoconstriction or bron- chodilation. The bronchoconstriction can be prevented by atropine and is presumably vagally mediated. This reflex may be important in provoking bronchospasm in some asthmatics. Negative pressure in the nasal cavities can also be sensed, producing a reflex increase in upper airway dilator action (see the following section on the pharynx). Olfaction depends on recognition of molecules by mucosal recep- tors at the very top of the nose. These olfactory cells have central axons that pass through multiple tiny holes in the skull (cribriform plate) to the brain. At this point they are very vulnerable to shearing forces during a blow to the head, leading to anosmia (loss of ability to smell). The pharynx Anatomical divisions The pharynx is divided into the nasopharynx, oropharynx, and laryngopharynx or hypopharynx—​behind the soft palate, the back of the oral cavity down to the tip of the epiglottis, and the tip of the epiglottis down to the cricoid cartilage, respectively. Thus the top end is level with the base of the skull and the bottom end is about level with the sixth cervical vertebra, giving an overall length of about 12 cm. When being used for breathing, the pharynx has to act as a rigid tube (like the trachea), but during swallowing it has to be a collapsible tube capable of peristalsis (like the oesophagus). This combination of functions is achieved by having a muscular tube that can constrict to propel food, but also has external muscles whose function is to brace open the pharynx when required. Pharyngeal muscles Fig. 18.1.1.2 shows the enormous complexity of the pharyngeal musculature, supplied mainly by the hypoglossal nerve (XII). The pharyngeal constrictors (superior, middle, and lower) are the main peristaltic muscles; the lower part of the inferior constrictor also functions as a sphincter to the top of the oesophagus, preventing air entry during inspiration. Most of the other pharyngeal muscles work in concert to hold open the pharynx. For example, the genioglossus pulls forward the tongue, the geniohyoid together with the strap muscles (sternothyroid, thyrohyoid, and others) pulls forward the hyoid (enlarging the oropharynx), and the stylopharyngeus probably pulls sideways on the lateral pharyngeal walls. The palatopharyngeus will hold open the pharynx if supported by the levator palati, but will also pull forward the palate to open the nasopharynx. The upper pharyngeal muscles (tensor palati and levator palati) also close off the nasal cavity during swallowing to prevent regurgitation of fluids into the nose. To prevent aspiration, closure of the larynx and the false cords above is coordinated with swallowing. Some of these Fig. 18.1.1.1  Coronal sections of human maxillary sinuses and the turbinates in the nose. The view in the panel on the left was taken after ephedrine drops and shows mucosal shrinkage. The consequent small increase in the size of the lumina was attended by a large increase in maximum nasal airflow. Courtesy of Professor F Gleeson.

18.1.1  The upper respiratory tract 3935 actions require sensory information about the exact location and consistency of any food being swallowed, carried via the glosso- pharyngeal and vagus nerves (IX and X). Sensory branches of these nerves also supply the ear, which explains why pharyngeal lesions may present with pain in the ear. Given the complexities of pharyngeal function, it is not surprising that severe swallowing difficulties with aspiration of food and drink are often seen following cerebrovascular accidents in the brainstem involving the control of pharyngeal muscles and sensory pathways. Powerful mechanisms maintain patency of the pharyngeal airway during breathing. As with the alae nasi, the pharyngeal di- lator muscles receive a respiratory input in time with diaphragm activation. The diaphragm receives a gradually increasing level of phrenic activity to overcome elastic recoil as tidal volume increases, whereas the pharyngeal activation follows more of a ‘square wave’. This makes teleological sense, since the collapsing force is dependent on inspiratory flow and this is roughly constant throughout inspir- ation. Dilator activity increases if pharyngeal patency is threat- ened. Fig. 18.1.1.3 shows the reflex increase in genioglossus tone in response to a fall in intrapharyngeal pressure that will pull in the pharyngeal walls, which is thought to be mediated by ‘distortion’ receptors of some kind. Snoring occurs when the pharynx narrows enough to vibrate, and there is some evidence that this vibration itself can also activate pharyngeal dilators, thus warding off full col- lapse. The factors predisposing to pharyngeal collapse during sleep are discussed in Chapter 18.5.2. Lymphoid tissue Waldeyer’s ring of lymphoid tissue, comprising the adenoids, the palatine tonsils, and the lingual tonsils (back of tongue), is situ- ated in the pharynx. These subepithelial collections of lymphoid tissue are ideally suited to process inhaled and swallowed antigens. Unfortunately, if they hypertrophy too much in response to recur- rent infections, they are also positioned such that they obstruct the airway, particularly in small children. This is usually first apparent during sleep, but may become severe enough to provoke inspiratory stridor, even while awake. Adenoidal enlargement, by blocking nasal airflow, will force mouth breathing which, if it occurs early enough (perhaps <18 months of age), retards development of the lower jaw (the so-​called adenoidal facies). This probably leads to overcrowding of the teeth and a narrower retroglossal space (further discussed in Chapter 18.5.2). The larynx The larynx (Fig. 18.1.1.4) has three important functions: communi- cation, protection of the airway, and dynamic control of lung volume. Communication and neuromuscular function A few of the intrinsic and extrinsic muscles of the larynx (e.g. crico- thyroid, posterior cricoarytenoid) open (abduct) or brace the vocal cords, whereas most (e.g. thyroarytenoid, transverse, and oblique arytenoids) close (adduct) the cords. The recurrent laryngeal nerve (from the vagus) supplies all the muscles apart from the cricothyroid (supplied from the superior laryngeal nerve, which is also a branch of the vagus; see Fig. 18.1.1.5). The left recurrent laryngeal nerve comes off the vagus and passes under the aortic arch before run- ning up close to the thyroid gland to the larynx. This means it can be damaged by a tumour at the left hilum and surgically during a thyroidectomy. The right recurrent laryngeal nerve passes under the right subclavian artery, where it can be damaged by a right-​sided apical lung tumour. Protection of the airway As mentioned earlier, there are reflexes initiated by supralaryngeal sensory fibres (mainly via the internal branch of the superior laryn- geal nerve) to protect the airway. Fluid or food landing on or near Palatopharyngeus Styloglossus Hyoid bone Palatopharyngeus Uvula Hamulus Tensor palati Levator palati Superior constrictor Middle constrictor Middle turbinate Levator veli palati Tensor veli palati Musculus uvulae Stylo- pharyngeus Stylohyoid ligament Nasal septum Fig. 18.1.1.2  Two views of the pharyngeal muscles: from inside the pharynx looking laterally (left panel), and from high up on the posterior pharyngeal wall looking anteriorly (right panel). These muscles act in concert and the physical effect of their contraction depends on which other muscles are simultaneously activated.

Section 18  Respiratory disorders 3936 the vocal cords will provoke coughing and/​or laryngeal closure. During sleep, irritation of the cords tends to produce apnoea and laryngeal adduction, and coughing occurs only when wakefulness supervenes. Dynamic control of lung volume One of the less well-​known functions of the larynx is to brake ex- piratory flow and thereby control lung volume. In some species, and in neonates, laryngeal expiratory braking is very important, acting rather like positive end-​expiratory pressure to maintain end-​expiratory lung volume above the passive functional residual 100 ms –15 cmH2O Rectified and integrated EMG (reset every 10 ms) Raw genioglossus EMG Fig. 18.1.1.3  Response of the genioglossus muscle in a conscious human to a sudden fall in intrapharyngeal pressure. The time delay (about 50 ms) is too short to be due to a cortical response and is presumably a spinal cord reflex. From Horner RL, et al. (1991). Evidence for reflex upper airway dilator muscle activation by sudden negative airway pressure in man. J Physiol, 436, 15–​29,
© 1991 The Physiological Society, with permission of Wiley-​Blackwell. Fig. 18.1.1.4  Bronchoscopic view of the larynx from above. The top of the picture is the anterior. © Pallav Shah. Right superior laryngeal nerve Right recurrent laryngeal nerve Left recurrent laryngeal nerve Left superior laryngeal nerve Larynx Fig. 18.1.1.5  The paths of the laryngeal nerves.

18.1.2 Airways and alveoli 3937 Peter D. Wagner an

18.1.2 Airways and alveoli 3937 Peter D. Wagner and Pallav L. Shah

18.1.2  Airways and alveoli 3937 capacity, thus preventing atelectasis. In adults there is no good evi- dence that the rate of expiration is underactive laryngeal control, but this mechanism may come into action during respiratory illnesses (such as pneumonia), especially if there is marked hypoxaemia. If the upper airway is bypassed, for instance, by tracheostomy or in- tubation, then other mechanisms come into play to maintain end-​ expiratory lung volume, such as post-​inspiratory contraction of the diaphragm (thus delaying expiration) and shortening of expiratory time (thus starting inspiration again before lung volume has fallen too far). Fig. 18.1.1.6 is from a tracheotomized dog with areas of atelectasis. This shows how once laryngeal braking is denied to the animal, expiration proceeds faster, lung volume falls, and expiratory time is shortened to produce tachypnoea. This reflex was not present when the areas of atelectasis had resolved. The clinical correlate of this is sometimes seen as an expiratory grunt in babies who have a respiratory illness. Intubation may worsen gas exchange in this situ- ation unless positive end-​expiratory pressure is also applied. Disorders of the larynx Recurrent laryngeal nerve paralysis Complete paralysis of the recurrent laryngeal nerve gives permanent hoarseness of the voice, and the affected cord assumes a position midway between full abduction and adduction. The cord is floppy and can be moved passively very easily, being ‘sucked’ towards the midline during inspiration and blown open during expiration. The unparalysed cord may eventually compensate to some degree and move nearer the paralysed cord, improving the voice. If paralysis of the recurrent laryngeal nerve is incomplete, the affected cord may take up the adducted position, presumably because the fibres running to the abductors are damaged first. When there is bilateral damage to the recurrent laryngeal nerves, loss of adequate abduction causes inspiratory stridor as the cords are passively drawn together. Laryngospasm and inducible laryngeal obstruction Laryngospasm should be considered in patients with sudden onset breathlessness and stridor due to rapid and complete laryngeal closure. The most common presentation is with variable exertional breathlessness and inspiratory stridor that is often mistaken for a wheeze, and often observed on exertion. The condition is often misdiagnosed as asthma, but further complicated as it may coexist in up to 25% of patients with asthma. In severe cases it is associated with hypoxia, and in some instances with loss of consciousness. The condition is often associated with psychological or psychi- atric factors, but may also be precipitated by drugs such as baclofen, haloperidol, neuroleptics, and β-agonists. The diagnosis can be made by nasendoscopy, which allows the vocal cords to be visualized during exercise (usually on a static bi- cycle), or by demonstration of reversible or variable flattening of the inspiratory portion of the flow volume loop during an episode of stridor. Speech therapy, relaxation, and breathing techniques are the mainstay of treatment. There is also a distinct entity of inducible laryngeal obstruction, which is associated with exercise. The symptoms occur rapidly on the onset of exercise and subside on cessation of exertion. In other cases there may be a hypersensitivity of the larynx leading to per- sistent cough in response to stimuli such as gastro-​oesophageal re- flux or chronic rhinosinusitis. FURTHER READING Brouillette RT, Thach BT (1979). A neuromuscular mechanism maintaining extrathoracic airway patency. J Appl Physiol, 46, 722–​9. Gautier H (1973). Control of the duration of expiration. Resp Physiol, 18, 205–​21. Horner RL (1991). Evidence for reflex upper airway dilator muscle activation by sudden negative airway pressure in man. J Physiol, 436, 15–​29. Matthew OP, Sant ‘Ambrogio GS (1988). Respiratory function of the upper airway. In: Lung biology in health and disease, Vol. 35. Marcel Dekker, New York. Remmers JE, Bartlett D (1977). Reflex control of expiratory airflow and duration. J Appl Physiol, 42, 80–​7. 18.1.2  Airways and alveoli Peter D. Wagner and Pallav L. Shah ESSENTIALS The lung is the organ of gas exchange, providing the means of trans- ferring oxygen (O2) from the air to the blood by passive diffusion for subsequent distribution to the tissues, and of similarly removing metabolically produced carbon dioxide (CO2) from the blood, which is then exhaled to the atmosphere. A large surface area of contact between alveolar gas and capil- lary blood is required to ensure sufficient gas flux across the blood–​ gas barrier to meet metabolic demand:  the lungs contain about 300 million very small (radius c.150 µm) alveoli. After the main stem bronchi have arisen from the trachea, the airways continue in a branching pattern with each bronchus divid­ ing into two to five branches. The smaller airways have essentially (a) Inspiration Expiration 5 s (b) Fig. 18.1.1.6  Recorder tracings in a dog with atelectasis showing the effect of switching from upper airway to tracheostomy breathing (arrow at a) and from tracheostomy to upper airway breathing (arrow at b). The signal from an inductive plethysmograph measuring movement of both the ribcage and abdomen which represents lung expansion and contraction.

Section 18  Respiratory disorders 3938 a dichotomous branching pattern until the alveoli are reached. Successive branching of connected conducting pipes to the sixteenth generation yields in the order of 50 000 to 100 000 airways (called terminal bronchioles), each of which supplies a functional lung unit comprising a further seven generations of divisions (three divisions of respiratory bronchioles, then alveolar ducts, finally alveoli). The lungs are enclosed within the thoracic cavity. Inspiration is driven by contraction of the intercostal muscles and the diaphragm, which expands the ribcage in both anteroposterior and lateral di- mensions, such that the pressure inside the thoracic cavity but ex- ternal to the lungs is reduced to below that of the air, which is thereby drawn in. Expiration to return lung volume to functional residual cap- acity after inspiration occurs by elastic recoil. Lung diseases of many types commonly affect each of the steps in- volved in gas exchange, and the clinical consequences can usually be readily understood if the structure–​function relationships are known. The organ of gas exchange The lung is the organ of gas exchange, providing the means of transferring oxygen (O2) from the air to the blood for subsequent distribution to the tissues. At the same time, it enables removal of metabolically produced carbon dioxide (CO2) from the blood, which is then exhaled to the atmosphere. Not just in health, but also in lung disease, the volumes of O2 taken up and CO2 removed by the lung per minute must equal the rate of O2 consumption and CO2 production by the whole body. The lung will also exchange any other gas that is presented to it, but the principles involved—​passive diffusion—​mirror those for O2 and CO2. Quantitative but not qualitative differences occur in how such gases (e.g. anaesthetic agents, carbon monoxide, toxic gases in- haled by accident) are handled by the lung. These differences stem from the means by which any particular gas is transported in the blood; whether in a simple physical solution alone, or also in some chemical combination with molecules such as haemoglobin. The principles are similar for gas uptake into blood and elimin- ation from the blood. In fact, because gas exchange occurs by passive diffusion, whether a gas is taken up from the air into the blood or eliminated from the blood into the air depends simply on the par- tial pressures of the gas on each side of the blood–​gas barrier, the 0.3 µm thick tissue layer separating alveolar gas from pulmonary capillary blood. For the transfer of a gas from the environment to the blood to occur, the gas in question must first be brought to the alveolar blood–​gas barrier by the process of ventilation. Diffusion across this barrier then occurs at a rate proportional to (1) the alveolar sur- face area available and (2) the partial pressure difference between alveoli and blood, and inversely proportional to the thickness of the barrier, in concordance with the rules of simple passive diffusion. The gas molecules, now present dissolved physically in plasma, also distribute into the red cells. Depending on the gas, chemical associ- ations may occur—​with haemoglobin in the case of O2, CO2, carbon monoxide (CO), and nitric oxide (NO), and through transformation to bicarbonate ion for CO2. The last element of the exchange process now occurs—​the transport of the gas in blood pumped by the heart through the systemic circulation to the tissues of the body. This chapter focuses on the first two of these three steps in gas exchange—​ventilation and diffusion. A separate chapter deals with the third step—​the pulmonary circulation (see Chapter  16.15.1). The structural basis of ventilation and diffusion, and the associated functional consequences, will be presented with particular emphasis on implications for disease. Lung diseases of many types commonly affect each of the steps involved in gas exchange, and the clinical consequences can usually be readily understood if the structure–​ function relationships are known. Basic airway and alveolar design In essence, the lung is a balloon undergoing cyclical inflation and deflation (ventilation, or tidal breathing) around some partially in- flated state; the main anatomical elements are shown in Fig. 18.1.2.1. The gas-​filled interior of the balloon corresponds to the alveolar gas spaces of the lung. The thin wall of the balloon may be likened to the blood–​gas barrier, with the pulmonary capillary network im- agined as covering the balloon’s surface, separated from the interior (alveolar) gas by the elastic material making up the balloon’s wall. The lung is inflated through the trachea with each inspiration, thus bringing fresh air (21% O2, no CO2) to the alveoli. This fresh gas is rapidly mixed with the resident gas already present. This resident gas is partially depleted of O2 by ongoing diffusion of O2 into the capil- laries, while at the same time CO2 is evolved into the gas from the capillary blood. Each inflation, by bringing fresh air into the alveoli, slightly increases alveolar Po2 and decreases alveolar Pco2. Each de- flation moves some of this alveolar gas back to the environment. This rids the lung of some CO2, but also removes some O2, albeit at Trachea Hilum (left) Parietial pleura Intrapleural space R and L of the diaphragm Pulmonary artery Lobar branchi Pulmonary vein Visceral pleura Right lung Left lung Fig. 18.1.2.1  The right and left lungs are separately encased within the thorax, and each is covered by a visceral pleural membrane. This is continuous with the parietal pleural membrane which lines the interior thoracic cavity, and the thin fluid-​filled space between the visceral and parietal pleurae constitutes the intrapleural space. The hila of the two lungs contain the mainstem bronchi, and accompanying pulmonary arteries and veins. The mainstem bronchi join at the carina to form the trachea. The pulmonary arteries emanate from the right ventricle; the pulmonary veins empty into the left atrium. Within the lungs, the airways and blood vessels continue branching for approximately 20 generations. The major muscle of inspiration, the diaphragm, consists of two domes upon which the right and left lungs sit, and which separate the thoracic and abdominal contents.

18.1.2  Airways and alveoli 3939 lower concentrations than in room air. In normal quiet breathing, al- veolar O2 concentration averages about 16% over a respiratory cycle, whereas that of CO2 is about 5%, and a long-​term steady state of gas exchange is achieved. Because the process of gas exchange depends on simple, passive diffusion, a large area of contact between alveolar gas and capillary blood is required to ensure sufficient gas flux across the blood–​gas barrier to meet metabolic demand. The balloon analogy, while useful as an initial concept, thus exhibits a major difference from how the real lung is configured. The real lung has its total gas volume constituted not as a single balloon-​like gas chamber, but as a very large number (about 300 million) of very small, almost spherical, balloons or alveoli (radius, r, c.150 µm). Since the volume (V) of a sphere is V = (4/​3) × π × r 3, while its surface area (A) is A = 4 × π × r 2, dividing a lung of a given volume (given because the lung must fit within the thoracic cage) into many small alveoli allows a much larger total surface area than if the lung were indeed a single large chamber. Given that a typical value for V is 4000 ml, a single sphere of this volume would have a radius of about 10 cm and a surface area of about 1200 cm2, whereas 300 million alveoli, each with a ra- dius of 150 µm have the same total volume but have a total surface area of about 800 000 cm2, which approximates the area of a tennis court. Given the laws of diffusion, maximal pulmonary O2 exchange would be insufficient for life were the lung a single chamber. The lungs inside the thoracic cavity As with a balloon, the lung cannot inflate itself (although, as an elastic structure, once inflated it is capable of unassisted deflation just like a balloon). Inflation requires creation of a pressure differ- ence between the outside and inside of the lung, pressure being higher inside. This may be accomplished in one of only two ways. One is by positive pressure inflation, typical of most clinical ven- tilators that are connected to the trachea and produce inflation by mechanically increasing intratracheal airway pressure. Spontaneous breathing throughout normal life does not happen in this way, and so the only possibility of normally achieving lung inflation is by the second option—​that of decreasing the pressure around the lungs below that of the surrounding air. This is accomplished by encasing the lungs within the closed thoracic cavity, and having the muscles in the wall of this cavity (the intercostal muscles and the diaphragm) contract when inflation is desired. Contraction of these muscles moves the diaphragm caudally and expands the ribcage in both anteroposterior and lateral dimensions. As a result, the pres- sure inside the thoracic cavity but external to the lungs (i.e. within the intrapleural space) is reduced to below that of the air. Since the alveolar tissue is extremely thin and easily deformable, the pressure within the alveolar gas spaces is also reduced to below that of the air, and thus inflation occurs as a result of a hydrostatic pressure gra- dient from the mouth to the alveoli. Inflation in the course of normal tidal breathing usually com- mences from a state of partial lung inflation that reflects that par- ticular volume of the lung at which its own elastic recoil tendency to collapse is exactly balanced by the opposite, natural tendency of the ribcage to expand outwards. This volume is known as the functional residual capacity (FRC) and because it reflects recoil balance be- tween lung and chest wall, it is the only volume which can be main- tained without muscular effort. Thus, to either inhale above FRC or to exhale below FRC requires respiratory muscle contraction, but the return to FRC from either higher or lower volumes can be passive, stored elastic energy provided by respiratory muscle con- traction from the preceding active volume change being used to re- verse the transpulmonary pressure difference and enable gas flow from the alveoli to the mouth. Clinical significance Elastic properties and lung volume If the elastic properties of either the lungs or the chest wall are altered by disease, FRC will change. Should the lungs become less elastic, typically seen in emphysema due to disorganization of the elastin and collagen fibres making up much of the alveolar wall structure, the tendency for the lung to collapse is less, and the lung/​chest wall recoil balance shifts to a higher lung volume, thus increasing FRC. By contrast, diseases characterized by proliferation of alveolar wall elements—​collagen in particular—​renders the lung more elastic and thus collapsible, shifting FRC to lower values. These changes in FRC may be used to aid in diagnosis and in following the natural history and response to treatment of such diseases, since FRC is readily meas- ured in the pulmonary function laboratory by either plethysmography or helium dilution methods. Changes in FRC also have important im- plications for lung function, discussed later in this chapter. While FRC is a key volume upon which to focus, the lung can normally be inflated to well above FRC, and also deflated to consid- erably below FRC. At maximal inflation, lung volume is referred to as the total lung capacity (TLC), while at maximal deflation, lung volume is called the residual volume (RV). Of major significance, RV is well above zero volume. As will be apparent, if all alveoli could be fully emptied of gas, they would be very difficult to reinflate to allow resumption of gas exchange, due to surface tension. The dif- ference between TLC and RV is called the vital capacity (VC). As with FRC, each of these volumes is readily measured during routine pulmonary function testing, and together they provide a simple yet informative profile useful in characterizing many lung diseases and their progress. Unlike some physiological variables, such as arterial pH or haemoglobin concentration, all of the above volumes depend to a major extent on body size. They also depend to a lesser degree on gender (smaller in females), age (deterioration with ageing), bodily habitus (often smaller in the obese), and ethnicity. Many tables of normal values have been published, and interpretation must allow for all of the determinants mentioned already here. Trachea, main bronchi, and pleura For all 300 million alveoli to participate in the gas exchange pro- cess, each must be connected to the environment by an air pathway. The analogy now changes from a balloon to a tree. Imagining an upside-​down tree, the main trunk represents the trachea, the single common airway segment through which inhaled and exhaled gas from all alveoli must pass. The upper end of the trachea begins at the lower margin of the larynx. The trachea lies anteriorly in the neck and chest, passing caudally in the midline retrosternally to the level of about the sternal attachment of the second rib. There it divides into left and right mainstem bronchi, each smaller and shorter than the trachea. These two airways angle caudally and laterally within the upper mediastinum to enter the left and right lungs at the left

Section 18  Respiratory disorders 3940 and right hilar regions, respectively, and they divide into the lobar bronchi, three on the right to feed the right upper, middle, and lower lobes, and two on the left to feed the two left lobes, upper and lower. Note that the two hilar regions are the only normal points of actual connection of the left and right lungs to any thoracic structures, and also contain the large pulmonary arteries and veins, lymphatics, and nerves. The entire remaining lungs, while opposed against the chest wall, are not connected to it and are able to slide easily over the inner chest wall surface. This inner surface is covered by the parietal pleural membrane, and the outer surface of the lungs is similarly covered by the visceral pleural membrane. These two pleural mem- branes are joined at the hilar regions to form a fully enclosed sac that separates the lung and chest wall. The left and right pleural sacs do not communicate with each other, and normally contain only a very thin layer of plasma-​like fluid and no gas at all. This arrangement may be pictured by imagining a sealed, but empty, plastic sandwich bag from which all air has been expelled and which contains a very small volume of water. If one’s right hand is balled into a fist and invaginates this bilayered bag against the cupped left hand, we have the analogy to the right (or left) lung and chest wall. The balled right fist is the lung; the right wrist and forearm represent the hilar struc- tures. The cupped left hand is the chest wall, and the two layers of the closed sandwich bag form the pleural membranes. Clinical significance Mainstem bronchial branching angles The mainstem bronchial branching from the trachea is not quite symmetrical. The right mainstem bronchus continues caudally a little more directly in line with the trachea above it than does the left, which angles laterally more sharply. As a result, accidentally inhaled foreign bodies more frequently lodge in the right than left lungs. For similar reasons, advancing an endotracheal tube too deeply may cause it to lodge in the right mainstem bronchus rather than where intended—​the trachea. This will result in lack of ventilation of the left lung, and if not recognized, hypoxaemia from continued perfu- sion of this unventilated lung with venous blood, and ultimately left lung collapse (over minutes to hours). The intrapleural space and pneumothorax The pressure within the pleural space (i.e. between visceral and par- ietal pleural surfaces) is normally subatmospheric because of the above-​mentioned counterbalancing inward lung and outward chest wall recoil forces. This prevents lung collapse. Disruption of either the visceral or parietal pleura (i.e. pneumothorax) allows air to enter the pleural space, increasing the intrapleural pressure back to atmos- pheric. This results in collapse of the lung, with abolition of ventila- tion even if chest wall muscle contraction continues. Gas exchange therefore ceases, threatening life. In humans, since the right and left lungs are encased in separate pleural sacs, if one side suffers pneumo- thorax, gas exchange can usually be maintained by the other. Pneumothorax can occur from rupture of lung surface alveoli in predisposed individuals, or from chest wall trauma in anyone. Whether the source of the intrapleural air is alveolar gas as in the former case or room air in the latter makes no difference. However, depending on conditions, intrapleural air pressure may actually rise above that of room air. This situation, the tension pneumothorax, can arise whenever air enters the pleural space via a valve-​like mech- anism, when the patient’s respiratory effort or that of a mechanical ventilator can lead to intrapleural pressure rising well above at- mospheric. The lung collapses, but the (increasingly desperate) re- spiratory effort or mechanical ventilator keeps pumping air into the pleural space via the torn lung surface. This is a true emergency re- quiring immediate needle puncture of the chest wall of the affected side to relieve the built-​up pressure. If this is not done, the high intrathoracic pressure compresses and distorts the mediastinum and vena cavae, impeding venous return. Both pulmonary gas exchange and the circulation fail, and death follows rapidly. Mediastinal shifts The separation of the right from left pleural spaces provides for lateral movement of the mediastinum should there be a difference in mechanical properties of the right and left lungs or their asso- ciated pleural spaces or chest wall structures. For example, fibrosis of the right lung, or alternatively its collapse from complete airway obstruction, will reduce the volume of intrathoracic contents and therefore pressure on that side, and mediastinal contents will shift towards the right, visible on chest radiography. In fact, the trachea may also be shifted from its normal midline location in this direc- tion, evident on clinical examination of tracheal position just above the suprasternal notch. Conversely, a pleural effusion on the right or a right pneumothorax (see next section) may raise intrathoracic pressure above that on the left, and have the opposite effects on me- diastinal and tracheal position. The bronchi and bronchioles After the mainstem bronchi have arisen from the trachea, the air- ways continue an essentially dichotomous branching pattern until the alveoli are reached. Thus, successive branching yields in the order of 50 000 to 100 000 airways (called terminal bronchioles) that constitute the sixteenth generation (216 = 65 536). The entire collec- tion of airways from the trachea to these last bronchioles before al- veoli begin forms a system of connected conducting pipes needed to deliver gas between the alveoli and the environment during ventila- tion (Fig. 18.1.2.2). As with the branching of a tree, both the diameter and the length of each successive branch fall. The trachea typically is 12 cm long and 2 cm in diameter. By contrast, the typical terminal bronchiole is just 1–​2 mm long and 0.6 mm in diameter. Airflow is normally mostly laminar (except for that in the upper airways) and there- fore is governed by Poiseuille’s law of fluid dynamics. The essence of this law is that resistance to airflow depends inversely on the fourth power of the airway radius, but varies only in direct proportion to airway length. As airways become both narrower and shorter with increasing branching, it is evident that resistance of a single airway increases dramatically because of the dominating effect of the fourth power of the radius. However, if one asks how the entire system behaves by plotting how airway pressure must fall from trachea to generation 16 (e.g. during steady inspiratory flow), one must allow for the fact that all airways of any single generation are arranged in parallel with one another. Because branching is essentially dichot- omous, there are twice as many airways in any given generation as in the one before. Thus, total airway resistance of any one generation is diminished in proportion to the exponentially increasing number of airways as branching continues. This actually overcomes the fourth

18.1.2  Airways and alveoli 3941 power disadvantage of Poiseuille’s law, such that most of the pressure drops, or put another way, most of the system airway resistance is as- sociated with the first few generations despite their large individual airway size. Another way to understand this somewhat counterintuitive re- sult is to consider the sum total of the cross-​sectional areas of all airways in a single generation. This is of course the area of a typ- ical airway multiplied by the number of airways in that generation. That number is low for the first few generations, but then rises dra- matically because of the exponentially increasing number of air- ways in each generation. Airway resistance of a generation therefore falls from the first few generations to the terminal bronchioles. The summed total volume of gas contained within all 16 generations of these conducting airways is only about 150 ml, despite their prodi- gious number. Clinical significance Dead space The interposition of airways between the mouth and the alveoli creates a volume of gas (c.150 ml as mentioned) called the anatom- ical dead space. The gas in this dead space simply passes back and forth during inspiration and expiration without contributing to gas exchange since the conducting airways contain no alveoli in their walls. It constitutes a penalty since it adds an obligatory 150 ml volume requirement to every breath taken. This is of no importance in health, but in patients with severe lung disease such as chronic obstructive lung disease or fibrosis, the energy cost of overcoming either high resistance in obstructed airways or low compliance of fibrotic lung tissue, and of thus mounting adequate ventilation, may be greatly increased. Then, the need to breathe some 150 ml more per breath than actually required for alveolar gas exchange can be clinically important as a factor contributing to respiratory failure. Recognition of this has led to the use of transtracheal insufflation of air, which permits the anatomical dead space of at least the upper airways to be circumvented and reduces the ventilation necessary for any given activity. Particle deposition Ventilation involves breathing some 6–​10 litres of air every minute of our lives. Air contains much particulate matter of very small size. Depending on particle size, rate of gas flow in the airways, and airway geometry, such particles may move harmlessly in and out with the next breath or they may be deposited somewhere on the epithelial surface in the bronchial tree. To the extent that they do deposit and are chemically or physically harmful to tissue, they can be respon- sible for disease. Pneumoconioses, chronic obstructive pulmonary disease, bacterial and viral infections, asthma, and other diseases may all be initiated and/​or affected by such mechanisms. The dividing airway structure described here already combines ever-​diminishing individual airway diameter with ever-​diminishing gas velocity (due to increasing summed cross-​sectional airway area of all airways in a generation) as branching continues. As airways narrow and flow velocity falls, the chance of airborne particles being deposited on airway walls increases. It is for this reason that coal dust, for example, settles mostly in the terminal bronchiolar region deep within the branching system. Thus, the basic nature of gas exchange, demanding the branching network of airways de- scribed, leads to intrinsic vulnerability to disease from airborne particulate matter. 10000 Trachea Bronchi Bronchioles Terminal bronchioles Respiratory bronchioles Alveolar ducts Alveolar sacs Transitional and respiratory zones Conducting zone Z 0 1 2 3 4 5 16 17 18 19 20 21 22 23 (a) 8000 6000 4000 2000 0 0 5 10 20 15 25 Total airway crossectional area (cm2) Airway generation number (b) Alveoli Trachea Fig. 18.1.2.2  (a) This shows a stylized model of the branching of the airways from trachea to alveoli, encompassing some 23 generations of branching. The first 16 generations contain no alveoli and are purely conducting airways, but the next seven generations contain progressively more alveoli in the airway walls and serve the dual purpose of conducting air to the alveolar sacs and also providing gas exchange. (b) Total cross-​ sectional area of each generation shown in (a). This is obtained by multiplying the average cross-​sectional area of a single airway by the number of airways in the particular generation. The cross-​sectional area is small throughout the conducting zone (first 16 generations), but then increases exponentially in the respiratory zone. The implications are that the forward velocity of inspired gas falls dramatically in the respiratory zone such that diffusion becomes the faster mode of molecular movement. In addition, this diagram implies that during flow between the mouth and alveoli, most of the airway resistance resides in the first 15 generations. Adapted from Weibel ER (1984). Pathway for oxygen: structure and function in the mammalian respiratory system. Harvard University Press, Cambridge, MA, with permission.

Section 18  Respiratory disorders 3942 Mucociliary function As seen commonly in evolutionary responses to deleterious phe- nomena, a protective system has been developed to mitigate the consequences of particle deposition in the airways. This is the mucociliary apparatus. It has several components. There are sub- mucosal glands in the walls of the conducting airways that secrete mucus into the airway lumen when stimulated by irritant signals. These glands are supported by other secretory cells in the epithelium of the airways such as goblet cells. The epithelial cells that line the entire conducting airway system are ciliated, and they function in a coordinated manner, beating rhythmically to move the secreted mucus upward from smaller to larger airways. The primary purpose of the mucus is to trap inhaled particulates before they can reach and damage the airway and lung tissues themselves. This upwardly transported mucus is clinically evident as sputum. The volumes of sputum produced normally are so small as to be unnoticeable, and are usually swallowed. However, inhalation of toxic irritants, infectious agents, and other particles will rapidly increase the volume of sputum to noticeable levels, and chronic airway inflammation from, for example, cigarette smoking will pro- duce chronically increased amounts of mucus that give rise to the syndrome of chronic bronchitis. It is especially noteworthy that in asthma, not only is the volume of mucus increased, probably from airway inflammation, but its composition is altered, rendering it much more tenacious and difficult to eliminate by the ciliary system. Mucus thus accumulates in the airway lumina, particularly those of the smaller conducting bronchioles, creating mucus plugs that cause obstruction to airflow and marked reduction in ventilation of alveoli lying distal to them. When this occurs, asthma is often refractory to usual pharmacological therapy, and patients dying from asthma uni- versally exhibit widespread airway mucus plugging. Dynamic airway compression Another intrinsic physiological problem of the branching airway system within the chest is related to the mechanical nature of respiration—​the need for inflating and deflating the lung by altering the pressure around it—​combined with the fact that the airways are not rigid tubes. The airways are thus susceptible to expansion and compression (and therefore to collapse) on inspiration and expiration, respectively. The intrapleural pressure may be transmitted to the con- ducting airways, and while reduction in this pressure on inspiration will only distend the airways, allowing air to flow more freely, opposite effects during expiration may not be innocuous. Passive expiration—​ that is, expiration fuelled only by the elastic energy stored in the lung tissue from the previous inspiration, without active expiratory muscle effort—​does not compress the airways because the intrapleural pres- sure remains subatmospheric. However, active expiratory muscle contraction, as occurs during a forced expiratory manoeuvre and during heavy exercise, leads to compression of the airways because intrapleural pressure is raised to above atmospheric. In fact, the greater the expiratory effort made, the greater the in- crease in intrapleural pressure and the degree of airway compres- sion. Because of this, flow rates during forced expiration cannot be increased by making a greater muscular effort: any greater driving pressure for expiratory flow is balanced by the increased resist- ance resulting from more compression. As a result, even in normal subjects, expiratory flow of air under these conditions is limited by this phenomenon, known as dynamic compression, which is illus- trated in Fig. 18.1.2.3. The loss of elastic recoil in emphysema, mentioned here earlier in the context of its effects on FRC, also has a major influence on dynamic compression. The airways are much more susceptible to dynamic compression (discussed next), such that even breathing at rest with just small increases in intrapleural pressure from active expiratory muscle contraction may be subject to flow limitation by this mechanism. When this problem is compounded by the separate phenomenon of increased airway luminal mucus from chronic in- flammation induced by cigarette smoking, it is easy to understand how chronic obstructive lung disease (emphysema and chronic bronchitis) has airway obstruction as its major disturbance. In the consideration of dynamic compression it is important to note that the alveoli are not physically independent of one an- other or of the conducting airways, which run within the lung par- enchyma from the lobar bronchi all the way out to the terminal bronchioles. The alveoli share walls in their mutual attachments, and the alveoli beside any intrapulmonary conducting airway are physically connected to the outside of that airway wall. A good ana- logy for how the alveolar parenchyma is configured comes from (a) Bronchiole Mouth −10 −10 −10 −10 −10 −10 0 0 0 0 (b) Airflow

18.1.2  Airways and alveoli 3943 examining the cut surface of a sponge, where the myriad air cells are surrounded by thin tissue walls. Every wall serves two adjacent air cells, and the overall structure is solid (rather than like the leaves of the tree which are physically independent of each other even while being connected to the same dividing network of branches). The net result of this matrix of alveolar and airway connections is that when the lung is inflated, the elastic tension in the parenchyma exerts radial traction on the conducting airways, increasingly so as the lung is further inflated. This stiffens the airway walls and acts to op- pose dynamic compression during active expiration. That maximal expiratory flows are greater at high than low lung volumes is ex- plained by the greater radial traction at high volumes as the alveoli are stretched more. The walls of the larger conducting airways (the trachea and first few generations of bronchi) are reinforced with cartilage rings that further help to counter the forces favouring dynamic compression. However, the smaller conducting airways do not enjoy this protec- tion, and it is in the smaller airways that dynamic compression usu- ally has its major effects. Airway smooth muscle All generations of conducting airways contain smooth muscle cells. When stimulated to contract, their concentric arrangement leads to reduction in airway lumen size, and airway obstruction results. While not a significant effect in normal individuals, patients with asthma have hyperresponsive airway smooth muscle that contracts in response to the inflammatory reaction usually present in the asthmatic airway walls. This is a major mechanism of airway ob- struction in asthma, and is the basis of the mainstay therapy in this disease—​bronchodilators. For reasons that remain unclear, smooth muscle contraction does not occur to the same degree in all airways of the asthmatic lung: there are different degrees of obstruction both with respect to airway generation number and among airways of a given generation. Ventilation of alveoli is thus very uneven, with many alveoli being very poorly supplied with air, yet others are well-​ supplied. Gas exchange becomes inefficient as a result, and arterial hypoxaemia is seen. Airway smooth muscle also contracts when local CO2 concentra- tions fall. This happens commonly in pulmonary thromboembolism, when vascular obstruction results in focal areas of hypoperfusion that remain relatively overventilated, such that their local alveolar CO2 tension falls. This, possibly in concert with bronchoactive in- flammatory mediators released in association with the embolic event, can produce local airway smooth muscle contraction and airway obstruction. This might tend to better matching of local ven- tilation with blood flow, but the benefit is generally small, and local bronchoconstriction can manifest as wheezing, which should not be mistaken for asthma. Dynamic tests of airflow All of the traits of the branched structure of the airways and their interconnectedness need to be considered if one is to understand common pulmonary function tests. How the ‘static’ lung volumes (FRC, TLC, VC, and RV) are affected by changes in elastic recoil are discussed earlier, but such measures form only a part of standard pulmonary function testing. Usually included are ‘dynamic’ tests that measure expiratory and inspiratory gas flow rates, conven- tionally during manoeuvres wherein the patient is asked to make a maximal inspiratory or expiratory muscle effort. These are discussed in Chapter 18.3.1. Distribution of ventilation The extremely large number of very small respiratory bronchioles creates an environment in which alveoli distal to each bronchiole become susceptible to impaired ventilation. Small intrinsic or pathological reductions in airway diameter of such bronchioles can impair distal ventilation substantially. When the effects of variation in mucus secretion, bronchial smooth muscle tone, and radial trac- tion are added to this inherently vulnerable system, it is surprising that the distribution of ventilation to the 300 million alveoli is as uniform as it is. Were it not, there would probably be considerable hypoxaemia, even in health. This topic is discussed further next. The parenchyma distal to 
the terminal bronchioles The terminal bronchioles (sixteenth generation airways) are the final divisions of the wholly conducting airways. They are completely lined with ciliated epithelium, and function primarily as simple conduits for gas, linking the air around us to the alveoli where gas exchange occurs. The next few divisions of the airways result in tran- sitional airways called respiratory bronchioles, so named because they serve a dual role—​as continued gas conduits and as the first locations for gas exchange. Respiratory bronchioles are partly lined with ciliated epithelium, but also have small alveolar outpouchings opening directly into the airway lumen. With continued branching of these bronchioles, more and more of the luminal surface is given to the alveolar outpouchings, and less and less to ciliated epithelium. After about three generations of re- spiratory bronchioles, the airways, while still essentially tubular in shape are made up entirely of alveolar tissue capable of gas exchange, and are called alveolar ducts. These alveolar ducts branch even fur- ther into collections of alveoli whose distal end is blind, known as alveolar sacs, at the end of the line of the airway branching system. A diagram of the functional lung unit is shown in Fig. 18.1.2.4. Pulmonary artery Terminal bronchiole Pulmonary vein Capillary network Alveoli Fig. 18.1.2.4  Diagram of the functional lung unit. The collection of alveoli and associated pulmonary arteries and veins distal to the terminal bronchiole constitutes a functionally homogeneous unit of gas exchange. The mixing of gas among alveoli and of blood in the capillary networks of the alveoli in the unit is sufficiently rapid that gas concentrations are in effect uniform throughout. This unit, also called the acinus, corresponds approximately to generations 17–​23 of Fig. 18.1.2.2.

Section 18  Respiratory disorders 3944 With some seven orders (or division points) of branching between the terminal bronchioles and the final alveoli, together with 16 or- ders of branching in the conducting airway segment, the whole airway tree consists of about 23 orders or branch points. Due to the alveolar sacs being blind after the final branch point, the process of ventilation must occur as a tidal (back and forth) event, alternately adding air to, and removing alveolar gas from, each alveolus with each breath. Gas transport The transport of gas in either direction between the trachea and the last conducting airway takes place principally by convective flow, much as water flowing in a pipe depends on the pressure difference between the two ends of the pipe and the flow resistance of the pipe. Since flow is mostly laminar, velocity profiles are largely parabolic, the flow being highest in the centre of the lumen and lowest at the airway wall, just as is the velocity profile across a quietly flowing river. There are, however, minor additional influences of diffusive movement at the interface between the convective front of each inspiration and residual gas from the previous breath. These inter- actions, and eddies that develop at each branch point, may assist gas mixing but their effects are physiologically small. Of much more sig- nificance is the fact that the total luminal cross-​sectional area of each generation increases exponentially as the airways divide. Since total volumetric flow of gas is the same in each generation, average gas velocity falls reciprocally with the increase in area. By the time inspired gas reaches the first alveoli, forward velocity has dropped to such a low level that random, thermally fuelled mo- lecular motion (i.e. diffusion) becomes a more important mech- anism of gas transport than convection. The small size of the alveoli, about 150 µm in radius, means that diffusive mixing of each new breath with gas resident in the alveoli from prior breaths is nearly instantaneous. Although careful physiological studies can show that low-​molecular-​weight gases mix slightly faster than those of high molecular weight, this turns out to be of essentially no quantitative significance to gas exchange. Even in emphysema, where many al- veolar spaces are enlarged, there is evidence that diffusive mixing in alveolar gas is functionally complete and does not pose a gas ex- change threat. Gas exchange Of more concern for gas exchange is whether all alveoli receive a similar share of each breath. It was pointed out earlier that the in- trinsic structure of the lungs makes it vulnerable to ventilatory inequality, and that this has the potential to disrupt gas exchange. Indeed, recent studies of the structural influence on gas distribution reveal that there are sometimes substantial differences in the ven- tilation of different alveoli. One property of the system that lessens the negative effects of such inhomogeneity on gas exchange is the finding that individual alveoli do not maintain gas exchange differ- ences from closely adjacent alveoli. In fact, a fairly large number of connected alveoli are normally able to function as a single homoge- neous unit of gas exchange. This is no doubt due partly to the rapid diffusive movement of molecules throughout the aforementioned alveolar gas, but it is also facilitated by the rich capillary network lying in the wall of each alveolus. The density of capillaries is so great that should flow fall in one, its neighbour can seamlessly take over its gas exchange role without any resultant inefficiency. It turns out that the functional unit of gas exchange, known as the acinus, cor- responds approximately to all the alveoli distal to the last terminal bronchiole. Clinical significance The functional lung unit Pathological events, in either the alveoli or the capillaries, occurring at a scale smaller than that of the functional lung unit will not per se have much impact on gas exchange. Thus, a large number of tiny pul- monary emboli each lodging in one capillary of different functional lung units will not impair gas exchange function, while a single large embolus of the same total mass obstructing one much larger vessel might. However, if enough microvessels within functional units be- come obstructed, their summed effects may become considerable. Surface tension and mechanical instability of the lung Another consequence of the branched nature of the lungs resulting in so many very small alveoli is inherent mechanical instability. The alveolar wall, where it interfaces with alveolar gas, forms a roughly spherical air–​liquid interface. In this context, the alveoli may be likened to a mass of soap bubbles lying together. All air–​liquid inter- faces are subject to surface tension, which in this case will act to minimize the surface area of each bubble. For an enclosed bubble, this tension increases the pressure inside the bubble, with the rela- tionship between the tension and the interior pressure given by the law of Laplace: pressure = 2 × surface tension/​radius. Thus, pressure inside a small bubble exceeds that inside a larger bubble, and if two such unequal bubbles are in contact and their interiors become con- nected, the small bubble will collapse into the larger. This process of bubble accretion may continue until the many small soap bubbles have collapsed into a single large one. Small alveoli Based on the opening premise of this chapter, if small alveoli had this tendency to collapse into larger neighbours due to surface ten- sion effects, the end result would be disaster for gas exchange. There would be massive alveolar collapse, and with loss of surface area, sufficient O2 exchange to support metabolic needs would not be possible. Only if all alveoli were identical in both size and surface tension would this problem be avoided, but when 300 million alveoli exist, it is impossible to imagine them all being identical, and indeed they are not. The lung The lung avoids this dilemma through two quite separate but com- plementary mechanisms of stabilization. The first, already men- tioned earlier in a different context, is the interconnected nature of the whole alveolar structure. Any tendency for one alveolus to collapse would have to increase the tension on all its immediately connected neighbours. This tension from surrounding alveoli will automatically serve to splint open the alveolus in question, thus opposing its tendency to collapse. This concept, termed al- veolar interdependence, is felt to be of considerable importance in maintaining alveolar stability. The second mechanism is the presence of phospholipid mol- ecules that reduce surface tension in the alveolar air–​liquid interface. Termed surfactant, and produced in conjunction with proteins from alveolar type II epithelial cells lying free in the

18.1.2  Airways and alveoli 3945 alveolar spaces against alveolar walls, this material reduces surface tension severalfold (Fig. 18.1.2.5). Thus, the surface tension of the alveolar lining fluid is only about 10 mN/​m, whereas that of water is some 75 mN/​m. Moreover, probably due to molecular realign- ment of surfactant molecules, surface tension is even lower when lung volume is reduced. Based on the law of Laplace given earlier, this can be seen to be even more advantageous for evening out surface tension differences among alveoli of different size. Surfactant Surfactant is thought to have another crucial role that promotes effi- cient gas exchange between alveolar gas and capillary blood. Given that adjacent alveoli share a common wall, the tendency for surface reduction in each alveolus will create a force that tends to reduce the interstitial tissue pressure around capillaries in the alveolar wall between the adjacent alveoli. From the Starling relationship that governs water escape out of capillaries in any tissue (based on the transcapillary differences in both hydrostatic and oncotic pressures), reducing pressure around the capillary will lead to increased water escape into the alveolar wall. This could have several deleterious consequences. First, the affected alveolar walls would become stiffer and harder to inflate, tending to reduce lung volume. Second, the tissue separating gas from capillary blood would become thicker, directly impairing diffusive transport between gas and blood. Third, this water would find its way into the pulmonary lymphatics, which begin in the alveolar interstitium and run along the large air- ways and vessels to the hilar regions, before exiting the lungs and emptying into the superior vena cava. Extra water frequently accu- mulates in the peribronchial and perivascular spaces and results in their partial compression, reducing distal ventilation, and/​or blood flow of subtended alveoli, causing maldistribution of either or both, and rendering gas exchange inefficient. The presence of surfactant is thought to reduce the rate of transcapillary water exchange, and therefore to contribute to efficient gas exchange. Clinical significance Impaired surfactant activity When surfactant is not present, when its rate of renewal is insuf- ficient, or when it is inactivated rapidly, pathological changes can be severe. Best known is the infant respiratory distress syndrome, occurring in otherwise normal premature infants born before the late-​maturing surfactant system is functional. Without exogenous surfactant replacement therapy, the condition may be fatal due to alveolar collapse and pulmonary oedema. Surfactant activity is also compromised in the adult respiratory distress syndrome and may compound the disturbances of pulmonary function arising from the primary cause of the pulmonary disease. Gravity and lung function Causes of potential unequal distribution of ventilation or blood flow to the alveoli extend beyond those associated with the intrinsic branching structure of the lungs discussed earlier. In particular, the presence of gravity influences lung function because key compo- nents of the lungs have significant weight. The weight of the paren- chyma itself, plus the blood within the alveolar capillaries, feeding arteries and draining veins, together cause the lungs to sag towards the diaphragm in the upright lung sitting at FRC. The upper pole of the lungs is still applied to the parietal pleural surface of the chest wall—​there is no pleural airspace created by this gravitational stress. Rather, the rest of the lung is displaced caudally, sagging much like a heavy sweater pegged to a clothes line. As expected, this creates stress in the alveolar walls, more in the uppermost than lowermost alveoli. A good analogy is the toy Slinky—​a coiled spring that when hanging vertically under its own weight shows wider separation be- tween adjacent coils at its top than at its bottom. Correspondingly, the uppermost alveoli in the upright lung are larger than the lower- most alveoli. The lowermost alveoli are thus more compliant—​that is, able to be further inflated more per unit transpulmonary pressure—​ than the uppermost alveoli, because the latter are stretched almost to their limit. Accordingly, normal ventilation from FRC results in greater ventilation of the lung bases than of the lung apices. Much the same effect is seen for blood flow: apical blood flow is less than that at the base of the upright lung. In this case it is the weight of the blood itself that is responsible: perfusion depends on pulmonary ar- terial pressure, which falls linearly with height up the lung. The apex to base differences in perfusion exceed those of ventila- tion, such that the ratio of ventilation to blood flow is higher at the Surfactant film Arrows depict net force inward from surface tension in the surfactant film Gas Pulmonary artery or vein Gas Gas Fig. 18.1.2.5  Diagram to indicate potential effects of surface tension on lung structure and function. Three gas-​filled alveoli are shown, each lined by a thin film of surfactant. A pulmonary artery or vein is shown in the corner formed where the three alveoli come together. Arrows show the net inward force produced by surface tension, tending to reduce alveolar gas volume and promote atelectasis. In addition, the pressure in the perivascular space around the corner vessel shown will be reduced by these inward surface forces, increasing the pressure difference from inside to outside the vessel lumen and thereby promoting fluid movement from plasma to interstitial space. The presence of surfactant reduces the magnitude of surface tension forces and therefore stabilizes the alveoli against atelectasis and reduces the transmural pressure difference, attenuating transvascular fluid movement.

Section 18  Respiratory disorders 3946 apex than at the base. The local ventilation/​perfusion (V’A/​Q’) ratio determines local alveolar Po2 and Pco2, Po2 increasing and Pco2 falling as the V’A/​Q’ ratio increases. Thus, Po2 at the apex is higher, and Pco2 lower than at the base. If the V’A/​Q’ ratio everywhere was the same, so too would be Po2 and Pco2, and the exchange of O2 and CO2 would be maximally efficient. However, the presence of a range of V’A/​Q’ ratios (no matter what its cause) results in gas exchange inefficiency and arterial hypoxaemia. Clinical significance Effects of gravity on lung function in disease Although gravity creates V’A/​Q’ maldistribution, common disease processes are in large part randomly distributed in the lungs, and their effects on V’A/​Q’ matching are generally much greater than those of gravity. Thus, while the effect of gravity on arterial Po2 is barely measurable, V’A/​Q’ mismatching based on nongravitational influences in many diseases leads to profound gas exchange disturb- ances. However, the presence of gravity must not be discounted in several disease states. Emphysema, and even the normal ageing process, often causes tissue breakdown in the apical lung regions, probably because, as in the Slinky analogy, the alveolar wall stresses are largest there. When mechanical failure occurs, it is most likely to happen in the regions of greatest stress and as a result the alveolar wall break- down so typical of emphysema, and to a much lesser extent normal ageing, is often exaggerated in the apices. An important gravita- tional influence occurs in patients in intensive care with severe lung disease. In any body position, both blood flow and alveolar fluid collection tend to be concentrated in dependent regions (e.g. posteriorly in the supine patient). Those regions with high blood flow may also have little or no ventilation if their alveoli are filled with fluid and cell debris. The blood flowing through such regions can therefore pick up little or no O2, and hypoxaemia may be se- vere. This has led some intensive care staff to rotate their patients from supine to lateral to prone and back; the argument being that the gravitational influences on blood flow are essentially instant- aneous, while those on alveolar fluid collection may take hours to respond to body positional changes. Thus, for a time after ro- tating a patient, the dependent region may enjoy high flow but not yet be fluid filled, and thus still be well ventilated. Gas exchange is therefore enhanced, and arterial hypoxaemia is mitigated. Such behaviour may also explain positional influences on gas exchange in patients with unilateral lung disease such as pneumonia, effu- sion, or atelectasis. FURTHER READING Crystal R, West JB (1997). The lung:  scientific foundations. Raven Press, New York. Weibel ER (1963). Morphometry of the human lung. Springer-​Verlag, Berlin. Weibel ER (1984). The pathway for oxygen:  structure and function in the mammalian respiratory system. Harvard University Press, Cambridge, MA. West JB (2004). Respiratory physiology, the essentials, 7th edition. Williams & Wilkins, Baltimore, MD.

18.10 Cystic fibrosis 4151 Andrew Bush and Carolin

18.10 Cystic fibrosis 4151 Andrew Bush and Caroline Elston

ESSENTIALS Cystic fibrosis (CF) is a recessively inherited disease caused by muta- tions in the cystic fibrosis gene, located on the long arm of chromo- some 7, which codes for a membrane protein—​the cystic fibrosis transmembrane regulator protein—​that is a chloride channel. More than 2000 CF mutations have been identified, with the ΔF508 muta- tion being the most common of around 250 mutations that definitely cause disease (70% of CF chromosomes in the European popula- tion). Birth incidence varies with country of origin from 1 in 2000 to 1 in 100 000. Pathophysiology—​the most popular hypothesis is that mutant cystic fibrosis transmembrane regulator protein fails to transport chloride ions normally, and there is secondary impairment of sodium, bicar- bonate, and water transport. This causes dehydration of pancreatic secretions, eventually leading to pancreatic failure, and in the lungs to increased fluid absorption from the airway lumen and reduction in the depth of the film of airway surface liquid (the ‘low volume hypothesis’), with impairment of ciliary function, mucus stasis, and thus chronic infection and inflammation. There is an increasing focus on bicarbonate transport and abnormal airway surface pH as being pathophysiologically important. Clinical features—​most cases of CF are diagnosed in early life by newborn screening, or later with the classical clinical picture of pancreatic insufficiency and suppurative lung disease, but patients with milder genetic mutations may present in late childhood or adulthood. Other pulmonary manifestations include haemoptysis, pneumothorax, allergic bronchopulmonary aspergillosis, and atyp- ical mycobacterial infection. Patients presenting in adult life are often clinically pancreatic sufficient, or they present with other conditions that are also associated with CF gene mutations (e.g. azoospermia, idiopathic pancreatitis). Diagnosis—​this is usually established by the sweat test (pilocar- pine iontophoresis or macroduct collection) revealing a high sweat chloride concentration, although increasingly the diagnosis is likely to be made by newborn screening (heel-​prick blood samples tested for immunoreactive trypsin and by polymerase chain reaction for common CF mutations). A newborn screening diagnosis is always confirmed with a sweat test. Prognosis—​pulmonary infection and inflammation account for most CF-​associated morbidity and mortality. The lungs become transiently infected in early childhood and ultimately chronic- ally infected, typically early on with Staphylococcus aureus and Haemophilus influenzae, and subsequently with Pseudomonas aeruginosa and increasingly commonly with other Gram-​negative rods, which are associated with a worse prognosis. Chronic infec- tion and inflammation lead to bronchiectasis, progressive airflow obstruction, and ultimately death from respiratory failure, although outcome has improved dramatically over the past 20 years such
that estimated survival for a child born with CF in the late 1990s is to the fifth and sixth decades. This has important implications for the planning of adult health services. Management of respiratory disease—​standard management includes airway clearance with regular physiotherapy. Antibiotic treatment is initially directed at preventing chronic infection. Chronic suppres- sive antibiotic therapy (colomycin, tobramycin, aztreonam, either nebulized or by dry powder device) is beneficial once patients be- come chronically infected with Pseudomonas. Mucolytic agents are often indicated. Azithromycin, a macrolide antibiotic that appears to modulate inflammation in CF by an ill-​understood mechanism, is used increasingly. Ivacaftor is licensed as a specific molecular therapy for the class 3 gating mutations: Orkambi is a combination therapy (ivacaftor and lumacaftor) licensed in Europe for ΔF508 homozygous patients; other specific molecular therapies are in the pipeline. Management of other features—​(1) Pancreatic insufficiency is as- sociated with malabsorption and requires pancreatic enzyme re- placement therapy and a high-​energy diet in most patients. (2) Distal intestinal obstruction syndrome—​severe constipation sometimes leading to bowel obstruction with faecal material in the distal ileum and associated abdominal pain—​is relatively common. (3) Diabetes—​ occurs in up to 30% of patients, with the incidence increasing with age; a high-​energy diet should be maintained, with insulin doses adjusted accordingly. (4)  Liver function—​mild abnormalities are common, with disease progression to cirrhosis in around 5% of patients. (5) Fertility—​nearly all men with CF are infertile, but most women with CF can conceive normally. (6) Osteopaenia—​low bone mineral density is found in 60% of patients. 18.10 Cystic fibrosis Andrew Bush and Caroline Elston

section 18  Respiratory disorders 4152 Definition Cystic fibrosis (CF) is a recessively inherited disease caused by mu- tations in the CF gene, which is located on the long arm of chromo- some 7. The classical clinical picture is a combination of pancreatic insufficiency, suppurative lung disease, and high sweat chloride concentration, presenting in early childhood and progressing to early death from respiratory failure. However, genetic analysis has identified many patients with less severe disease, and the clinical spectrum of CF has been expanded by recognition of mutations in association with other conditions, including azoospermia, al- lergic bronchopulmonary aspergillosis, and idiopathic pancreatitis. Carriers are usually healthy, although they may have an increased prevalence of single organ manifestations like severe sinusitis and bronchiectasis, but although the relative risk is increased, the abso- lute risk remains very small. Since the last edition of this book, there has been a paradigm shift in management. Hitherto, treatment has been directed at the early detection of complications such as infection, and treating them very aggressively; improvement with treatment was obvious. Now diag- nosis is in well babies, and treatment is increasingly directed at the fundamental molecular defect, and benefit is much harder to dem- onstrate in a well population. The genetic defect The CF gene codes for a 168-​kDa membrane protein, the CF trans- membrane regulator protein (CFTR). CFTR is an ATP-​responsive chloride channel, but it also influences other cellular functions such as sodium transport across the respiratory epithelium, cell-​surface glycoprotein composition, and normal antibacterial defences, at least 20 functions in all having been described. The protein is ex- pressed in organs involved in CF disease—​lungs, pancreas, sweat glands, and so on—​but also in some places that do not seem to be af- fected clinically, such as the choroid plexus, heart, and renal tubules. More than 2000 related mutations of the CF gene have been de- scribed, the nomenclature of which has (somewhat confusingly) been changed recently (see https://​www.genet.sickkids.on.ca/​cftr/​). Around 200 are definitely known to be disease producing, and there is an ongoing project, funded by the US CF Foundation, to differen- tiate harmless polymorphisms from true disease-​producing muta- tions (see http://​www.cftr2.org). Known disease-​producing mutations have been classified ac- cording to their impact at a cellular level: class 1, no protein; class 2, disordered trafficking, with intracellular destruction of CFTR; class 3, defective regulation, the so-​called gating mutations; class 4, defective channel function; class 5, reduced protein synthesis. A sixth class is reduced half-​life of CFTR at the apical cell membrane, due to increased breakdown. The understanding of these abnormalities is valuable as a basis for new generation of actual and potentially corrective treatments, as illustrated in Fig. 18.10.1. Perhaps more important is the distinction between mutations which do not reach the epithelial surface to any degree (classes 1 and 2), and those that have abnormal CFTR at the apical membrane (classes 3–​6), because the latter group may be targets for the potentiator ivacaftor. Most mutations are very rare; the commonest in European popu- lations is ΔF508 (now known as p.Phe508del), which is found on Fig. 18.10.1  Classes of CFTR mutations. Reprinted from The Lancet, 1(2), Boyle MP and De Boeck K, A new era in the treatment of cystic fibrosis: correction of the underlying CFTR defect, 158–​63, Copyright
© 2013, with permission from Elsevier.

18.10  Cystic fibrosis 4153 70% of affected chromosomes, with some variation across Europe. Most genetic laboratories restrict routine testing to the commonest 50 mutations, which together account for over 90% of mutations within a given population. Genotype–​phenotype correlations have shown linkage of so-​called severe mutations, such as ΔF508, to pan- creatic insufficiency and a tendency to more severe lung disease, while mild mutations go with pancreatic sufficiency and a tendency to less severe lung disease. However, in general, the correlation be- tween genotype and the severity of lung disease is poor. Virtually all disease-​associated mutations are linked with congenital absence of the vas deferens, resulting in infertility in more than 98% of men with CF, while rarer mutations are linked with isolated male infer- tility with no other evidence of CF disease. Targeting the fundamental defect is the new focus of research and treatment. The first licensed compound, which was discovered as a result of high throughput screening, was ivacaftor (VX-​770, Kalydeco). Initially studied in the commonest class 3 gating muta- tion, G551D, but now licensed for all class 3 mutations, the effects are dramatic, with increases in lung function by more than 10%, weight gain, and, dramatically, a halving of sweat chloride. Even more excitingly, some pancreatic insufficient infants have had pan- creatic function restored by Ivacaftor, and no longer take pancre- atic enzyme replacement therapy. Benefits also extend to young children and patients with mild lung disease. Trials are ongoing in other mutations which reach the cell surface, especially the class 4 mutation R117H. Lumacaftor (VX-​809) is designed to correct pro- tein misfolding of class 2 mutations. When given in combination with ivacaftor to patients homozygous (but not heterozygous) for the class 2 mutation ΔF508, the effects on pulmonary function were less dramatic (improvement of FEV1 by approximately 4%), but pul- monary exacerbations fell by nearly 40%. The current focus is on trials of triple therapy, which apppear at least in Phase II trials to have similar magnitude effects on homozygous and heterozygous ΔF508 patients as does Ivacaftor on Class 3 mutations. A trial of ivacaftor in the class 4 mutation R117H failed to reach its primary endpoint (FEV1); in adults but not children there were encouraging improve- ments in some secondary endpoints. Ataluren (PTC124) overrides premature stop codons, and thus are potential therapies for class 1 mutations, as well as other genetic diseases such as Duchenne mus- cular dystrophy. An initial trial failed to meet the primary endpoint, but work is ongoing. Finally, gene therapy may become available and be applicable to all CF patients. The UK trial showed a statistically significant difference in FEV1 (stability over one year in the treated group, reduction by 4% in the placebo group). In summary, current studies have led to an explosion of interest in developing new mol- ecules and better vectors. The future challenge will be to reconcile the expectations of the patients with what is in fact a clinically useful benefit, in the context of the risk of long-​term side effects of a novel therapy administered for decades and the likely enormous fiscal costs (ivacaftor costs around £250 000/​patient/​year currently). Pathogenesis Sweat duct The primary secretion of the sweat duct is normal in volume and electrolyte concentration. However, as this secretion passes along the sweat duct mutant CFTR fails to absorb chloride ions, which therefore remain in the lumen, with secondary impairment of so- dium absorption. The resultant sweat has high concentrations of both sodium and chloride, which is useful for diagnosis and can lead to salt depletion in hot weather. Pancreas The synthesis and secretion of pancreatic enzymes in the acinus is normal, but disordered ion transport—​primarily of chloride and secondarily of bicarbonate—​results in relative dehydration of pan- creatic secretions. This in turn leads to low flow and stagnation of se- cretions in the pancreatic ducts with subsequent autodigestion. The clinical consequences are that low volumes of bicarbonate-​depleted pancreatic secretions reach the duodenum, with consequent malabsorption and progressive destruction of the pancreas with cyst formation. Although the islet cells are relatively unaffected at first, they too are progressively destroyed, leading to insulin deficiency. Biliary tract Intrahepatic biliary secretions are probably normal in CF, but dis- ordered electrolyte transport across the bile duct results in reduced water movement into the lumen. The bile is therefore concentrated and its volume depleted, leading to plugging and chronic local damage. This eventually causes biliary cirrhosis and associated extrahepatic biliary stenoses. There are secondary changes in bile acids. Other factors may also be important, including human leuco- cyte antigen haplotype, and the effect of modifier genes. Gut Gastric secretions have decreased volume with increased viscosity and sodium concentration. The chloride transport defect similarly leads to altered fluid movement across large and small intestine. These changes are worsened by the addition of dehydrated biliary and pancreatic secretions, as well as by alterations in the osmotic load in the lumen secondary to pancreatic exocrine failure. The resulting deficiency of intraluminal water contributes to meconium ileus in neonates and the distal intestinal obstruction syndrome in adults. Respiratory tract The epithelium in the nose, paranasal sinuses, and intrapulmonary conducting airways is disordered in CF, but alveolar function is normal. Defective chloride transport is associated with increased sodium absorption from the lumen. This leads to the net surface electrical charge being altered from a normal of –​20 mV to about –​ 40 mV, which can be used for diagnosis. However, the link between the absence or impaired function of CFTR and lung disease is not clear. Perhaps the most likely explanation—​the ‘low volume hypoth- esis’—​is that uncontrolled sodium and hence water absorption from the lumen leads to a reduction in the depth of the film of airway sur- face liquid, with impairment of ciliary function, mucus stasis, and thus chronic infection and inflammation. Less plausible is the ‘high salt hypothesis’, which argues that local antibacterial defences—​ including lactoferrin, lysozyme, and the cationic antibacterial pep- tides such as the β-​defensins—​may be impaired by local changes in salt concentration. Other, not necessarily mutually exclusive explan- ations include that bacterial adherence to epithelial cells is increased by changes in cell-​surface glycoproteins; and that there is reduced binding of microorganisms to CFTR and thus impaired internaliza- tion and clearance by the epithelial cells. The net effect is to promote

section 18  Respiratory disorders 4154 chronic bacterial infection, and to reduce bacterial clearance, with subsequent inflammatory lung damage. Finally, the role of bicar- bonate transport and alteration of airway pH leading to inactivation of components of the innate immune system has recently come to the fore, in part as a result of studies in the CF pig. In summary, al- though the low volume hypothesis is most popular, there are other possible factors involved, and more work is needed to understand CF airway pathophysiology. One consequence of chronic bacterial infection of the lower re- spiratory tract is an exuberant neutrophilic inflammatory response involving especially interleukin-​8 (IL-​8) and neutrophil elastase. The combination of elastase and other inflammatory mediators, while initially providing a useful antibacterial defence, is thought to contribute to lung damage and speed the progression of bronchi- ectasis and small airway narrowing. This has led to the seemingly somewhat paradoxical concept of using prednisolone and other anti-​inflammatory compounds to reduce inflammation in the set- ting of chronic bacterial infection. Heterozygote advantage The high frequency of the carrier state in European populations (1 in 25) has led to several suggested advantages for the carrier, none of which are proven. These range from reduced susceptibility to infections such as cholera (reduced gut chloride secretion) and ty- phoid (reduced ingestion of bacteria by gut epithelium) to increased fertility among CF carriers. As yet, no carrier advantage has been proven. Epidemiology Genotype The prevalence and distribution of the disease-​related mutations in the CF gene vary with ethnic origin. ΔF508 is commonest in nor- thern European populations, accounting for 82% of CF chromo- somes in Denmark but only 32% in Turkey. The W1282X mutation is common in Ashkenazi Jews (48% of CF chromosomes) but rare in other populations. All disease-​associated mutations are rare in African and almost unknown in Chinese populations. Phenotype Birth incidence varies with country of origin from 1 in 2000 to 1 in 100 000, as listed in Table 18.10.1. Prevalence figures are few and less reliable. CF is likely to be underdiagnosed in the developing world because early childhood malnutrition, diarrhoea, and chest infec- tions are so common in children with no underlying disease. There are at least 10 000 people in the United Kingdom and 30 000 in the United States of America with CF, and these numbers are increasing along with life expectancy. There are now more adults than children with CF in the UK. Survival From 1938 to 1960, most children with CF died before the age of 10. Since 1968, the first-​year mortality (chiefly from meconium ileus) has fallen from 18% to virtually zero, and survival curves are linear thereafter, showing progressive improvement over succeeding dec- ades (Fig. 18.10.2). In 1986, the median survival was 25 years and in 1999 about 30 years. Cohort survival analysis shows continuing improvement, and estimated survival for a child born with CF in the late 1990s is 40–​50 years. Age-​specific mortality rates for fe- males are a little worse than for males, although this difference is narrowing and the world record longevity for both sexes is now over 70 years. Table 18.10.1  Frequency of cystic fibrosis in different populations Country Incidence Calculated carrier frequency United Kingdom 1:2500 1:25 Turkey 1:3000 1:27 United States of America 1:2000–​1:4000 1:22–​1:32 Israel 1:5000 1:35 Italy 1:15 000 1:60 African Americans 1:17 000 1:65 Finland 1:40 000 1:100 China ?1:100 000 ?1:160 (a) (b) Fig. 18.10.2  (a) The typical chest radiograph appearances of advanced cystic fibrosis lung disease. There is also a right pneumothorax. (b) The chest radiograph in an adolescent boy with cystic fibrosis complicated by allergic bronchopulmonary aspergillosis. Note the wedge-​shaped shadow in the right mid zone.

18.10  Cystic fibrosis 4155 Clinical features The various age-​related problems that can lead to a diagnosis of CF are given in Table 18.10.2. Paediatric presentations are relevant to adult life in that if an adult with atypical respiratory disease turns out to have a family history of a child with CF or an illness shown in Table 18.10.2, then CF should be considered in the adult. The new diagnosis of CF in a younger relative will also prompt cascade screening (see next), usually aiming to discover carriers, but occa- sionally someone with a clinically mild CF phenotype is discovered. The United States Cystic Fibrosis Foundation Registry data show that as many as 10% of CF patients are not diagnosed until adult life. As in infants, adult physicians may encounter patients with an equivocal diagnosis, for example intermediate sweat chloride with one CF gene. Referral to a specialist centre for ancillary testing such as nasal potential differences should be considered, and whatever diagnostic label is eventually attached, the clinical manifestations of the disease should be treated energetically. Less than 5% pancreatic function is necessary for normal di- gestive function, and those presenting with CF in adult life are often clinically pancreatic sufficient. The main presentation is with respiratory problems, usually recurrent lower respiratory infec- tions with chronic sputum production. Some patients have a prior diagnosis of bronchiectasis, atypical asthma, nasal polyposis, acute pancreatitis, nontuberculous mycobacterial infection, or allergic bronchopulmonary aspergillosis. A new CF diagnosis has been de- scribed even in adults in their seventh decade. Depletion of sodium chloride and potassium due to excessive sweating, and secondary renal chloride retention, may result in presentation with dehydra- tion and heat exhaustion in an otherwise apparently completely fit adult. Another important mode of presentation is male infertility due to azoospermia because of congenital bilateral absence of the vas deferens (CABVD). There are different forms of this condition: (1) in association with congenital malformations of the upper urinary tract, in which case there is no increased incidence of CF mutations; (2) as part of classical CF; and (3) as a truly isolated forme fruste of CF, with only a single CF mutation and ion transport abnormalities overlapping with, but different from, true CF. Portal hypertension secondary to macronodular cirrhosis in adult life may also be the first presentation of CF. There is considerable debate as to the status of adults with single organ manifestations characteristic of, but not confined to, CF (e.g. idiopathic pancreatitis or allergic bronchopulmonary aspergillosis). Some series report a higher than expected incidence of CF muta- tions, and the occasional unsuspected CF compound heterozygote. In practice, although CF should be excluded as far as possible by appropriate investigations in the patient with a possible single organ disease, most will not have the traditional clinical CF disease as it is currently defined. Such single organ manifestations should be treated on their own merits, whatever the disease is called. Diagnosis The vast majority of patients (>98%) with CF can be diagnosed by a sweat test. The occasional patient, particularly with a mutation giving rise to a mild or atypical clinical phenotype, may require more sophisticated testing. However, the major difficulty is usually not in confirming the diagnosis, but in thinking of it in an appro- priate context (see next section, and Table 18.10.2). Increasingly, the diagnosis is made by newborn screening. Conversely, false-​positive diagnoses are not rare, and a new referral of a patient with CF to the adult clinic should prompt a full review of the diagnosis. Newborn screening for CF is now standard across the United Kingdom, with babies tested on the heel-​prick blood spot taken at age 7–​10 days. Measurement of immunoreactive trypsin (iRT) and genetic testing for the four commonest CF genes are performed initially. Equivocal cases have a second heel-​prick for iRT and ex- tended genetic testing performed, and a positive screening test should always be confirmed with a sweat test, in case there has been Table 18.10.2  Presentation of cystic fibrosis by age group Age group Presenting complaint Antenatal Chorionic villus sampling Ultrasound diagnosis of bowel perforation a Fetal hyperechogenic bowel b At or soon
after birth Bowel obstruction (meconium ileus,a bowel atresia) Haemorrhagic disease of the newborn Prolonged jaundice Screening (population based or previous affected sibling) Infancy and childhood Recurrent respiratory infections Diarrhoea and failure to thrive c Rectal prolapse d Nasal polyps e Acute pancreatitis Portal hypertension and variceal haemorrhage f Pseudo-​Bartter’s syndrome, electrolyte abnormality Hypoproteinaemia and oedema Screening as a result of cystic fibrosis diagnosis in a sibling/​relative Adolescence
and adult life Recurrent respiratory infections Atypical asthma Bronchiectasis Male infertility (congenital bilateral absence of the vas deferens) Electrolyte disturbance/​heat exhaustion Atypical mycobacterial infection Acute pancreatitis Screening as a result of diagnosis in affected relative Portal hypertension and variceal haemorrhage a Note that meconium ileus may be seen in pancreatic-​sufficient infants with CF, as well as rarely in those without the disease. b Most fetuses with hyperechogenic bowel are normal; around 6% have a trisomy, and 4% CF. c Note that up to 15% may be pancreatic sufficient, at least at diagnosis; thriving does not exclude CF. d One in six cases of rectal prolapse is due to CF, if obvious anatomical abnormalities are excluded. e Unlike in adults, where aspirin-​sensitive asthma is commonly associated with polyps, children with polyps almost invariably have CF. f Presentation with hepatocellular failure is very rare.

section 18  Respiratory disorders 4156 a laboratory error. This staged protocol leads to the diagnosis being made early in more than 95% of CF babies, hence making a diag- nosis of ‘typical’ CF will become less usual, although CF will still continue to be a diagnostic consideration in many circumstances: • The infant may have missed out on being screened • Parents may have refused screening (0.06%) • There may have been a laboratory error • The infant may be a true false negative (usually pancreatic sufficient) • The infant may have been born before screening was introduced • The infant may have moved from a country where screening is not performed The newly diagnosed CF infant should be seen early on in a spe- cialist CF clinic so treatment can be commenced. Sweat testing The test must only be performed by experienced personnel. Techniques include the classical pilocarpine iontophoresis of Gibson and Cooke, and more recently the macroduct collection. For the diagnosis to be established, tests should be performed in duplicate. The normal concentrations of sweat sodium and chloride increase with age. To diagnose CF in a child, the sweat chloride concentration should be greater than 60 mmol/​litre, and the sweat sodium concentration less than that of chloride. In the newborn period, in Europe the upper limit of sweat chloride is considered to be 30 mmol/​litre. A sweat chloride of less than 40 mmol/​litre is normal in older children and adults, and intermediate concentra- tions are equivocal. However, there are undoubted cases of CF with normal sweat electrolytes, and the sweat test should always be in- terpreted in the light of the whole clinical picture. There are a few rare conditions that also cause elevation in sweat electrolyte con- centration, but these are rarely a serious diagnostic consideration in practice (Box 18.10.1). Nasal electrical potential difference The abnormal potential difference across mucosal surfaces can be measured by passing a soft catheter under the inferior turbinate, ref- erencing it to an electrode placed on abraded skin of the forearm. Normal values are –​10 to –​30 mV and the CF range is –​34 to –​60 mV. The test is unreliable if the patient has an upper respiratory tract in- fection. The diagnosis can be further refined by perfusing the nose with solutions of amiloride to block sodium transport, and isopren- aline/​low chloride to stimulate CFTR. Nasal potentials require ex- tensive experience if results are to be accurate. Ion transport can be measured directly from intestinal biopsies in an Ussing chamber, but in most centres this remains a research technique only. Cystic fibrosis genotype More than 2000 different mutations causing CF have been reported, of which around 250 are disease producing. Testing for all of them is not currently practical in most centres, although whole exome sequencing of the CFTR gene is increasingly performed. It is es- sential to distinguish disease-​producing mutations from harmless polymorphisms. Thus DNA analysis can confirm the diagnosis if two known, disease-causing, mutations are found, but not exclude it. Linkage analysis can be used for antenatal diagnosis if a couple have already had an affected child, even if the actual mutations are not known. Other investigations In doubtful cases, evidence of subclinical organ dysfunction may be sought. Pancreatic dysfunction may be manifest by low stool elas- tase, elevation in 3-​day faecal fat excretion, or abnormal results of pancreatic stimulation tests. CT scan of the chest or bronchoscopy may be used to discover minor bronchiectatic changes or infection with typical CF organisms. Azoospermia is strongly supportive of the diagnosis of CF. But note, however, that it is important not to place too much diagnostic weight on clinically minor changes. Summary The diagnosis of CF is usually easy to confirm with a properly per- formed sweat test. There remain a few atypical cases which defy a firm diagnosis. In that event, clinical organ dysfunction should be treated appropriately, and the patient followed up very care- fully: often time will clarify the diagnosis. Screening Screening tests allow an early diagnosis of CF in populations in order for treatment to be instituted before irreversible organ damage occurs, and to detect CF carriers to allow antenatal diagnosis and the option of termination of affected pregnancies. In both areas there is controversy as to the indications and methods to be used. Universal screening of babies is now offered everywhere in the United Kingdom. Methods In the past, crude tests on meconium have been used, but these lacked accuracy and have been superseded by tests carried out on the routine heel-​prick blood sample collected from all babies in the first few days of life. These include estimation of immunoreactive trypsin, often combined with polymerase chain reaction (PCR) methods for one or more common abnormal genes, or pancreatitis-​ related protein. Routine neonatal screening in the United Kingdom is with both immunoreactive trypsin and PCR. Pancreatitis-​related Box 18.10.1  Conditions characterized by elevated sweat electrolyte concentrations In most cases, confusion with cystic fibrosis is very unlikely • Cystic fibrosis • Untreated adrenal insufficiency • Type 1 glycogen storage disease • Nephrogenic diabetes insipidus • Malnutrition • Panhypopituitarism • Acquired immunodeficiency syndrome • Artefact (incorrectly performed sweat test, eczema) • Fucosidosis • Hypothyroidism • Ectodermal dysplasia • Mucopolysaccharidosis

18.10  Cystic fibrosis 4157 protein screening may perform equally well, and obviates the need for genetic testing, which may be an advantage in some cultures. Across Europe, many different protocols are used, and clearly the genes which should be sought will depend on the frequency in the particular population. Carrier screening is by PCR for several of the common CF genes on a blood or mouthwash sample. In principle, this sort of screening may be offered to relatives of known CF patients (cascade screening), by written invitation to the general population, or opportunistically at routine antenatal clinic visits or the GP surgery. It is generally con- sidered that carrier testing at birth will not be useful because of the time lag between obtaining and utilizing the information. Outcome The evidence for the value of screening for the disease has come from certain retrospective trials, all showing benefit, but with the disad- vantage of using historical controls. There has been one prospective randomized trial of neonatal screening from Wisconsin (United States of America) in which 650 341 babies were screened. Of those in whom the diagnosis of CF was made, in 56 the diagnosis was com- municated to the parents, and in 40 the diagnosis was suppressed until it emerged on clinical grounds. There were small but clear-​cut nutritional benefits in the group in which the screening diagnosis was communicated, persisting to 10 years of age. Furthermore, there were subtle neurocognitive defects detectable in the nonscreened population, who had the lowest fat-​soluble vitamin levels at 10 years of age. The nutritional benefits were clearest early in life, at the time when growth is at its most rapid. In general, carrier screening is poorly taken up when done by in- vitation, and at antenatal clinics it may be difficult to obtain a sample from the putative father. Cascade screening is generally better util- ized, and should be offered at the time of making a new diagnosis. Summary Any screening test has false positives, which engender unnecessary anxiety, and false negatives, which may result in complacency. The balance of evidence is clearly in favour of neonatal screening so that early treatment can be given, and antenatal diagnosis offered for future pregnancies. The anxiety about false positives seems transient and deemed by the parents to be an acceptable price for subsequent reassurance. Carrier screening other than by cascade is more difficult, and, unless combined with wider public educa- tion, is unlikely to have a major impact. It should be noted that universal screening means it is increasingly rare to make a new diagnosis clinically. However, some mild patients will inevitably be missed on screening and present late; hence it will be important to remember the possibility of a new case of CF, even in a screened population. Microbiology People with CF have no detectable immune deficiency and, except for the respiratory tract, have no increased susceptibility to infection. Conventional culture-​based microbiology demonstrates that the lungs show evidence of transient infection and inflammation very early in childhood and thereafter become chronically infected, char- acteristically by Staphylococcus aureus and Haemophilus influenzae, followed by Pseudomonas aeruginosa; infection which is common even in early life. Many other organisms have been implicated, es- pecially in advanced disease, including the different genomovars of Burkholderia cepacia, Alcaligenes, Achromobacter, Pandoria, Ralstonia, and Stenotrophomonas maltophilia. Methicillin-​resistant S.  aureus (MRSA) is becoming an increasing problem. With increasing longevity and more aggressive use of antibiotics, the ex- pected bacteria are becoming more antibiotic resistant, and novel microorganisms are emerging, and this pattern is likely to continue. Aspergillus fumigatus is frequently isolated, but is more often asso- ciated with allergic rather than invasive disease, although this is not a benign organism; other fungi are increasingly detected. Atypical mycobacteria, in particular Mycobacterium abscessus, are a major problem, in particular in those with milder disease and S. aureus ra- ther than P. aeruginosa infection. Viral, chlamydial, pneumococcal, and other respiratory infections are not more common or severe in CF, but the consequences of these infections may be more important in the damaged and permanently infected CF lung. The microbiology of the nose and sinuses is the same as for the lung, but the clinical consequences are usually less important. The advent of molecular based techniques has thrown a whole new light on CF airway infection. There is at least initially much greater bacterial diversity, including anaerobes, in the lower airway. As the disease progresses, diversity is lost. The significance of these molecular findings, including the possibility that some microorgan- isms are beneficial to the host by inhibiting the growth of pathogens, is still being explored. Staphylococcus aureus This is the commonest colonizing organism in childhood, with a prevalence of over 50% in children aged under the age of 9 years. The predilection of S. aureus for CF lungs has been ascribed to high electrolyte content of airway surface liquid or enhanced retention in the airways. No phage type predominates and the organism usually remains sensitive to flucloxacillin in spite of prolonged antibiotic treatment. Resistance to tetracycline or erythromycin is relatively common, but multiple antibiotic resistance is rare, although MRSA, both hospital and community acquired, is becoming an increasing problem. The prevalence of staphylococcal colonization falls in adult life when P. aeruginosa predominates. Pseudomonas aeruginosa This is the commonest infecting organism after the age of 10 years, with reported prevalence varying between 40 and 80%. Enhanced adherence to CF airways promotes infection, but prior anti- biotic treatment—​in particular if cephalosporin prophylaxis is employed—​may play a part. No particular strain predominates, but siblings with CF often carry the same type, and environmental sources have been identified in CF centres, dentistry equipment, hydrotherapy pools, and nebulizers. After some months or years of infection, P. aeruginosa produces mucoid alginate as a protective biofilm and the organisms live in mucoid microcolonies. This mucoid variant is associated with a worse prognosis and greater antibiotic resistance. Most infecting strains of P. aeruginosa are sen- sitive to antibiotics at first, but over the years and in association with antibiotic treatment they develop multiple resistance to most antibiotics (except colomycin). There is increasing concern about

section 18  Respiratory disorders 4158 epidemic strains of P. aeruginosa, which may spread through clinics and carry a worse prognosis. This has resulted in increased em- phasis on infection control precautions. Haemophilus influenzae Noncapsulated H. influenzae is a relatively frequent infecting or- ganism, with prevalence of up to 30%, although it may not be isolated due to overgrowth of Staphylococcus or Pseudomonas. Antibiotic re- sistance is seldom a problem. Burkholderia cepacia complex There are at least nine different families (‘genomovars’) of this or- ganism. Genomovar III (B. cenocepacia) is the most resistant and virulent organism, but other genomovars are not necessarily benign. The overall prevalence of this organism is low, at 3–​5%, but it poses a particular problem due to cross-​infection, and some forms can cause rapid deterioration in patients previously only mildly affected. More usual is chronic asymptomatic carriage or progressive deteri- oration in the late stage of lung disease. Multiple antibiotic resistance is characteristic. Respiratory management Most of the morbidity and mortality of CF is due to respira- tory disease. Much of the treatment effort is therefore devoted to preventing chronic infection and inflammation, which lead to bron- chiectasis, progressive airflow obstruction, cor pulmonale, and ultimately death. Typical physical findings are cough with purulent sputum, to- gether with crackles and occasional wheezes, chiefly in the upper lobes and occasionally finger clubbing. There are scoring systems such as the comprehensive Schwachman and simpler Taussig scores, but the use of these in clinical practice is limited. The chest radiograph is often normal but may show thick- ened bronchial walls and small areas of consolidation which start in the upper lobes, and may progress to involve the whole lung (Fig. 18.10.2a). A variety of radiographic scoring systems have been proposed (e.g. Crispin–​Norman, Brasfield, Northern, and Brody scores). However, chest radiographs are relatively insensitive, es- pecially to early CF lung disease, and the early and repeated use of high-​resolution CT (HRCT) scanning, both as a monitoring tool in clinical practice and an endpoint in randomized controlled trials, is increasingly advocated. There is no doubt HRCT detects early disease, but that outcomes are improved is not clear, and there are concerns about lifetime cumulative radiation exposure. Magnetic resonance imaging is getting better at detecting lung disease, and may replace HRCT in the future. Lung function tests show obstruction with relatively well-​ preserved gas transfer. The forced expiratory volume in 1 s (FEV1) is conventionally used to assess the extent and progression of lung disease; however, this is an insensitive test, and increasingly more subtle indices of gas mixing derived from multibreath washout tests, such as lung clearance index, are being used both clinically and as an endpoint in randomized controlled trials. Exercise tolerance and arterial blood gases are well maintained until there is extensive lung damage, when hypoxaemic respiratory failure supervenes. CO2 re- tention occurs late. Basic respiratory care is mandatory for all CF patients, including avoidance of active and passive tobacco exposure, avoidance where possible of pollution, regular exercise and full immunization, includ­ ing influenza annually. More specific treatments are discussed next. Antimicrobials Oral antibiotics The use of prophylactic antistaphylococcal antibiotics is controver- sial, and is currently the subject of a large multicentre trial (http:// www.cfstart.org.uk/) most would use continuous twice-​daily oral flucloxacillin if there is evidence of chronic infection. Minor ex- acerbations of respiratory symptoms in the patient not infected with P. aeruginosa should be treated with a 1-​month course of a high-​dose antibiotic that will cover S. aureus and H. influenza, with changes made depending on culture results. Ciprofloxacin is used at the time of first isolation of P. aerugi- nosa, combined with nebulized antibiotics (see next) to try to pre- vent chronic infection:  the duration of therapy is controversial. Ciprofloxacin is also used to cover milder exacerbations of symp- toms in the patient chronically infected with P.  aeruginosa, but ciprofloxacin resistance soon becomes common. Nebulized antibiotics Nebulized colomycin combined with oral ciprofloxacin is indicated at the time of first isolation of P. aeruginosa. Increasingly, a one-​ month course of nebulized tobramycin is being used instead; there is no advantage to adding a second month. This approach has been shown in a randomized trial to delay chronic infection. However, the combination of oral, intravenous, and nebulized antibiotics that is most effective in preventing the progression from first isolation to chronic infection has not been established. Once P. aeruginosa infection is established, randomized controlled trials have shown benefit from long-​term nebulized antibiotics. In Europe, colomycin is the drug most often used. In the United States of America, nebulized tobramycin is preferred. No medium-​ term comparison of the two has been reported. Occasional patients bronchoconstrict with nebulized antibiotics: a test dose should there- fore be given, with spirometry measured before and afterwards, and if necessary pretreatment with a bronchodilator prescribed. Colomycin and tobramycin can both now be given through dry powder devices; a bronchoconstrictor trial should be done even if the nebulized prep- aration has been tolerated. Nebulized aztreonam is another thera- peutic option. There are ongoing trials of newer antibiotics, and also studies to determine the best protocols. Intravenous antibiotics Infective exacerbations not responding to oral antibiotics, par- ticularly those of P.  aeruginosa, are usually treated with a com- bination of an intravenous aminoglycoside and a semisynthetic antipseudomonal penicillin or cephalosporin. These are frequently given at home. A large randomized controlled trial has established that once-​daily tobramycin is equally efficacious and at least as safe as three times daily treatment. Drug metabolism in the CF patient is very different from normals and other patient groups. Although some centres recommend 3-​monthly courses of intravenous anti- biotics, irrespective of symptoms, for all CF patients chronically infected with P. aeruginosa, this approach is rarely if ever used in UK adult centres. However, the threshold for giving intravenous

18.10  Cystic fibrosis 4159 antibiotics has become low, with very few clinicians waiting until the patient has developed several new symptoms. It is increasingly being realized that CF pulmonary exacerbations are not benign. Around a quarter of patients never regain their base- line spirometry, and frequent exacerbations are associated with an accelerated decline in lung function and a greater likelihood of death or lung transplantation. Hence, reduction in the frequency of ex- acerbations is increasingly being used as an endpoint in randomized controlled trials of treatment. Particular issues related to infection Cross-​infection Fear of nosocomial acquisition of resistant organisms is wide- spread in the CF community. The apparent increase in prevalence of P. aeruginosa in specialized clinics probably reflects more assiduous bacterial culture techniques. However, most centres advocate sep- arate clinics for CF patients with and without P. aeruginosa. Ideally, patients on arrival should be allocated their own room where they remain for the duration of the visit, with the professionals coming to the room, rather than the conventional model. The use of masks, gloves, and gowns by professionals is controversial, and not widely practised in the United Kingdom. Strict cohorting has also been advocated with regard to more resistant organisms, in particular B. cenocepacia and Mycobacterium abscessus. Sensible guidelines should be applied to all CF patients:  these include diligent handwashing, no sharing of physiotherapy equip- ment, and the use of single cubicles ideally for all inpatients, but mandatory for those with difficult organisms. Communal physio- therapy and keep-​fit sessions should be discouraged, and there is no doubt that conferences for CF patients can result in transmission of infection. Careful microbiological surveillance is essential, and spe- cial measures may be needed if there is a true epidemic strain within a particular clinic. Viral infections Viral infections, trivial in themselves, have been implicated in causing transient reduction in airway defences and an increased risk of P. aeruginosa acquisition. Most physicians would at least give oral antibiotics (as already mentioned in this chapter) to cover viral ex- acerbations. Annual influenza immunization is advisable. Nontuberculous mycobacteria These organisms may be harmless commensals. Unlike M. tubercu- losis, evidence of tissue invasion is generally held to be required to diagnose infection, but this evidence cannot often be sought in CF and decisions as to whether to treat are difficult. Evidence from aut- opsy studies suggests that atypical mycobacteria should be treated only if they are repeatedly found in sputum. CT scanning may be helpful in reaching a decision as to whether to treat, with indica- tions for treatment being deterioration in clinical state and CT ap- pearances in a patient with repeated positive isolates. M. abscessus seems to carry a particularly poor prognosis and there should be a low threshold for its treatment. The prevalence of nontuberculous mycobacteria has increased over the past 10  years. Particular concern has focused on the emerging predominance of Mycobacterium abscessus, with studies reporting infection rates of between 3 and 10% in the United States and Europe. It is now recognized as a major respiratory pathogen in CF, leading to accelerated decline in lung function, and infec- tion with it is considered a contraindication to lung transplantation in most UK centres, although infected patients should at least be discussed with a transplant centre. Treatment is challenging and requires extended therapy with a combination of antibiotics that are often poorly tolerated, and treatment failure is not uncommon. Typical regimen include an intravenous induction phase followed by consolidation for many months with combinations of oral and nebulized therapies. A recent publication of evidence using whole genome sequencing is a significant concern. This demonstrated between patient trans- mission of Mycobacterium abscessus in a UK CF centre despite con- ventional cross-​infection measures, although the exact route of transmission remains to be established. There are now published US/​European guidelines for the diagnosis and management of nontuberculous mycobacteria in CF. Aspergillus, including allergic bronchopulmonary aspergillosis Evidence of exposure to A. fumigatus is common in CF (e.g. posi- tive skin prick test, RAST, IgG precipitins, and sputum culture). It is becoming clearer that this organism, even in the absence of allergic bronchopulmonary aspergillosis (ABPA, see Chapter 18.14.2), may not be as benign as was once thought. The prevalence of ABPA is disputed, but probably around 10%, although the major diagnostic criteria for this condition are also common features of otherwise uncomplicated CF. Sophisticated im- munological testing has been used to try to refine the diagnosis, but an abrupt fourfold rise in total IgE, often in association with IgG precipitins to aspergillus, is the simplest and most reliable inves- tigation. By contrast to typical infective exacerbations of CF, large fleeting radiographic shadows are typical (Fig. 18.10.2b). Treatment is with oral corticosteroids or pulsed methyl prednisolone; the roles of itraconazole and voriconazole are controversial, but they are increasingly used. Scedosporium and other fungi are also coming to the fore as causing similar complications in CF. Other methods of treatment Airway clearance Chest physiotherapy should be performed twice-​daily as a routine, increasing at times of infective exacerbation. Different groups ad- vocate different techniques (e.g. active cycle of breathing, autogenic drainage, and mechanical devices, such as the positive expiratory pressure mask, flutter, and external oscillation jacket). External os- cillation has been shown to be less good than conventional airway clearance, and the equipment is much more expensive. There are otherwise no good comparisons between these approaches, and none has emerged as best. It is probably best to offer a choice of tech- niques to the patient. Physical exercise such as swimming supple- ments but should not replace formal airway clearance sessions. See Chapter 18.9 for further discussion. Alteration in mucus properties Human recombinant DNase in vitro reduces sputum viscosity. In the then largest randomized controlled trial in the CF literature,

section 18  Respiratory disorders 4160 once-​daily nebulized human recombinant DNase resulted in small but sustained improvement in lung function and reduction in pulmonary exacerbations. However, individual responses are very variable, and the treatment is expensive. A carefully moni- tored n = 1 trial is recommended before starting long-​term therapy. Two trials of hypertonic saline have shown minimal improve- ment in lung function, but the second trial, which was the only one powered for this purpose, showed a significant reduction in infective exacerbations. The burden of two extra nebulized treatments must be considered if this is to be prescribed. Dry powder mannitol is also available as an aid to airway clear- ance. It is thought to act by rehydrating the airway surface. The ex- pense and inconvenience (multiple capsules have to be inhaled at each treatment) mean that mannitol is only recommended when other treatments are not working, but some patients find this a very effective treatment and the aforementioned considerations should not be a deterrent. Oxygen and other respiratory support By analogy with the Medical Research Council and Nocturnal Oxygen Treatment Trial (NOTT) trials of oxygen in chronic ob- structive pulmonary disease (see Chapters 18.8 and 18.15), one would anticipate that long-​term oxygen would be beneficial to the chronically hypoxic CF patient. The only trial of this approach was underpowered and thus inconclusive. Oxygen is usually pre- scribed for symptoms, and for patients with chronic hypoxia ir- respective of symptoms. Nasal ventilation may used during acute deteriorations, and as a useful short-​term expedient while trans- plantation is awaited. It may usefully palliate symptoms during terminal care. Bronchodilatation Bronchial hyperreactivity is common. Troublesome wheeze may need treatment with short-​acting bronchodilators. However, β2-​ agonists may cause paradoxical bronchoconstriction, and should be used cautiously. Long-​acting β2-​agonists should only be given if there is clear-​cut evidence of benefit. Persistent recurrent wheeze, particularly in the atopic CF patient, may be treated with inhaled or oral corticosteroids (ICS). However, it should be noted that ICS use in other contexts is associated with an increased prevalence of pneu- monia, tuberculosis, and atypical mycobacterial infection, so they should only be used if there is clear evidence of benefit, particularly in view of the expense, the already considerable treatment burden, and the worrying evidence that ICS may in fact prolong neutrophil survival in the airway. Anti-​inflammatory therapy The pathogenesis of CF lung disease includes an exuberant neutrophil-​mediated inflammatory response which, via the release of neutrophil elastase and other mediators, may cause much of the tissue damage in the airways. Early in the course of the disease it is unclear whether infection is a prerequisite for inflammation, or if CF is intrinsically proinflammatory. However, in established CF airway disease, both are present. This has led to the seemingly paradox- ical proposal that patients with chronic bronchopulmonary sepsis should be iatrogenically immunosuppressed. Various approaches have been tried, although none is in wide clinical use. Oral corticosteroids Usage in severe airway obstruction and allergic bronchopulmonary aspergillosis is discussed earlier. Long-​term routine use was assessed in a multicentre, double-​blind trial comparing prednisolone 2 mg/​ kg on alternate days, 1 mg/​kg on alternate days, and placebo. This showed: (1) no benefit, except in patients infected with P. aerugi- nosa; (2) sustained improvement in lung function in colonized pa- tients; (3) unacceptable side effects (growth failure, cataract, glucose intolerance), necessitating stopping the higher dose after 2 years and the lower dose after 4 years. Although regular alternate-​day steroids may be considered for up to 2 years in some patients, their routine use cannot be justified. Inhaled corticosteroids Since oral steroids are beneficial, but at the cost of unacceptable side effects, it would seem logical to use long-​term ICS. However, a re- cent study showed no detrimental effects if inhaled corticosteroids were withdrawn from a large group of CF patients. Although an observational database review suggested some benefit, most would consider that they should not be a routine part of treatment. If they are used, consideration should be given to stepping down the dose at every clinic visit, analogous to the treatment of asthma. Ibuprofen A multicentre, double-​blind, placebo-​controlled trial of ibuprofen showed a slowing of the rate of decline of lung function, particularly in young patients. However, ibuprofen is not widely used. A second, underpowered study showed better forced vital capacity (FVC) but not FEV1, on ibuprofen. This may be because: (1) not all age groups benefited; (2) there are theoretical reasons for believing that lower doses may actually be harmful, meaning that ibuprofen levels need to be measured and a high dose given; and (3) if intravenous aminoglycosides have to be administered for an acute exacerbation of chest disease, there is a significant risk of nephrotoxicity. Macrolide antibiotics These are included in this section because modulation of inflamma- tion is their likeliest mode of action. They were first used in a CF-​like illness, diffuse panbronchiolitis, prevalent in middle-​aged people in East Asia. Diffuse panbronchiolitis is characterized by chronic airway infection with mucoid strains of P. aeruginosa, the hallmark of CF. It was shown serendipitously that treatment with low-​dose erythromycin reduced the 10-​year mortality from 90% to less than 10%. Subsequently, randomized controlled trials have demonstrated benefit of azithromycin in CF, and this treatment is used increas- ingly. Macrolides have multiple actions on the immune system and growth factors in vitro, but their precise mechanism of action in CF has not been determined. A Cochrane review reported that evidence for treatment benefit beyond six months is limited. Other anti-​inflammatory approaches Although anti-​inflammatory defences are normal in CF, they are overwhelmed by the burden of neutrophil elastase. Boosting the natural defences (α1-​antitrypsin, secretory leukoprotease inhibitor) by nebulizer has been the subject of small and inconclusive trials; α1-​antitrypsin therapy has been shown to be ineffective in a large trial; a trial of a leukotriene B4 receptor antagonist was halted because

18.10  Cystic fibrosis 4161 of increased infective exacerbations in the active treatment arm, underscoring the fact that immune modulation may not always be beneficial. There are anecdotal reports of the successful use of methotrexate, ciclosporin, and intravenous immunoglobulin in CF, particularly in those with severe, nonbronchiectatic airflow obstruction. There are no large trials of these approaches. Particular respiratory complications Haemoptysis Blood streaking of sputum is common in CF and requires no special treatment. Massive haemoptysis is variously defined, usually as the expectoration of more than 250 ml of blood in 24 h, and is an acute emergency which requires active management. It is often, but by no means always a complication of severe lung disease, and the source is from hypertrophied bronchial arteries. The patient should be ad- mitted, given antipseudomonal intravenous antibiotics, and any clotting abnormalities corrected. Careful chest physiotherapy should be continued. Tranexamic acid and terlipressin are sometimes used to try to control haemorrhage. If bleeding does not settle, or recurs, then bronchial artery embolism should be considered. All sizeable bronchial arteries should be occluded. Preoperative bronchoscopy does not influence management, and often fails to define the side of bleeding. The major risk of embolization is inadvertent occlusion of a major spinal artery, resulting in paraplegia. Lobectomy is rarely necessary, and carries a high risk in these patients, who are often very compromised. Pneumothorax This is usually a complication of late-​stage lung disease. Small pneumothoraces may require no special measures; moderate or large pneumothoraces are initially treated with tube drainage. HRCT scanning may be necessary to define optimal placement of drainage tubes in complex pneumothoraces. Careful physiotherapy must be continued, and intravenous antibiotics given. If there is a continued air leak, pleurodesis should be undertaken. However, it is important to consult with the local transplant service before doing this, because aggressive pleurectomy is seen by some to be a contra- indication to subsequent transplantation. Upper airway disease Nasal polyps are seen in up to 50% of adults with CF. Treatment is with nasal steroids in the first instance. If medical management fails, surgical polypectomy is indicated, but 50% will require a second procedure within 2 years. Abnormal sinus radiographs are universal, but symptomatic sinusitis relatively rare. If present, sinusitis should be treated medically with prolonged antibiotics, nasal steroids, and possibly decongestants in the first instance; surgery may be required although symptoms often return after a couple of years. Rarely, sur- gery is needed for mucocele of the frontal sinuses. Gastrointestinal management Pancreatic insufficiency needs to be treated in 85% of cases; meco- nium ileus or distal intestinal obstruction syndrome affects up to 30%; symptomatic liver disease occurs in about 5%, but in general the gastrointestinal manifestations of CF are less important than the lung disease. For a few patients, however, they are the dominant problem. Pancreatic insufficiency This is usually present from birth, with low levels of bicarbonate and lipolytic and proteolytic enzymes in pancreatic secretions. Those with clinical pancreatic sufficiency secrete low but adequate levels of enzymes. Some develop pancreatic insufficiency later in life. The usual presentations are neonatal meconium ileus (which is occasionally seen in pancreatic-​sufficient CF patients and normal babies) or failure to thrive with associated steatorrhoea and mal- nutrition. Consequences can include anaemia, vitamin deficiency, and occasionally oedema; complications include rectal pro- lapse, intussusception, volvulus, and distal intestinal obstruction syndrome. The diagnosis is confirmed by estimation of human faecal elas- tase (which can be used even if the patient has been started on pan- creatic enzymes), demonstration of unsplit fat globules in the stool, or increased faecal fat on a 2-​ or 3-​day stool collection. Formal testing of pancreatic function is seldom required. Treatment with pancreatic enzyme and vitamin supplementation is usually straightforward and successful. Enteric-​coated enzyme preparations are taken before meals and the quantity adjusted to achieve normal stools. The commonest cause of failure is poor com- pliance, although occasionally lactose intolerance, inflammatory bowel disease, coeliac disease, or bowel infection/​infestation may coexist. Hence a gastrointestinal review should be instituted rather than uncritical dose escalation of pancreatin in nonresponding pa- tients. A few patients need to take H2 blockers, proton pump inhibi- tors, or antacids to achieve better control of symptoms. Large-​bowel strictures have developed in some patients (usually children) taking high-​strength enzyme preparations, probably as a toxic effect of the coating rather than the enzymes themselves. Nutrition Vitamin supplementation should be given to all patients to cover fat-​soluble vitamin deficiency. Most multivitamin tablets contain vitamins A and D, but vitamin E needs to be given separately to maintain adequate intake. Vitamin K supplementation is prescribed for its effects on bone health. The diet should otherwise be normal, with a high calorie intake, usually 130% of recommended daily al- lowance. However, a recent study suggested that oral high-​calorie supplements are often ineffective, and patients unable to maintain weight in spite of optimal dietary advice can be helped by enteral feeding, which is better tolerated by gastrostomy than by a nasogas- tric tube in the long term. Distal intestinal obstruction syndrome Constipation and a loaded colon are relatively common in CF and usually respond to modification of the diet, pancreatic supplements, and a high fluid and roughage intake; occasionally lactulose and/​ or a macrogol laxative (e.g. Movicol) is helpful. Severe constipation merges into the distal intestinal obstruction syndrome with pain, palpable faecal masses, and complete obstruction with faecal ma- terial in the distal ileum or ascending colon. The cause is multifac- torial with imbalance of pancreatic enzymes and diet, disturbed fluid and electrolyte transport, faecal dehydration, and abnormal intestinal mobility all playing a part.

section 18  Respiratory disorders 4162 Patients present with chronic intermittent pain or episodes of complete obstruction. Although the differential diagnosis is wide and includes common conditions such as appendicitis, most patients improve with medical treatment and surgery should be avoided un- less there is clear evidence of another diagnosis. Treatment with a balanced intestinal lavage solution, 500–​1000 ml/​h by nasogastric tube, usually moves the faecal blockage within 4–​6 h. Alternatives are gastrografin by mouth or enema, or oral N-​acetylcysteine. Occasionally, removal of inspissated faeces at colonoscopy is needed. Other gastrointestinal complications Pancreatitis is rare but should be excluded in cases of abdominal pain. It usually affects those who are clinically pancreatic sufficient. Treatment is conventional, with special attention to pulmonary infections, because the pain of pancreatitis may interfere with physiotherapy. Gastro-​oesophageal reflux is common, in particular in severe CF lung disease, sometimes with overt vomiting, and may be as- sociated with coughing, physiotherapy, and bronchodilators which may relax the oesophageal sphincter. Aspiration of stomach con- tents is seldom a clinical problem. Although peptic ulcer disease might be expected in view of the low pancreatic bicarbonate secre- tion, there is only one report of an increased frequency of ulcer- ation. Helicobacter pylori infection is uncommon, perhaps because of antibiotic treatment. Lactose intolerance, coeliac disease, and inflammatory bowel dis- ease occur with slightly increased frequency in the CF population, but symptoms may be misattributed to CF and diagnosis there- fore delayed. Both giardiasis and Clostridium difficile gut infection have been reported as being more frequent in CF, but these are not common clinical problems. As adults survive longer, it is clear that there is an increased risk of colon cancer, and possibly other malignancies. Whether CF adults should undergo screening with faecal occult bloods, and if so, how frequently, is not known. Liver disease Liver disease causes problems in 5% and death in 2% of people with CF, but abnormal liver function tests are very common and up to 50% have biliary cirrhosis demonstrable at autopsy. With increasing survival, liver disease may become more important. Although liver enlargement and jaundice occasionally occur in early childhood, liver disease is usually signalled by hepatosplenomegaly or abnormal liver function on routine testing. Decompensation with jaundice, ascites, or encephalopathy is rare and occurs late. Variceal bleeding only occurs in a minority of those with established chronic liver disease, but may be the presenting symptom of CF itself, or of liver disease in a patient known to have CF. Minor or modest ele- vations of aminotransferase, γ-​glutamyl transpeptidase, or alkaline phosphatase levels are very common but do not correlate with estab- lished liver disease unless the enzyme levels are greater than four times normal. Routine ultrasonography detects fatty change or multilobular cirrhosis: the finding of portal vein dilatation, splenomegaly, or col- lateral vessels indicating portal hypertension. Cholangiography is occasionally needed for diagnosis of gallstones: this may reveal irregu- larities of the intrahepatic ducts, suggesting chronic liver disease, and significant strictures of the common bile duct may also be seen. Liver biopsy is seldom needed. No treatment has been shown to modify the course of chronic liver disease in CF, although clinical and biochemical improve- ments have been shown following treatment with ursodeoxycholic acid. This bile acid stimulates bile flow, may protect the hepatocyte from toxicity of bile acids, and is helpful in primary biliary cirrhosis. Many hepatologists therefore recommend its use in CF. Jaundice must be investigated to exclude drug hepatotoxicity or treatable obstructive cause, but is otherwise a late event with poor prognosis. Variceal bleeding is treated with injection sclerotherapy or banding ligation, and in the short-​term balloon tamponade or vasoconstrictor drugs may buy a little time. Surgical treatment is hazardous due to lung disease and in a few patients the insertion of a transjugular intrahepatic portal systemic shunt may be an alterna- tive. Prophylactic treatment of varices has not been shown to help and may be detrimental. Ascites and encephalopathy are rare and are usually preterminal events to be managed conventionally. In most cases of complicated chronic liver disease, management is made more difficult by the presence of lung infection that must be aggressively treated. Respiratory failure may develop concurrently. When this occurs, intubation and ventilation are seldom successful. Diabetes Glucose intolerance in CF increases with age, being rare under 10 years, affecting 14% by 15 years, and over 65% at 25 years. By this age 32% are frankly diabetic. Even when glucose tolerance is normal, reduced insulin secretion is frequent, and should be sought in a pa- tient who is deteriorating on conventional treatment. This is caused by gradual and progressive loss of β cell mass in line with pancreatic fibrosis. Peripheral insulin sensitivity is usually normal and auto- immune factors are not involved. Diagnosis is based on conventional World Health Organization (WHO) recommendations. Many recommend annual oral glucose tolerance tests, but screening for diabetes in a CF clinic is sometimes done by measurement of HbA1c (not thought by most to be a useful screening tool), together with random or fasting blood sugar levels. Increasingly, continuous glucose monitoring is used for diagnosis. Diabetes is usually diagnosed at such screening, but a few patients pre- sent with weight loss and increased frequency and severity of chest in- fections, although polyuria and polydipsia occasionally develop first. It has been suggested that the onset of diabetes is a marker of general deterioration, but many patients return to their previous level of health when diabetes is controlled. Interestingly, improved insulin secretion has been reported in young patients with class 3 mutations treated with Ivacaftor (above). Oral hypoglycaemic agents should not be used outside the context of a randomized controlled trial; the treatment of insulin deficiency is insulin replacement. Control of blood sugar is relatively simple, with flexible use of short-​ and long-​acting insulins. The usual dietary recommendation is to maintain an energy intake of 150% of normal with frequent balanced meals, with adjustment of in- sulin to suit. Ketoacidosis and insulin resistance are almost unknown. Early microangiopathy has been shown in CF patients with dia- betes, but retinopathy, neuropathy, and nephropathy are rare. This may be in part due to the mildness of the diabetes, but is likely to be- come more common as survival improves. Nevertheless, CF patients

18.10  Cystic fibrosis 4163 (in particular women) with diabetes tend to have excess morbidity and slightly increased rate of decline in weight and lung function, but this is being improved by early detection and treatment of in- sulin deficiency. Other organ systems Reproductive Almost all men with CF have obstructive azoospermia with other- wise normal sexual function. This is due to absence of the vas def- erens, and although there are no sperm in the ejaculate (which is usually of reduced volume) there is normal spermatogenesis and Leydig cell function. Counselling about infertility should be done well before the time of puberty, and certainly before permanent re- lationships develop. Most men opt to confirm the azoospermia by a sperm count. In vitro fertilization using aspirated sperm has been successful and there are now many CF fathers. Early reports of reduced fertility in women with CF have not been confirmed and most can conceive normally. The child by definition carries one mutation from the mother: the risk of CF in the baby is therefore 1 in 50 in white populations, with a carrier frequency of 1 in 25. Counselling and paternal genotyping allows reassurance for most CF pregnancies and identifies a 1 in 2 risk when the father is a carrier. Successful pregnancies have been completed by many hundreds of CF women, but women with severe lung disease may not be able to complete a pregnancy safely, the risks rising with im- paired lung function and especially when the FEV1 is less than 30% predicted. Children born have been healthy, without an increased frequency of birth defects despite the mothers’ extensive drug treat- ment. Lactation is normal. Vaginal candidiasis secondary to antibiotic treatment is relatively common in CF. Stress incontinence is particularly distressing in both sexes, and may interfere with coughing, physiotherapy, and normal sexual relationships. Sexual behaviour in both genders may be inhibited by low weight, delayed puberty, cough, sputum, haem- optysis, breathlessness, and indwelling catheters, but most people adapt well and persistent problems are few. Skin and joints Clubbing is almost universal in those with significant lung disease., and regresses after successful lung transplantation. Hypertrophic osteoarthropathy is rare. Episodic arthritis, predominantly affecting the large joints, is quite common and associated with chest infec- tions. Erosive arthritis is rare. Pain responds to nonsteroidal anti-​ inflammatory drugs (NSAIDs), and steroids or immunosuppression are seldom needed. Systemic vasculitis has occasionally been re- ported but is surprisingly rare considering the extent of immune ac- tivation, the frequency of circulating immune complexes, and the number of drugs taken. Kidneys Glomerulonephritis has been reported but is probably no more frequent than in the normal population. Acute tubular necrosis is rare and usually associated with higher than recommended aminoglycoside levels or the additional prescription of NSAIDs. Very large numbers of aminoglycoside treatments and CF-​related diabetes are associated with progressive decrements in renal function. Renal stones are common in CF, probably due to excess ox- alate absorption secondary to altered bowel bacterial flora. Systemic amyloidosis has occasionally been reported secondary to prolonged pulmonary infection. Central nervous system Acute ototoxicity occasionally results from aminoglycoside treat- ment but is not seen when serum levels are well controlled, but there does seem to be a cumulative effect from repeated aminoglycoside courses. Cerebral abscess rarely complicates lung sepsis. Vitamin E deficiency leads to a cerebellar syndrome combined with peripheral neuropathy. CF-​related bone disease Reduced bone mineral density is common in CF, with prevalence among adults of up to 60%, and onset in children has been de- scribed. This is partly due to general malnutrition as well as vitamin D malabsorption, but relative immobility is sometimes a factor. Other factors may include delayed puberty and hypogonadism, the effect of the systemic inflammatory response, immobility, inhaled and oral steroid therapy, and vitamin K deficiency. However, CFTR is expressed in bone and CF bone disease may be seen in otherwise well patients, including children. An increased rate of fractures has been reported, and rib fractures from coughing can interfere with adequate physiotherapy. Vertebral compression fractures are fortunately rare. Regular bone mineral density measurements are recommended, with extra vitamin D and calcium supplementation when low. Bisphosphonates can cause bone pain when given intravenously. Oral preparations can be used, and trials are ongoing to determine the optimal timing of treatment. Prevention is by encouraging a high dairy intake, weight-​bearing exercise, and supplementation with vitamin K. Management of respiratory failure Recurrent and persistent chest infection leads to progressive decline in lung function with eventual respiratory failure in most patients, although in about 2% the liver fails first. At this stage, the issues of transplantation should be addressed. If a patient wishes to ex- plore the possibility of transplantation, then preoperative work-​up, counselling, surgical assessment, and placement on the waiting list should take place 2 years before the predicted date of death. Others may opt for palliative care. Lung transplantation Selection criteria are listed in Table 18.10.3. Prediction of prognosis is difficult; whereas in the 1990s patients with an FEV1 less than 30% had a median survival of two years, now the figure is more than five years. The timing of assessment is judged on the level and rate of decline of lung function, arterial blood gases, and the frequency and severity of chest infections. Patients on the waiting list must be managed optimally to main- tain lung function and nutrition, often with gastrostomy feeding. Noninvasive ventilatory support can provide a bridge to transplant- ation for patients with progressive respiratory failure, but intubation and conventional ventilation are not recommended.

section 18  Respiratory disorders 4164 Donor organs are scarce and at least 50% of listed CF patients never receive a transplant. The results for lung transplantation are the same as for other lung diseases, with a survival of 70% at 1 year and 50% at 3 years. See Chapter 18.16 for further discussion. Recently, living donor lobar transplantation has been offered to CF patients, with comparable results. Liver transplantation is appropriate for the occasional patient dying of liver failure with relatively good lung function: survival at 5 years is 85%. Terminal care The timing of the decision to switch to palliative care is difficult and should be made in conjunction with the patient and relatives. The most distressing symptoms are cough, sputum retention, breathless- ness, and exhaustion. Small doses of morphine are usually well tol- erated and only seldom worsen respiratory failure. The CF team As with many chronic diseases, the purely medical care of CF is relatively straightforward. Proper holistic care requires a team ap- proach, and without such a team, care will be second rate. Typically, the core of the team is formed by a specialist nurse, a physiother- apist, a dietitian, a psychologist, and a social worker, together with a specialist doctor. It is unrealistic to expect every hospital to pro- vide this, and hence close contact with a tertiary centre is advisable. Many of the physical issues (airway clearance, nutritional man- agement) have been discussed here already. Equally important are many of the psychological problems springing from the presence of a chronic disease. The normal process of adolescence includes rebelling and breaking free of parental care. In those with CF this may never have been achieved, because the parents have wanted to keep con- trol of treatment regimens, and have been reluctant to allow in- dependence. Although paediatric clinics should have established a pattern of the adolescent coming into the consulting room alone, frequently this does not happen, and the adult physician is often confronted with parents who resent the idea that their now grown-​up child should be seen on their own. Conversely, the con- sequences of a full-​blown adolescent revolt (nonacceptance of treatment, abuse of cigarettes, alcohol, soft and hard drugs, and high-​risk sexual behaviour) may be particularly catastrophic in the patient with CF. The authors still know of no easy answer to adoles- cence and its aftermath. Knowledge of fertility issues is notoriously poor among adult men with CF: these may need to be tackled tactfully. The issues sur- rounding pregnancy in the woman with CF, who may herself be se- verely breathless, but desperately wishing for a child, also require sensitive handling (see earlier). Further education and employment are also difficult issues in the setting of chronic physical disability, but skilled help may allow pa- tients with CF to maximize their potential. A fuller account of the many and complex psychosocial issues surrounding care can be found elsewhere, but appreciation of these issues is just as important as knowing the correct management of the physical problems of CF. Future prospects The first CF animal model was the mouse, generated more than 20  years ago by using molecular techniques to disrupt CFTR. Although clearly this was a major step in CF research, mice did not recapitulate many important features of human CF disease. They de- veloped intestinal disease but were not pancreatic insufficient, and they did not have spontaneous CF lower airway disease. This may relate to species differences in the extent of expression of CFTR and other ion channels. However the mouse nose has similar bioelectric properties to the human CF nose, and has been used for early phase CF treatment studies. Somatic cell nuclear transfer, the technique used to create Dolly the sheep, has now also been used to create CF pigs and ferrets. CF pigs develop intestinal disease, but are exocrine and endocrine pancreatic insufficient and have a lung phenotype similar to human CF. Neonatal CF ferrets have intestinal disease and pancreatic disease as well as early lung infection. The CF ferret does not universally develop meconium ileus, and endocrine pancreatic function is better preserved than in the CF pig, making it possibly an even better model of human disease. However, caution is necessary in extrapolating findings from animals to man; there is no doubt that they are a significant advance, but animals are not humans. The growth in basic scientific understanding of CF will lead to fur- ther new treatments directed at the mutant CFTR gene or protein. The ultimate aim must be to have specific molecular therapies for everyone with CF, irrespective of genotype. CFTR undergoes com- plex folding, both during and after translation, and it may be that more than one compound will be needed to correct this. Ivacaftor will increasingly be explored in all class 3–​6 mutations to increase CFTR function, and also in combination with therapies for classes 1 and 2, and also gene therapy, to amplify the effects of getting CFTR to the cell surface. Research is ongoing into correction of the disordered electro- physiology with sodium channel blockers, promoters of chloride transport via alternative channels, is already well advanced. Inhaled bicarbonate is being considered, to correct airway surface pH. There is, therefore, a real prospect that new fundamental treatments will prevent the development of CF disease and lead to improved health, prolonged survival, and reduction in lifelong supportive therapy not merely in the class 3 mutations, but in all CF patients. The two main challenges to be overcome are (a) how to show benefit in an increas- ingly well patient group; and (b) how to fund these medications—​ ivacaftor costs $330 000 per patient per year. Table 18.10.3  Selection criteria for lung transplantation Indications Severe respiratory failure in spite of optimal treatment Severely impaired quality of life Patient positively wants a transplant Strong contraindications Active aspergillus or mycobacterial infection Noncompliance with treatment Other end-​organ failure Gross malnutrition Relative contraindications Preoperative ventilation Previous thoracic surgery Chemical pleurodesis

18.10  Cystic fibrosis 4165 FURTHER READING Alton EW, et al. (2015). Repeated nebulisation of non-​viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-​blind, placebo-​controlled, phase 2b trial. Lancet Respir Med, 3, 684–​91. Borowitz D, Gelfond D (2013). Intestinal complications of cystic fi- brosis. Curr Opin Pulm Med, 19, 676–​80. Brennan AL, et al. (2004). Clinical importance of cystic fibrosis-​related diabetes. J Cyst Fibros, 3, 209–​22. Cantin A, et  al. (2015). Inflammation in cystic fibrosis lung dis- ease: pathogenesis and therapy. J Cystic Fibros, 14, 419–​30. Cohn JA, et al. (1998). Relations between mutations of the cystic fi- brosis gene and idiopathic pancreatitis. N Engl J Med, 339, 653–​8. Corris PA (2013). Lung transplantation for cystic fibrosis and bronchi- ectasis. Semin Respir Crit Care Med, 34, 297–​304. Cystic Fibrosis Genotype–​Phenotype Consortium (1993). Correlation between genotype and phenotype in patients with cystic fibrosis. N Engl J Med, 329, 1308–​13. Davies JC, et al. (2018). VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med, 379, 1599–611. De Boeck K, et al. (2006). Cystic fibrosis: terminology and diagnostic algorithms. Thorax, 61, 627–​35. Debray D (2011). Best practice guidelines for the diagnosis and man- agement of cystic fibrosis associated liver disease. J Cyst Fibros, 10, S29–​36. Edenborough FP, et al. (2008). Guidelines for the management of preg- nancy in women with cystic fibrosis. J Cyst Fibros, 7 Suppl 1, S2–​32. Eigen H, et al. (1995). A multicenter study of alternate-​day prednisone therapy in patients with cystic fibrosis. J Pediatr, 126, 515–​23. Elkins MR, et al. (2006). A controlled trial of long-​term inhaled hyper- tonic saline in patients with cystic fibrosis. New Engl J Med, 354, 229–​40. Farrell PM, et al. (1997). Nutritional benefits of neonatal screening for cystic fibrosis. N Engl J Med, 337, 963–​9. Farrell PM, et al. (2008). Guidelines for diagnosis of cystic fibrosis in newborns through older adults:  Cystic Fibrosis Foundation con- sensus report. J Pediatr, 153, S4–​S14. Flume P (2011). Pneumothorax in cystic fibrosis. Curr Opin Pulm Med, 17, 220–​5. Frederiksen B, Koch C, Hoiby N (1997). Antibiotic treatment of ini- tial colonization with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol, 23, 330–​5. Fuchs HJ, et  al. (1994). Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med, 331, 637–​42. Gibson RL, Burns JL, Ramsey BW (2003). Pathophysiology and man- agement of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med, 168, 918–​51. Griesenbach U, Geddes DM, Alton EWFW (2006). Gene therapy pro- gress and prospects: cystic fibrosis. Gene Ther, 13, 1061–​7. Hodson ME, Geddes DM, Bush A (eds) (2007). Cystic fibrosis. Chapman & Hall, London. Hurt K, Simmonds N (2012). Cystic fibrosis: management of haemop- tysis. Paediatr Respir Rev, 13, 200–​5. Kelly A, Moran A (2013). Update on cystic fibrosis related diabetes.
J Cyst Fibros, 12, 318–​31. Kelly A, et al. (2019). Islet hormone and incretin secretion in cystic fibrosis after four months of ivacaftor therapy. Am J Respir Crit Care Med, 199, 342–51. Kerem E, et  al. (2014). Ataluren for the treatment of nonsense-​ mutation cystic fibrosis:  a randomised, double-​blind, placebo-​ controlled phase 3 trial. Lancet Respir Med, 2, 539–​47. Konstan MW, et al. (1995). Effect of high-​dose ibuprofen in patients with cystic fibrosis. N Engl J Med, 332, 848–​54. Marchant JL, Warner JO, Bush A (1994). Rise in total IgE as an indi- cator of allergic broncho-​pulmonary aspergillosis in cystic fibrosis. Thorax, 49, 1002–​5. Mendizabal M, et  al. (2011). Liver transplantation in patients with cystic fibrosis: analysis of United Network for Organ Sharing data. Liver Transpl, 17, 243–​50. Middleton PG, Geddes DM, Alton EWFW (1994). Protocols for in vivo measurement of the ion transport defects in cystic fibrosis nasal epithelium. Eur Respir J, 7, 2050–​6. Mogayzel PJ Jr, et al. (2014). Cystic Fibrosis Foundation pulmonary guideline. pharmacologic approaches to prevention and eradication of initial Pseudomonas aeruginosa infection. Ann Am Thorac Soc, 11, 1640–​50. Moss RB, et al. (2015). Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-​CFTR mutation: a double-​ blind, randomised controlled trial. Lancet Resp Med, 3, 524–​33. Ramsey BW, et  al. (1999). Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N Engl J Med, 340, 23–​30. Ramsey BW, et al. (2011). A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med, 365, 1663–​72. Ratjen F (2006). Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis. Curr Opin Pulm Med, 12, 428–​32. Ratjen F, et al. (2015). Cystic fibrosis. Nature Reviews Disease Primers, 1, 15010. Ren CL, et al. (2018). Cystic Fibrosis Foundation Pulmonary guide- lines. Use of cystic fibrosis transmembrane conductance regulator modulator therapy in patients with cystic fibrosis. Ann Am Thorac Soc, 15, 271–80. Schneider-Futschik EK (2019). Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis. Gene Ther, doi: 10.1038/ s41434-019-0092-5. Shidrawi RG, et al. (2002). Emergency colonoscopy for distal intestinal obstruction syndrome in cystic fibrosis patients. Gut, 51, 285–​6. Smyth AR, Walters S (2014). Prophylactic anti-​staphylococcal antibiotics for cystic fibrosis. Cochrane Database Syst Rev, 11, CD001912. Southern KW, et al. (2012). Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev, 11, CD002203. Vokova N, et al. (2019). Disease progression in patients with cystic fi- brosis treated with ivacaftor: Data from national US and UK regis- tries. J Cyst Fibrosis, pii: S1569-1993(19)30767-2. doi: 10.1016/j. jcf.2019.05.015. Wainwright CE, et al. (2015). Lumacaftor-​ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med, 373, 220–​31.

18.11 Diffuse parenchymal lung diseases 4166 18.11

18.11 Diffuse parenchymal lung diseases 4166 18.11.1 Diffuse parenchymal lung disease: An introduction 4166 F. Teo and A.U. Wells

CONTENTS 18.11.1 Diffuse parenchymal lung disease:
An introduction  4166 F. Teo and A.U. Wells 18.11.2 Idiopathic pulmonary fibrosis  4177 P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells 18.11.3 Bronchiolitis obliterans and cryptogenic organizing pneumonia  4185 Vasilis Kouranos and A.U. Wells 18.11.4 The lung in autoimmune rheumatic disorders  4191 M.A. Kokosi and A.U. Wells 18.11.5 The lung in vasculitis  4200 G.A. Margaritopoulos and A.U. Wells 18.11.1  Diffuse parenchymal lung disease: An introduction F. Teo and A.U. Wells ESSENTIALS The nomenclature of diffuse parenchymal lung disease (also known as interstitial lung disease) has caused a great deal of confusion, with use of complicated histopathological terms not always corres- ponding to clinico-​radiological entities. Five major groupings are now recognized: (1) idiopathic interstitial pneumonias; (2) diseases associated with systemic conditions, including rheumatological disorders; (3) diseases caused by environmental triggers or drugs; (4) granulomatous diseases; and (5) other diffuse lung diseases. Idiopathic interstitial pneumonias Classification is based on recognition of clinical, radiological, and histo- pathological patterns, as opposed to the purely histopathological ter- minology. Diagnosis is complicated by the large number of disorders grouped within the diffuse parenchymal lung diseases. A systematic diagnostic algorithm, based upon careful clinical evaluation and a lo- gical sequence of tests, is essential. Clinical history, clinical examination, chest radiography, pulmonary function tests, and selective blood tests should be followed by high-​resolution CT, bronchoalveolar lavage (in some cases), and lung biopsy (in a few cases). The chronic diffuse parenchymal lung diseases can be broadly subclassified into five patterns of longitudinal disease behaviour, based upon cause, severity, the relative degree of inflammation and fibrosis, and observed change in the short term. Each clinical pattern is associated with a separate approach to management. Reversible and self-​limited disease—​usually caused by an extrinsic agent and typically responds to withdrawal of an offending agent. Reversible major disease with risk of progression, with or without supervening fibrosis—​a feature of drug-​induced lung disease and some other conditions; usually treated with high-​dose corticoster- oids, with dose reduction to minimum possible once inflammation is controlled. Residual but stable fibrotic disease—​most commonly encountered in sarcoidosis, following drug-​induced lung disease, and in patients with formerly active rheumatological disorders; treatment is not required. Progressive fibrotic disease—​in which stabilization is a realistic goal—​frequently seen in sarcoidosis, hypersensitivity pneumonitis, rheumatological conditions, and in many patients with fibrotic non-​ specific interstitial pneumonia; aggressive initial treatment is usually warranted and long-​term therapy is often required. Inexorably progressive fibrotic disease—​the hallmark of idiopathic pulmonary fibrosis; long-​term treatment may slow disease progres- sion and reduce mortality; early recognition of relentless progression is important when lung transplantation is possible, and to assure provision of effective palliation when it is not. Definition The nomenclature of diffuse parenchymal lung disease has caused confusion over the decades. Contributory factors include non-​ standardized terminology (e.g. ‘extrinsic allergic alveolitis’ and ‘hypersensitivity pneumonitis’ as alternative terms for the same entity), the inappropriate grouping of otherwise diverse clinico-​ pathological entities (previous use of the umbrella term ‘crypto- genic fibrosing alveolitis/​idiopathic pulmonary fibrosis’ to describe all idiopathic interstitial pneumonias), and the use of similarly 18.11 Diffuse parenchymal lung diseases

18.11.1  Diffuse parenchymal lung disease 4167 worded yet distinct disease definitions (e.g. bronchiolitis obliterans organizing pneumonia and bronchiolitis obliterans syndrome). The terminology has been refined as our understanding of disease mech- anisms, presentations, and prognosis has evolved. Diffuse parenchymal lung disease is synonymous with interstitial lung disease. The former terminology reflects, perhaps more aptly, the fact that disease processes involve the lung parenchyma, but also the airspace components of the acini in many cases. Infective pneumonias, pulmonary oedema, and some malignancies involve the acinar regions of the lung but are not, by convention, grouped with the diffuse parenchymal lung diseases, although they may pre- sent with similar clinical and radiological findings and should be considered in the formulation of a differential diagnosis. However, a decision was made to adopt the term interstitial lung disease in the British Thoracic Society (in collaboration with the Thoracic Society of Australia and New Zealand and Irish Thoracic Society) document to achieve consistency with other international guidelines. Specific disease will be considered in subsequent chapters. In this introduction, a broad approach to the classification of the diffuse lung diseases and their diagnosis and investigation will be discussed. Classification Diffuse parenchymal lung diseases can be subdivided into five major groupings:

  1. Idiopathic interstitial pneumonias
  2. Systemic disease (including rheumatological) associated inter- stitial lung disease
  3. Environmental or drug related interstitial lung disease
  4. Granulomatous diseases
  5. Other diffuse lung diseases (e.g. histiocytosis and lymphangioleiomyomatosis) In most patients with environmentally and drug-​induced lung dis- ease, granulomatous lung disease or systemic disease-​associated interstitial lung disease (groups 2–​5), the cause and, thus, the diagnosis is immediately apparent or is rapidly disclosed by standard investigations detailed next. By contrast, diagnosis is less straightforward when a cause is not immediately apparent (group 1). By definition, most of these patients can be categorized as having one of the idiopathic interstitial pneumonias, discussed in detail in the remainder of this chapter. Table 18.11.1.1 lists diseases of known and unknown cause within the broad headings given here, and disorders that present more acutely are shown in Table 18.11.1.2. Idiopathic interstitial pneumonias The diseases grouped as the ‘idiopathic interstitial pneumo- nias’ have given rise to particular confusion, largely because terms used to describe histopathological patterns have been used interchangeably but inaccurately with disease ‘labels’. In 1944, Hamman and Rich first described a presentation of rapidly Table 18.11.1.1  Diffuse parenchymal lung disease Associated with systemic diseases Rheumatological: Systemic sclerosis, rheumatoid arthritis, polymyositis/​dermatomyositis, systemic lupus erythematosus, Sjögren’s syndrome, ankylosing spondylitis Vasculitis: Wegener’s granulomatosis, Churg–​ Strauss granulomatosis, microscopic polyangiitis, pulmonary–​renal syndrome (including Goodpasture’s syndrome), capillaritis, Behçet’s syndrome Vascular: Primary pulmonary hypertension, idiopathic pulmonary haemosiderosis, pulmonary veno-​occlusive disease, antiphospholipid syndrome Diseases caused by environmental triggers or drug ingestion Hypersensitivity pneumonitis: fungal, bacterial, avian, chemical Fibrogenic inorganic dusts: asbestosis, silica, hard metal alloyberyllium, coal, aluminium Therapeutic agents,a illicit drugs, radiation, pesticides, oxygen and other inhaled gases Granulomatous diseases Sarcoidosis, hypersensitivity pneumonitis, berylliosis, Langerhans cell histiocytosis, Wegener’s granulomatosis, Churg–​Strauss syndrome, lymphomatoid granulomatosis, bronchocentric granulomatosis Idiopathic interstitial pneumonias Idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis–​interstitial lung disease, acute interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis Other diffuse lung diseases Inherited disorders: tuberous sclerosis, neurofibromatosis, Hermansky–​Pudlak syndrome, lipid storage disorders, familial idiopathic pulmonary fibrosis Pulmonary eosinophilia: known causes (fungi, parasites, drugs), acute idiopathic, chronic idiopathic Lymphangioleiomyomatosis Alveolar proteinosis Alveolar microlithiasis Amyloidosis Chronic aspiration a see www.pneumotox.com for full listing.

section 18  Respiratory disorders 4168 progressive fatal disease, in which the cardinal histological fea- tures were interstitial inflammation and fibrosis. It subsequently became clear that chronic insidiously progressive fibrosing dis- ease was not uncommon. A typical clinical picture was defined, consisting of progressive dyspnoea, bilateral predominantly basal crackles on auscultation, reticulonodular predominantly basal abnormalities on chest radiography, and a restrictive ventilatory defect on lung function testing. This clinical entity was termed ‘cryptogenic fibrosing alveolitis (CFA)’ or ‘idiopathic pulmonary fibrosis (IPF)’. However, it became clear that the outcome asso- ciated with this presentation, hereafter termed the ‘CFA clinical syndrome’, was highly heterogeneous. Although most patients progressed inexorably to a fatal outcome, usually within three to four years, a more insidious course was seen in a significant minority, and in 10–​15% of cases there was a response to cortico- steroid therapy and, usually, a good long-​term outcome. Histological patterns of disease encountered in the CFA clinical syndrome were first classified by Liebow in 1975 as usual inter- stitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), bronchiolitis obliterans with usual interstitial pneumonia (BIP), lymphocytic interstitial pneumonia (LIP), and giant cell interstitial pneumonia. However, it subsequently became clear that these patterns of disease were also present outside an idio- pathic setting. The most frequent, UIP, was occasionally found in connective tissue disease, drug-​induced lung disease, and chronic hypersensitivity pneumonitis, and LIP was most commonly as- sociated with rheumatological disease and, more recently, AIDS-​ related disease. Giant cell interstitial pneumonia was seldom idiopathic but was caused by exposure to hard metals (cobalt, tungsten carbide, titanium salts). It also became apparent that the historical histological pattern of UIP did, in fact, encompass separate patterns of UIP and nonspecific interstitial pneumonia (NSIP), which denoted a better outcome. These considerations led to a revision of Liebow’s classifica- tion. The interstitial pneumonias of known cause were removed (although smoking-​related disorders were retained). The re- vised classification, in an attempt by a nomenclature committee of the American Thoracic Society and European Respiratory Society in 2001 to integrate clinical, radiological, and histo- pathological patterns as opposed to hitherto purely histo- pathological terminology, included UIP, NSIP, DIP, respiratory bronchiolitis–​interstitial lung disease (RB-​ILD), diffuse al- veolar damage (DAD), LIP, and cryptogenic organizing pneu- monia (Table 18.11.1.3). The term CFA became synonymous with IPF, requiring an underlying histological pattern of UIP or compatible high-​resolution computed tomography (HRCT) appearances, and was distinguished from the nonspecific ‘CFA clinical syndrome’. It was also recognized that different histo- logical patterns may be found within the same disease (e.g. NSIP with UIP pattern in idiopathic pulmonary fibrosis), and this underscored the importance of integrating clinical, radio- logical, and pathological information in arriving at a unifying diagnosis. In 2013, the American Thoracic Society and European Respiratory Society further revised the classification of idiopathic intersti- tial pneumonias (IIP). NSIP, hitherto a provisional diagnosis with poorly characterized clinical and radiologic features, became accepted as a distinct major clinical entity, and idiopathic LIP was classified as a rare IIP. Major IIPs were distinguished from rare (idiopathic LIP and pleuroparenchymal fibroelastosis) and unclassifiable IIPs, and subgrouped into chronic fibrosing (IPF and NSIP), smoking-​related (RB-​ILD and DIP) and acute/​sub- acute IIPs (acute interstitial pneumonia and cryptogenic organ- izing pneumonia). (Table 18.11.1.3). Rare histological patterns of acute fibrinous and organizing pneumonia and interstitial pneu- monias with a bronchiolocentric distribution were introduced. Finally, a clinical disease behaviour classification was proposed to capture thought processes of clinicians and serve as a rationale for treatment and monitoring decisions in disease that is difficult to classify. The pattern of UIP and its associated disorder, IPF, and cryptogenic organizing pneumonia are covered separately in Chapter 18.11.2. The other idiopathic interstitial pneumonias are reviewed briefly next. Table 18.11.1.2  Acute presentations of diffuse parenchymal lung disease: differential diagnosis Primary diffuse parenchymal lung disorders Acute interstitial pneumonia Acute exacerbations of idiopathic pulmonary fibrosis Diffuse alveolar haemorrhage due to vasculitis or coagulopathy Fulminant cryptogenic and secondary organizing pneumonia Acute pneumonitis due to rheumatological disease Hypersensitivity pneumonitis Acute pulmonary eosinophilia Drug-​induced lung disease Mimics of diffuse parenchymal lung disease Pulmonary oedema due to left ventricular failure, uraemia or other causes Infection, especially opportunistic with Pneumocystis carinii Extensive, rapidly progressive metastatic malignancy Table 18.11.1.3  American Thoracic Society/​European Respiratory Society nomenclature of idiopathic interstitial pneumonias Clinical-​radiological diagnosis Pathology pattern Cryptogenic fibrosing alveolitis (idiopathic pulmonary fibrosis) Usual interstitial pneumonia Nonspecific interstitial pneumonia Nonspecific interstitial pneumonia (provisional) Desquamative interstitial pneumonia (alternative name: alveolar macrophage pneumonia) Desquamative interstitial Pneumonia Respiratory bronchiolitis–​interstitial lung Disease Respiratory bronchiolitis–​interstitial lung disease Acute interstitial pneumonia Diffuse alveolar damage Cryptogenic organizing pneumonia Organizing pneumonia Lymphocytic interstitial pneumonia Lymphocytic interstitial pneumonia Pleuroparenchymal fibroelastosis Pleuroparenchymal fibroelastosis

18.11.1  Diffuse parenchymal lung disease 4169 Major idiopathic interstitial pneumonias Chronic fibrosing interstitial pneumonias Idiopathic pulmonary fibrosis See Chapter 18.11.2. Nonspecific interstitial pneumonia Nonspecific interstitial pneumonia is the least satisfactory entity among the idiopathic interstitial pneumonias. Histologically, there is variable interstitial inflammation and fibrosis but, unlike usual interstitial pneumonia, the pattern with which it is most likely to be confused, disease is uniform throughout biopsy specimens, both in severity and in the age of fibrosis (Fig. 18.11.1.1). Fibroblastic foci, the cardinal finding in usual interstitial pneumonia, are absent or sparse. The radiological and clinical manifestations of NSIP are diverse. Inflammation predominates in a few cases and the treated outcome is uniformly good, but in most patients with fibrotic NSIP, fibrosis is as prominent as, or more prominent than, inflammation. Certain clinico-​radiological profiles are increasingly recognized in NSIP:

  1. NSIP/​IPF: the most prevalent profile in most European countries and the United States, it is clinically and physiologically indistin- guishable from that of IPF, despite major outcome differences. On HRCT, the basal distribution of disease is similar to that of IPF, but unlike IPF, there is prominent ground-​glass attenuation and honeycombing is absent or minimal (Fig. 18.11.1.2).
  2. NSIP/​OP: this profile is typically present in pulmonary fibrosis associated with inflammatory myopathy. In this large subgroup, predominating in reports from South Korea and Japan, the clin- ical and radiological features are those of organizing pneumonia admixed with fibrosis and there is a prominent lymphocytosis on bronchoalveolar lavage.
  3. NSIP/​HP:  this profile arose mainly from reports in France and Mexico, with clinical exposure histories, HRCT and bronchoalveolar lavage (BAL) features closely resembling that of hypersensitivity pneumonitis, despite the absence of granulomas in biopsy tissue. In more recent reports, a subgroup of hyper- sensitivity pneumonitis patients with typical NSIP at biopsy is recognized. The prognosis is variable. Corticosteroid and immunosuppres- sive therapy are often effective in producing regression or sta- bilization of disease, but in a few cases, largely confined to those presenting with clinical and HRCT features overlapping with those of IPF, there is inexorable progression to a fatal outcome despite treatment. Smoking-​related interstitial pneumonias Desquamative interstitial pneumonia The cardinal histological feature is diffuse accumulation of macro- phages in alveolar spaces in a uniform pattern, variably associated with minor interstitial inflammation and fibrosis (Fig. 18.11.1.3). DIP is a rare disorder almost exclusively found in smokers in their fourth or fifth decades, with a male to female predominance of 2:1. Typical HRCT appearances comprise extensive ground-​glass at- tenuation (Fig. 18.11.1.4). The disease presents with the features of the CFA clinical syndrome, with finger clubbing present in 50% of patients. Unlike IPF, a response to corticosteroids is seen in at least 70% and the longer-​term treated outcome in these patients is often good. Current smokers should be advised to quit. Respiratory bronchiolitis–​interstitial lung disease (RB-​ILD) As in DIP, the histological features of RB-​ILD are dominated by the presence of pigmented macrophages, but unlike DIP, these ac- cumulate around the bronchioles (respiratory bronchiolitis; see Fig. 18.11.1.5), often with associated peribronchiolar inter- stitial inflammation and fibrosis, with preserved pulmonary Fig. 18.11.1.1  A case of fibrotic nonspecific interstitial pneumonia showing established interstitial fibrosis with a moderate degree of associated chronic inflammation. In areas of affected lung, the features appear homogeneous and diffuse, unlike appearances in usual interstitial pneumonia (see Chapter 18.11.2), and fibroblastic foci are not present. Fig. 18.11.1.2  HRCT appearances from the lower lung zone in a patient with biopsy-​proven fibrotic NSIP. There is widespread ground-​glass attenuation with mild traction bronchiectasis and, in some regions, a subtle admixed reticular element, resulting in a sense of increased texture within abnormal lung.

section 18  Respiratory disorders 4170 parenchyma. Typical HRCT findings include bronchial wall thick- ening, poorly defined centrilobular nodules, and patchy ground-​ glass attenuation and emphysema. RB-​ILD is found only in current or recent former smokers and in many patients, there is overlap in histological features between RB-​ILD and DIP. The histological appearances in RB-​ILD are identical to those of asymptomatic re- spiratory bronchiolitis, which is always present in current smokers. The distinction between RB-​ILD and respiratory bronchiolitis is based upon disease severity, as defined by symptoms, the se- verity of lung function impairment and the extent of disease on HRCT. RB-​ILD is diagnosed when a clinically significant diffuse lung disease is considered to be present. It is increasingly recog- nized that RB-​ILD may be diagnosed without surgical lung bi- opsy in smokers with the aforementioned HRCT features and a macrophage-​predominance in bronchoalveolar lavage. The dis- order usually has a good outcome and often regresses with smoking cessation but based on limited data, corticosteroid therapy is seldom efficacious. Acute/​subacute interstitial pneumonias Acute interstitial pneumonia Acute interstitial pneumonia, also known as the Hamman-​Rich syndrome (or idiopathic adult respiratory distress syndrome), is characterized by a histological pattern of diffuse alveolar damage, with hyaline membranes lining damaged alveoli (Fig. 18.11.1.6) and buds of organization in the alveoli of those acini that have been damaged and are undergoing the healing process. Presentation is most commonly reported in the fifth or sixth decade, with no gender predilection. Symptoms are typically heralded by a viral prodrome, with progressive dyspnoea over days to weeks. There is widespread ground-​glass consolidation, often with trac- tion bronchiectasis, and dependent consolidation on HRCT. Outcome is fatal in 80–​90% of cases. Although high dose cortico- steroid therapy and immunosuppressive agents are commonly given, there is no evidence that treatment influences outcome in most cases. Fig. 18.11.1.3  A case of DIP with typical appearances of macrophage filling of alveolar spaces diffusely within pulmonary acini. There is also mild interstitial fibrosis and focal background emphysema, in keeping with the association between DIP and cigarette smoking. Fig. 18.11.1.4  HRCT appearances in a patient with histologically proven DIP. There is extensive ground-​glass attenuation with no traction bronchiectasis or admixed reticular abnormalities. Although typical of DIP, these appearances are nonspecific, denoting a high likelihood of reversible inflammatory disease. Fig. 18.11.1.5  Biopsy from a patient with respiratory bronchiolitis–​ associated interstitial lung disease showing macrophages with similar histological appearances to those of DIP, but the aggregation is centred on bronchioles where there is also a mild chronic inflammatory cell infiltrate within the airway walls.

18.11.1  Diffuse parenchymal lung disease 4171 Cryptogenic organizing pneumonia See Chapter 18.11.3. Rare idiopathic interstitial pneumonias Lymphocytic interstitial pneumonia The histopathological pattern of lymphocytic interstitial pneu- monia is most commonly found in patients with rheumatological disease and in immunodeficiency syndromes but can rarely occur as an idiopathic disorder. The histological findings consist of dif- fuse interstitial lymphocytic infiltration (Fig. 18.11.1.7), variably associated with follicular bronchiolitis. The HRCT features consist of patchy and sometimes extensive ground-​glass attenuation with a variable nodular component. Corticosteroid and immunosuppres- sive therapy is effective in over 50% of cases. Pleuroparenchymal fibroelastosis Idiopathic pleuroparenchymal fibroelastosis is a rare condition characterized by histologic evidence of dense intra-​alveolar fibrosis and corresponding prominent alveolar wall elastosis with fibrous thickening of the involved visceral pleura. Clinical presentation is often in the fourth or fifth decade of life, with no gender predilec- tion. Radiographic hallmarks are pleural and adjacent parenchymal fibrosis in a predominant upper lobe distribution. Symptoms in- clude cough and shortness of breath evolving over 6  months to years, with a significant number of patients having experienced recurrent infections and recurrent pneumothoraces. Disease pro- gression occurs in 60% of patients with death from disease in 40% in initial reports, although these series are dominated by severe dis- ease and are unlikely to be representative of the whole spectrum of pleuroparenchymal fibroelastosis. There is presently no effective treatment available. Diagnostic approach Diagnosis is complicated by the large number of disorders grouped within the diffuse parenchymal lung diseases. A systematic diag- nostic algorithm, based upon careful clinical evaluation and a logical sequence of tests, is essential. This approach can be broken down into in two phases: Phase 1 1 clinical history 2 clinical examination 3 chest radiography 4 pulmonary function tests 5 selective blood tests Phase 2 1 high-​resolution computed tomography 2 bronchoalveolar lavage 3 lung biopsy Phase 1 Clinical history In most patients, the presentation is insidious dyspnoea, vari- ably accompanied by cough which is usually nonproductive. The duration of dyspnoea is diagnostically important: an acute pres- entation narrows the differential diagnosis considerably (see Table 18.11.1.2). Wheeze is a useful discriminatory symptom as the pres- ence of an airway-​centred component informs the differential diagnosis. Disorders with variable but sometimes prominent wheeze include hypersensitivity pneumonitis, sarcoidosis, Fig. 18.11.1.6  A case of acute interstitial pneumonia (AIP) showing the exudative phase of diffuse alveolar damage with hyaline membranes lining alveolar walls, indicating AIP when present in an idiopathic setting. Fig. 18.11.1.7  A case of lymphoid interstitial pneumonia showing dense interstitial chronic inflammation diffusely involving the alveolar parenchyma, in this case associated with minimal interstitial fibrosis.

section 18  Respiratory disorders 4172 lymphangioleiomyomatosis, and Langerhans cell histiocytosis. Other less frequent respiratory symptoms are also diagnostic- ally useful. Pleuritic chest discomfort often occurs in the rheum- atological diseases and occasionally in drug-​induced disease, but never in idiopathic pulmonary fibrosis or hypersensitivity pneumonitis. Haemoptysis may be indicative of diffuse al- veolar haemorrhage due to capillaritis, occurring in certain dis- orders: haemoptysis may be trivial, even when haemorrhage is severe. A history of pneumothorax should prompt suspicion of cystic lung disease, especially Langerhans cell histiocytosis and lymphangioleiomyomatosis. The previous medical history may provide crucial information, including diagnoses of rheumatological disease or other relevant systemic diseases (including vasculitis). Even when no previous sys- temic diagnosis has been made, the nature of preceding systemic symptoms may point strongly to a hitherto undiagnosed rheumato- logical disorder. Knowledge of underlying cardiac and malignant disease is also essential as disseminated malignancy and cardiac failure may both simulate diffuse parenchymal lung disease, clinic- ally and radiologically. A detailed list of medications serves to alert the clinician to the possibility of drug-​induced lung disease. The agents most frequently responsible include nitrofurantoin, metho- trexate, and bleomycin but a long list of other drugs occasionally cause lung disease. The comprehensive website, pneumotox.com, provides a rapid and fruitful means of checking possible pulmonary toxicities. The occupational history should include all occupations from school-​leaving: diseases caused by some exposures (including as- bestos exposure) manifest decades later. Environmental conditions in which pneumoconiosis most commonly arise include sawing, grinding, and drilling. Hypersensitivity pneumonitis arises from the inhalation of organic dusts including fungal contaminates of hay (as in farmers lung) and avian proteins found on the bloom and in the excreta of domestic birds. Many other organic antigens can give rise to hypersensitivity pneumonitis, with over 200 causes now recognized. Other relevant historical information includes foreign travel, which may raise the possibility of parasitic infection as an explan- ation of pulmonary eosinophilia. A  history of cigarette smoking identifies a predisposition to Langerhans cell histiocytosis, DIP, and RB-​ILD and is also a risk factor for exacerbations of pulmonary vas- culitis. Paradoxically, smoking appears to protect against the devel- opment of sarcoidosis and hypersensitivity pneumonitis. Clinical examination Digital clubbing is common in IPF and NSIP, and is not infre- quent in hypersensitivity pneumonitis, but is unusual in the other diffuse parenchymal lung diseases. Predominantly basal fine end inspiratory crackles are a cardinal feature of the CFA clinical syn- drome and are expected in IPF and variably present in the other idiopathic interstitial pneumonias. Sporadic crackles are heard in many diffuse parenchymal lung diseases, but are seldom present in sarcoidosis. Expiratory wheeze is indicative of airway disease. Inspiratory squawks are strongly predictive of hypersensitivity pneumonitis or obliterative bronchiolitis. In advanced disease, clinical evidence of secondary pulmonary hypertension should be sought, as oxygen supplementation may have a pivotal role in management. Relevant systemic findings include ocular disease (in sarcoid- osis or vasculitis), skin disease (in sarcoidosis or rheumatological disease), musculoskeletal signs (in rheumatological disease) and neurological abnormalities (mononeuritis multiplex in sarcoidosis, rheumatological disease, and vasculitis; a wide variety of central and peripheral signs in sarcoidosis). Chest radiography Chest radiography was formerly a central part of the evaluation of diagnosis of diffuse parenchymal lung disease. Although HRCT has now supplanted chest radiography in routine diagnosis, the chest radiograph continues to provide useful information. Radiographic findings suggestive of pulmonary fibrosis are a required feature of the CFA clinical syndrome. Patients with fibrosing lung diseases tend have reduced lung volumes. If other clinical features are indicative of IPF, normal-​sized or large lungs on chest radiography are suggestive of the coexistence of emphy- sema and pulmonary fibrosis, a frequent association in cigarette smokers with IPF. Large or normal sized lungs on chest radiog- raphy, in association with nodular or reticular shadowing, also occur in Langerhans cell histiocytosis, lymphangioleiomyomatosis (a disorder involving smooth muscle proliferation arising in pre- menopausal women), and the closely related disorder, tuberous sclerosis. Idiopathic bronchiectasis or cystic fibrosis, with increased radiographic volumes due to hyperinflation, can also be mistaken radiologically for diffuse parenchymal lung disease, although the clinical profile of chronic purulent sputum production is usually discriminatory. The distribution of disease is often helpful. Primary fibrosing disorders, including IPF, fibrotic NSIP, pulmonary fibrosis in rheumatologic disease and asbestosis, produce predominantly basal reticular or reticulonodular abnormalities, which may also be overtly peripheral when disease is not advanced. By contrast, granulomatous disorders, including sarcoidosis and hypersensitivity pneumonitis (as well as tuberculosis and allergic bronchopulmonary asbestosis) most often have a predominantly upper and mid zone distribution. In the correct clinical setting, chest radiographic findings typical of sarcoidosis (predominantly upper zone fibrotic change, variably associated with lymphadenopathy and hilar retraction towards the apices) often suffice for a confident diagnosis. The size and shape of abnormalities is sometimes diagnostically useful, although this aspect of radiological evaluation has largely been supplanted by HRCT. Chest radiographic nodules of more than 5 mm in diameter are often present in Wegener’s granulomatosis, lymphoma, and other malignancies. Cavitating nodules are a frequent feature in Wegener’s granulomatosis, but necrotizing carcinomas and multiple staphylococcal abscesses should also be considered. The presence of nodules of differing size and shape is strongly suggestive of metastatic malignancy. An alveolar filling pat- tern, consisting of widespread confluent shadowing, usually denotes the presence of life-​threatening disease. The differential diagnosis includes pulmonary oedema (due to left ventricular failure or mi- tral stenosis), diffuse alveolar haemorrhage, uraemia, drug-​induced lung disease (and other forms of diffuse alveolar damage), infection (especially opportunistic infection in immunosuppressed patients) and alveolar proteinosis. When widespread confluent shadowing is chronic, alveolar cell carcinoma, lymphoma, and pulmonary eo- sinophilia should also be considered.

18.11.1  Diffuse parenchymal lung disease 4173 Previous chest radiographs are often highly revealing, especially in the patient presenting with multifocal consolidation. Waxing and waning of consolidation effectively excludes malignant disease and is strongly suggestive of immunologically mediated disorders, including cryptogenic organizing pneumonia, vasculitis, and pul- monary eosinophilia. Fixed consolidation may also occur in all of these disorders but should also prompt suspicion of lymphoma, al- veolar cell carcinoma, and chronic infection. Pleural thickening, with or without effusion, occurs commonly in rheumatological disease, rheumatoid arthritis, and systemic lupus erythematosus. Pleural abnormalities also occur commonly in asbestosis and in Churg–​Strauss granulomatosis and Wegener’s granulomatosis. The presence of pleural disease should always prompt consideration of a second disease process, including ma- lignancy, heart failure, tuberculosis, pulmonary embolism, and drug-​induced lung disease. Pleural involvement is not a feature of uncomplicated hypersensitivity pneumonitis or IPF and is seldom present in the other idiopathic interstitial pneumonias, although oc- casionally encountered in sarcoidosis and cryptogenic organizing pneumonia. Symmetrical hilar lymphadenopathy is usually indicative of sar- coidosis, but tuberculosis, lymphoma, and other malignancies should always be considered, especially if the changes are unilateral. Lymphadenopathy is seldom present on chest radiography in other diffuse lung diseases, with the exception of silicosis. Hilar calcifica- tion occurs in sarcoidosis, silicosis, and tuberculosis. Pulmonary function testing In most patients with diffuse parenchymal lung disease, there is a restrictive ventilatory defect with reduced gas transfer (DLCO). Arterial oxygen tensions (Pao2) are normal or mildly reduced until disease is advanced, although the alveolar–​arterial oxygen gra- dient is often widened in associated with Paco2 levels that are at the lower end of the normal range. In early disease, maximal exercise testing may unmask abnormalities or, when normal, may reassure the clinician that the disease is not clinically significant. In IPF, maximal exercise testing typically a fall in the Pao2 and widening of the alveolar–​arterial oxygen gradient (A–​a gradient), reflecting ventilation–​perfusion mismatch and, at maximal exercise, impair- ment of diffusion. The anatomical dead space to tidal volume ratio (VD/​VT) normally falls on exercise in the healthy individual but is unchanged or increases in restrictive lung disease. Striking rises in the VD/​VT ratio are strongly suggestive of disproportionate pul- monary vascular limitation. A mixed (restrictive-​obstructive) ventilatory defect is seen in dis- orders in which airway involvement is associated with diffuse par- enchymal lung disease. This ventilatory pattern most commonly occurs in hypersensitivity pneumonitis, sarcoidosis, and rheumato- logical disorders. The coexistence of pulmonary fibrosis and emphy- sema, usually found in cigarette smokers with IPF or fibrotic NSIP, may also give rise to a mixed ventilatory defect, but more commonly, there is spurious preservation of lung volumes and a dispropor- tionate reduction in DLCO. Blood tests Routine haematology and biochemical tests have little discrim- inatory value in the diffuse lung diseases. A peripheral blood eo- sinophilia (above 1.5 × 109/​litre) is a prerequisite for diagnosis of Churg–​Strauss vasculitis and may also be indicative of pulmonary eosinophilia (although not always present in that disorder). Increased levels of angiotensin converting enzymes are a helpful an- cillary diagnostic finding in some patients with sarcoidosis and may also confirm ongoing disease activity. Routine immunoglobulin es- timation may disclose hypogammaglobulinaemia in undiagnosed granulomatous disorders but has no diagnostic value in other dif- fuse lung disorders. Autoantibody testing is an essential part of routine evaluation. The presence of a positive antinuclear antibody, with specific extractable nuclear antigen profiles, or rheumatoid factor, may disclose an oc- cult systemic rheumatological condition. The autoantibody profile is sometimes indicative of the likely pattern of pulmonary involve- ment. In systemic sclerosis:  the anti-​DNA topoisomerase auto- antibody is often associated with clinically significant pulmonary fibrosis whereas the anticentromere antibody is linked to pulmonary vascular disease. The anti-​t-​RNA synthetase autoantibodies occur when polymyositis is associated with diffuse parenchymal lung disease. Other common associations include anti-​Sm in systemic lupus erythematosus, SS-​A, and SS-​B in Sjögren’s syndrome and the anti-​RNP autoantibody in mixed connective tissue disease. Mild increases in antinuclear antibody and rheumatoid factor titres are commonly found in IPF and idiopathic fibrotic NSIP but appear to have no clinical significance. Increased antineutrophil cytoplasmic antibodies with a cytoplasmic pattern are strongly suggestive of Wegener’s granulomatosis or microscopic polyangiitis. The peri- nuclear (pANCA) pattern is less discriminatory. The presence of specific precipitins to organic antigens is often diagnostically useful in hypersensitivity pneumonitis. However, positive precipitins are not, in isolation, diagnostic, confirming only the presence of immunological recognition. Avian precipitins, for example, are often present in healthy pigeon breeders. Moreover, the absence of precipitins does not exclude a diagnosis of hypersensi- tivity pneumonitis: avian proteins causing disease in an individual may be species specific or, even, specific to a single bird. Phase 2 High-​resolution computed tomography High-​resolution computed tomography provides a three-​ dimensional anatomical reconstruction of both lungs, resulting in improved diagnostic accuracy, compared to chest radiography. Several HRCT patterns can now be viewed as pathognomonic and HRCT is often diagnostic in other patients when the findings are integrated with clinical information. The diagnostic use of HRCT essentially consists of an evaluation of the distribution and pattern of disease. A detailed review of the rapidly enlarging HRCT litera- ture lies beyond the scope of this chapter and the reader is referred to sources listed in the ‘Further reading’ section. HRCT is much more sensitive than chest radiography, leading to the earlier diagnosis of limited disease. While this is sometimes highly advantageous, the sensitivity of HRCT sometimes causes its own problems. The detection of limited abnormalities in cigarette smokers, or when HRCT is used as a screening tool in rheumato- logical disorders, sometimes leads to difficulty in assigning clinical significance to the findings. In this context, pulmonary function tests have a pivotal role but are sometimes difficult to interpret when functional impairment is minor, due to the wide normal range: a

section 18  Respiratory disorders 4174 forced vital capacity (FVC) of 75% of predicted can equally represent a minor fall or a major reduction from premorbid values of 80% and 120% of predicted, respectively. Absence of oxygen desaturation on maximal exercise testing is especially helpful in this scenario. A simple HRCT diagnostic algorithm can be usefully be ap- plied to apparently idiopathic diffuse lung disease. Confirmation of fibrosing disease is readily demonstrated by the presence of reticular abnormalities, anatomical distortion or, when ground-​glass attenu- ation predominates, traction bronchiectasis. The essential prelim- inary question is whether HRCT appearances are typical of IPF (i.e. predominantly basal reticular abnormalities, with or without honeycombing, with little ground-​glass attenuation). If not, it is ap- propriate to look for the HRCT features of fibrotic NSIP, sarcoidosis, hypersensitivity pneumonitis, and organizing pneumonia with fi- brosis, disorders which, with IPF, account for up to 95% of diagnoses in apparently idiopathic disease. When HRCT appearances are not typical of one of these disorders and disease is progressive, IPF with atypical HRCT features is the most frequent diagnosis made at sur- gical biopsy. HRCT has some other advantages. Even when the HRCT diag- nosis is uncertain, the signs of fibrosis listed earlier often make it clear that disease is irreversible. The identification of reversible dis- ease is less straightforward. Prominent ground-​glass attenuation often denotes inflammation, but only when there is no admixed re- ticular pattern or traction bronchiectasis. HRCT is also invaluable in allowing the thoracic surgeon to select optimal sites for biopsy, by which means the full range of morphological abnormalities and disease severity can be sampled. Serial HRCT is sometimes useful in monitoring changes in disease severity, especially when pulmonary function trends are inconclusive, although HRCT should be used for this purpose in order to cast light on clinically important questions in individual patients and not performed rigidly by protocol. Finally, HRCT is often revealing when disease processes are ad- mixed. In rheumatological disorders and in smoking-​related dis- ease, patterns of functional impairment are often complex and an assessment of the extent of interstitial disease allows a better understanding of the presence and likely functional impact of em- physema and airway disease. The complications of diffuse lung dis- ease are often disclosed by HRCT. Lung malignancy is increased in prevalence in fibrosing lung disease but can sometimes be difficult to detect on chest radiography when interstitial fibrosis is exten- sive. Infection is also sometimes masked in extensive disease, and this applies especially to aspergillomas, which tend to develop in fibrobullous sarcoidosis. Bronchoalveolar lavage When first employed, it was hoped that BAL might replace diag- nostic surgical biopsy or provide accurate prognostic information, and that serial BAL might disclose important changes in disease ac- tivity. Further evidence did not support these expectations, and the role of BAL has now been down-​graded. However, BAL has an an- cillary diagnostic role in diffuse lung diseases and is also sometimes helpful in excluding infection. Granulomatous and drug-​induced lung diseases are characterized by an excess of lymphocytes with or without granulocytes. The presence of a BAL lymphocytosis is oc- casionally pivotal in alerting the clinician to the possibility that a fibrosing process may be due to hypersensitivity pneumonitis or sar- coidosis. Bronchoalveolar lavage can also be diagnostic in some rare lung disorders, including alveolar proteinosis (milky effluent; PAS-​ positive material), Langerhans cell histiocytosis (increased numbers of Langerhans cells identified by CD1a staining), alveolar haemor- rhage (iron-​laden macrophages) and hard metal lung disease (bi- zarre multinuclear giant cells). By contrast, a BAL neutrophilia is an expected finding when pulmonary fibrosis is moderately exten- sive and has little diagnostic value, particularly where clinical and HRCT evaluation are characteristic of IPF. It appears increasing likely, based on recent data, that the observed linkage between dis- ease progression and a BAL neutrophilia in rheumatological disease reflects the presence of more severe disease, which is, itself, more likely to progress. BAL is an essential part of the diagnostic algorithm in patients pre- senting acutely with widespread interstitial abnormalities. Diffuse alveolar haemorrhage does not always manifest with haemoptysis but is readily disclosed by BAL. In patients receiving immunosup- pressive drugs, increased treatment may be urgently required in the hope of reversing disease progression. However, acute decompen- sation due to opportunistic infection may be excluded more confi- dently only with BAL. Lung biopsy Assessment of a surgical lung biopsy offers the important advantage that further investigation is unlikely to clarify the situation and a final diagnosis must now be made, integrating all clinical, radio- logical, and histological information. A confident diagnosis leads to more confident management, with a more accurate evaluation of the balance of risk and benefit with suggested treatments. Clinicians are better able to inform the patient of the likely natural history and treated course of disease. In many patients, a firm diagnosis can be made from clinical and HRCT data, and a surgical biopsy is redun- dant. In other cases, a biopsy is contraindicated by advanced age, the severity of disease, major comorbidity, or the wishes of the pa- tient. The acquisition of biopsies from more than one lobar site in- creases the likelihood of obtaining representative tissue. The limited thoracotomy approach used historically has now been supplanted by video-​assisted thoracoscopic surgical procedures, which are less invasive, provide equivalently sized samples and are associated with less morbidity. The morbidity and mortality associated with diagnostic sur- gical biopsy are low provided that pulmonary reserve is adequate. However, postoperative mortality increases significantly when dis- ease is extensive and exceeded 15% in one IPF series in which the average level of functional impairment were severe. Thus, if the DLCO level is less than 35% of predicted, a surgical biopsy should be performed only if considered indispensable. The histological diag- nosis is, in any case, less prognostically useful in advanced disease. Mortality is very similar in IPF and fibrotic NSIP when DLCO levels are less than 35%, despite striking differences in survival when dis- ease is less severe. Transbronchial lung biopsies Transbronchial lung biopsies (TBLB) are most useful in diagnosing airway-​centred disorders. In sarcoidosis and lymphangitis carcin- omatosis, the histological appearances are sufficiently characteristic to allow a confident diagnosis to be made from very small biopsy specimens. However, for most diffuse lung diseases, including the idiopathic interstitial pneumonias, their morphological complexity

18.11.1  Diffuse parenchymal lung disease 4175 renders the overall pattern of disease difficult to meaningfully evaluate without a larger surgical biopsy. Over the recent years, transbronchial lung cryobiopsy (TBLC) has emerged as a promising new technique in the diagnostic evalu- ation of diffuse parenchymal lung disease. Originally developed to treat endobronchial tumours, TBLC confers the advantage of being able to harvest larger and architecturally better-​preserved pieces of lung parenchymal tissue compared to TBLB. Several studies have reported improved diagnostic yield with TBLC compared to con- ventional TBLB; this enabled a definitive histological pattern to be identified with a high level of confidence in significantly more sam- ples harvested by TBLC than TBLB. Whether this translated to a change of initial consensus at diagnosis or enabled the multidiscip- linary team to reach a definitive diagnosis is less clear. Safety issues are also a concern, namely, a higher risk of significant bleeding, and to a lesser extent, pneumothorax, with TBLC. It was also noted that most studies excluded patients with a DLCO of less than 35%, where surgical lung biopsy might have been contraindicated, thus not of- fering an advantage in this respect to patients with marginal lung function. At present, surgical lung biopsy remains the gold standard procedure for obtaining a histological diagnosis in diffuse paren- chymal lung disease but the reader is alerted to the possibility that TBLC may supplant surgical biopsy in the near future as more data are rapidly accumulated. Transbronchial needle aspiration In patients with suspected stage I and II sarcoidosis, transbronchial needle aspiration (TBNA) of intrathoracic lymph nodes by conven- tional TBNA or endosonography (endobronchial or oesophageal ultrasound -​guided) may be a useful tool in detecting the pres- ence of noncaseating granulomas. In the largest yet multicentre randomized control trial comparing the diagnostic yield of bron- choscopy (with transbronchial or endobronchial mucosal bi- opsy) vs. endosonography for stage I and II sarcoidosis, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in a greater yield (80% vs. 53%) with an equivalent safety profile. Key clinical issues Integrated diagnosis Although a histological diagnosis made at surgical biopsy was once viewed as definitive in diffuse parenchymal lung disease, it is now widely accepted that all clinical, radiological, and histopathological data must be integrated into the final diagnosis. The limitations of a histological diagnosis are now better understood. ‘Sampling error’ consists of the acquisition of nonrepresentative tissue: in some pa- tients with IPF, there are lung regions with the histological appear- ances of fibrotic NSIP, but this finding has no prognostic significance. Sampling error can be minimized by ensuring that large samples are taken, by sampling more than one site, and by selecting the sites of biopsy to sample the full range of disease morphology and severity, based on HRCT appearances. However, diagnostic variation be- tween pathologists remains problematic, with less agreement than documented with many clinically useful tests. Moreover, in some cases, there is ‘appropriate’ interobserver variation, reflecting the fact that histological appearances occasionally lie intermediate between classical entities. To complicate matters further, the diagnostic sig- nificance of a histological pattern is critically dependent upon the clinical context. For example, usual interstitial pneumonia is the re- quired histological pattern in IPF but sometimes has a better out- come when occurring in patients with rheumatological disorders, drug-​induced lung disease, or hypersensitivity pneumonitis. Thus, the gold standard for diagnosis in diffuse parenchymal lung disease is now a multidisciplinary diagnosis, with participation by clinicians, radiologists and, when applicable, histopathologists. As a useful rule of thumb, in nonbiopsied cases the clinical and HRCT evaluation is, on average, equally influential, and careful clinical as- sessment should not be curtailed because of the ready availability of HRCT. In patients undergoing surgical biopsy, clinical and HRCT findings are usually inconclusive and the histological features tends to carry the most diagnostic weight. However, it is accepted that the final diagnosis should differ from the histological diagnosis in a significant minority of patients, when all available information is integrated. The principles of management The chronic diffuse parenchymal lung diseases can be broadly subclassified into five patterns of longitudinal disease behaviour, based upon cause, severity, the relative degree of inflammation and fibrosis, and observed change in the short term. Each clinical pattern is associated with a separate approach to management.

  1. Reversible and self-​limited disease is usually caused by an ex- trinsic agent (as in drug-​induced disease, hypersensitivity pneu- monitis and RB-​ILD) but may also be idiopathic as in a subset of patients with sarcoidosis. Disease usually responds to with- drawal of an offending agent, therapy is often unnecessary, and monitoring consists of confirming that disease has regressed.
  2. Reversible major disease with risk of progression, with or without supervening fibrosis is often a feature of drug-​induced lung dis- ease and this category also applies to some patients with crypto- genic organizing pneumonia, DIP, cellular and some fibrotic NSIP, hypersensitivity pneumonitis, and sarcoidosis. High-​dose therapy is usual, often with corticosteroids, and the short-​term response is quantified, often at four to six weeks. Once inflam- mation is controlled and the residual level of functional impair- ment has been quantified, treatment is gradually reduced with monitoring centred around serial pulmonary function tests, usually at three to four monthly intervals. In this way, the min- imum dose required to maintain control of disease is established.
  3. Residual but stable fibrotic disease is most commonly encoun- tered in sarcoidosis, following drug-​induced lung disease, and in patients with formerly active rheumatological disorders. Treatment is not required but long-​term monitoring is needed to ensure that disease is truly stable, usually with serial pulmonary function tests until a long-​term ‘track record’ of disease stability has been established.
  4. Progressive fibrotic disease, in which stabilization is a realistic goal, is frequently seen in sarcoidosis, hypersensitivity pneu- monitis, rheumatological conditions, and in many patients with fibrotic NSIP. In this scenario, long-​term therapy is often re- quired and long-​term monitoring with serial pulmonary func- tion tests, often at increasing time intervals, is needed to ensure

section 18  Respiratory disorders 4176 that stabilization has been achieved and maintained. Aggressive initial treatment is usually warranted to ensure optimal control of disease activity. 5. Inexorably progressive fibrotic disease is the hallmark of IPF, but an IPF-​like course is sometimes observed in idiopathic fi- brotic NSIP, rheumatological disease, and in a small subset of patients with chronic hypersensitivity pneumonitis. Long-​term treatment may slow disease progression and reduce mortality, as evidenced by recent data on anti-​IPF specific therapies (such as pirfenidone and nintedanib—​discussed further in Chapter 18.11.2). The early realization that fibrotic disease may be relentlessly progressive, either because IPF is diagnosed or because disease continues to progress despite treatment, is especially important when lung transplantation or, in cases where this may not be possible, effective palliation, is realistic. Monitoring is performed to quantify disease progression, usu- ally at three to four monthly intervals. This schema is proposed in order to capture key thought processes of clinicians and to serve as a rationale for treatment and moni- toring decisions. In many cases, the pattern of disease behaviour is evident at presentation, but careful short-​term observation is highly informative in other instances. When should a surgical biopsy be performed? A broad classification of disease behaviour also serves as a rational- ization of when to recommend a diagnostic surgical biopsy. When the underlying diagnosis is uncertain and the clinician is unable to assign likely disease behaviour, and therefore management is diffi- dent, a surgical biopsy is usually warranted (age, disease severity, and comorbidity permitting). However, if the diagnosis is uncertain but the pattern of disease behaviour is already clear, a diagnostic bi- opsy is much less likely to inform management. For example, when it is already known from previous investigations that fibrotic abnor- malities are long-​standing and wholly stable, a histological diagnosis is unlikely to change management. When considering whether or not to recommend biopsy, it is useful to construct scenarios in which long-​term management may differ significantly depending upon histological findings. It is important to reach an early decision. The empirical approach of initiating treatment, with recourse to biopsy if the response is unsat- isfactory, has serious flaws. Modification of the histological appear- ances by treatment may make diagnosis more difficult and, more importantly, deterioration during the interim period may make the biopsy more hazardous, as well as increasing the likelihood of side effects to treatment, including postoperative infection and impaired wound healing. Thus, the best time to perform a biopsy is shortly after presentation, before treatment is instituted. FURTHER READING BAL Co-​operative Group Steering Committee (1990). Bronchoalveolar lavage constituents in healthy individuals, idiopathic pulmonary fi- brosis, and selected comparison groups. Am Rev Respir Dis, 141, S169–​S202. Bjoraker JA, et al. (1998). Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 157, 199–​203. Bradley B, et al. (2008). Interstitial lung disease guidelines: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax, 63, Suppl. 5, v1–​v58. Desai SR, Wells AU (2007). Imaging. In:  Costabel U, du Bois RM, and Egan JJ (eds). Diffuse parenchymal lung disease, pp. 29–​43. Karger, Basel. Flaherty KR, et al. (2001). Histologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med, 164, 1722–​7. Flaherty KR, et al. (2004). Idiopathic interstitial pneumonia. What is the effect of a multi-​disciplinary approach to diagnosis? Am J Respir Crit Care Med, 170, 904–​10. Joint American Thoracic Society and European Respiratory Society Group (2000). Idiopathic pulmonary fibrosis: diagnosis and treat- ment. International consensus statement. Am J Respir Crit Care Med, 161, 646–​64. Joint American Thoracic Society and European Respiratory Society Group (2002). International multidisciplinary consensus classifica- tion of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med, 165, 277–​304. Joint American Thoracic Society and European Respiratory Society Group (2013). Update of the international multidisciplinary con- sensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med, 188, 733–​48. Katzenstein AL, Myers JL (1998). Idiopathic pulmonary fibrosis: clin- ical relevance of pathologic classification. Am J Respir Crit Care Med, 157, 1301–​15. Liebow AA (1975). Definition and classification of interstitial pneu- monias in human pathology. In: Basset F, Georges R (eds). Progress in respiration research, pp. 1–​33. Karger, New York. Muller NL, Colby TV (1997). Idiopathic interstitial pneumonias:
high-​resolution CT and histologic findings. Radiographics, 17, 1016–​22. Nicholson AG, et al. (2004). Inter-​observer variation between patholo- gists in diffuse parenchymal lung disease. Thorax, 59, 500–​5. Nicholson AG, et al. (2000). The prognostic significance of the histo- logic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med, 162, 2213–​17. Pajares V, et al. (2014). Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease:  a randomized trial. Respirology, 19, 900–​6. Reddy TL, et  al. (2012). Pleuroparenchymal fibroelastosis:  a spec- trum of histopathological and imaging phenotypes. Eur Respir J, 40, 377–​85. von Bartheld MB, et  al. (2013). Endosonography vs conventional bronchoscopy for the diagnosis of sarcoidosis: the GRANULOMA randomized clinical trial. JAMA, 309, 2457–​64. Wells AU (2003). High resolution computed tomography in the diag- nosis of diffuse lung disease: a clinical perspective. Semin Respir Crit Care Med, 24, 347–​56. Wells AU (2004). Histopathologic diagnosis in diffuse lung disease: an ailing gold standard. Am J Respir Crit Care Med, 170, 828–​9. Wells AU, Hansell DM, Nicholson AG (2007). What is this thing called CFA? Thorax, 62, 3–​4.

18.11.2 Idiopathic pulmonary fibrosis 4177 P.L. Mo

18.11.2 Idiopathic pulmonary fibrosis 4177 P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells

18.11.2  Idiopathic pulmonary fibrosis 4177 18.11.2  Idiopathic pulmonary fibrosis P.L. Molyneaux, A.G. Nicholson, N. Hirani,
and A.U. Wells ESSENTIALS The synonymous terms idiopathic pulmonary fibrosis and crypto- genic fibrosing alveolitis refer to a relentlessly progressive fibrotic lung disorder. Incidence is about 5 to 15 per 100 000, men are more often affected than women, and it most commonly presents in the seventh and eighth decades. Aetiology remains uncertain. Clinical features—​typical presentation is with progressive exertional dyspnoea without wheeze, a nonproductive cough, digital clubbing, and very fine end-​inspiratory crackles. Central cyanosis and clinical evidence of pulmonary hypertension are late features. Diagnosis—​depends on careful exclusion of known causes of inter- stitial lung disease, followed by demonstration by radiological imaging or biopsy of the pathognomonic lesion of usual interstitial pneumonia. Management—​two antifibrotic compounds, pirfenidone and nintedanib, have been proven to slow functional decline in idio- pathic pulmonary fibrosis. Treatments that target inflammation
(e.g. corticosteroids and immunosuppressive agents) are generally
of no benefit and may do harm, although acute exacerbations, which affect 10–​15% of patients each year and are often fatal, are typically given a trial of high-​dose corticosteroid. Lung transplant- ation is appropriate in selected cases. Supportive therapy is central to the management of advanced disease. Five-​year survival is 10–​15%. Introduction The disorder previously known as fibrosing alveolitis, first described in 1907, was increasingly recognized following the description of a small group of patients with rapidly progressive fatal disease, grouped as the Hamman–​Rich syndrome. Until late in the twentieth century, a stereotypical clinical presentation of idiopathic intersti- tial lung disease was termed idiopathic pulmonary fibrosis (IPF) or cryptogenic fibrosing alveolitis (CFA), with several histological pat- terns unified under this term. However, it became increasingly clear that the clinical presentation of IPF/​CFA (‘CFA clinical syndrome’) was shared by diseases including predominantly inflammatory and predominantly fibrotic disorders, now known collectively as the idiopathic interstitial pneumonias. Their separation is essentially pragmatic, justified by large differences in treated outcome. The new classification proposed by an American Thoracic Society/​European Respiratory Society nomenclature committee is now widely accepted and can be readily applied to routine prac- tice, with increasing recognition of characteristic patterns of disease on high resolution computed tomography (HRCT). Histological evaluation tends to be reserved for the few patients in whom best management cannot be based on clinical and HRCT findings. The synonymous terms IPF and CFA now refer to a relentlessly progres- sive fibrotic disorder, associated with a histological pattern of usual interstitial pneumonia (UIP) or typical HRCT and clinical features in nonbiopsied cases. Epidemiological and aetiological data are briefly reviewed and the clinical picture is summarized. Key clinical issues are then dis- cussed, including diagnosis, prognostic evaluation, routine moni- toring, and treatment. Epidemiology and aetiology IPF most commonly affects men, rarely presents before the age of 50, and exhibits considerable geographic variation. The incidence and prevalence have risen steadily in recent decades, with the incidence now likely to approximate 10–​15 per 100 000, based upon evalu- ation of death certificates and registry studies in the United States, United Kingdom, and elsewhere. A recent study, using case defin- itions more reliably indicative of IPF, has suggested an incidence of 5 to 10 per 100 000. The pathogenesis of IPF remains unknown. It was historically considered that inflammation preceded fibrosis, but the paucity of evidence of inflammation in histopathological samples and the lack of efficacy of immunosuppressive therapy led to a shift in thinking. Current evidence suggests IPF develops in genetically susceptible individuals with dysfunctional alveolar epithelial repair mech- anisms following repeated episodes of alveolar injury. Repetitive injury results in myofibroblast recruitment and activation, and col- lagen deposition causing progressive accumulation of scar tissue, re- sulting in the classical radiological and histological patterns of UIP. Destruction of the lung architecture causes loss of alveolar struc- ture, impairing gas exchange and ultimately resulting in respiratory failure. The presumptive model of development therefore suggests a role in IPF for both host and environmental factors, with inter- actions between the two in all likelihood. Environmental factors Several environmental triggers have been suggested as plausible causative factors, but as yet the initial stimulus remains unidenti- fied. A history of smoking is associated with an increased risk of developing both the familial and sporadic forms of IPF, but cigarette smoke alone cannot be the only trigger as the disease also occurs in non​smokers. Epidemiological studies have also implicated environ- mental and occupational exposures to metal dusts and wood fires, which confer an increased risk of IPF. Genetic factors Familial forms of IPF, where two or more members of a family are affected, provide strong evidence for an underlying genetic compo- nent to the disease. Familial forms of fibrosis have been linked to variants in the genes encoding two surfactant proteins (SFTPC & SFTPA2), genes that maintain telomere length (hTERT and TERC), and most recently the mucin 5B (MUC5B) gene. The strongest and most reproducible genetic association with IPF to date is that of the mucin 5B (MUC5B) gene: a polymorphism (rs35705950) in its promoter region is associated with the develop- ment of both sporadic and familial IPF. Subjects carrying the mu- tation demonstrate an increased expression of MUC5B in the lung, which accumulates within areas of honeycombing. This association has now been robustly replicated and the association with MUC5B was also the dominant finding in two recent genome-​wide associ- ation studies.

section 18  Respiratory disorders 4178 The mucin glycoproteins are a major structural component of the mucus barrier, maintaining the hydration of the airway epithe- lium and crucially entrapping particles for removal by mucociliary clearance. This has led to the hypothesis that excess production of MUC5B reduces mucociliary clearance of inhaled particles, re- sulting in prolonged and repetitive exposure, triggering an exagger- ated interstitial injury, and eventually leading to the development of fibrosis. Diagnostic criteria The publication of the ATS, ERS, JRS, and ALAT joint statement on IPF in 2011 marked a significant shift in the diagnostic paradigm for IPF. The major/​minor diagnostic criteria set out in previous guidelines were eliminated, and more emphasis was placed on the multidisciplinary approach to diagnosis. The role and importance of surgical lung biopsies in the diagnostic process was also re-​visited, given the emerging wealth of data regarding the specificity for the recognition of the histopathologic UIP pattern on HRCT. These 2011 diagnostic guidelines were revised and updated in 2018. The suggested diagnostic pathway (Fig. 18.11.2.1) starts with careful exclusion of known causes of interstitial lung diseases. This is achieved through a thorough history, examination, and serological testing to identify predisposing domestic and occupational envir- onmental exposures, and underlying medical conditions. A detailed family history is also necessary as some estimates suggest that up to 10% of cases of IPF are familial. If no underlying cause can be identified the patient may have IPF, and evidence of the pathognomonic lesion of UIP is sought, initially radiologically. The 2018 guidelines clearly state the precise HRCT features that meet the criteria for ‘UIP’, ‘probable UIP pat- tern’, ‘indeterminate for UIP pattern’ and ‘alternative diagnosis’. In the appropriate clinical setting, satisfaction of HRCT criteria for a pattern of UIP obviates the need for further investigations such as cellular analysis of bronchoalveolar lavage (BAL) fluid, trans- bronchial biopsy or surgical lung biopsy. By contrast, cellular ana- lysis of bronchoalveolar lavage (BAL) fluid or surgical lung biopsy should be considered when the diagnosis is thought to be probable UIP, ­indeterminate for UIP or an alternative diagnosis. The weight of combined clinical, histopathological, and radiological informa- tion is then used by a multidisciplinary team to confirm or refute a diagnosis of IPF (Table 18.11.2.1). Histological features and pathogenesis In UIP, the histological pattern underlying IPF (Fig 18.11.2.2), tem- poral and spatial heterogeneity of disease is the cardinal feature. Normal lung is seen adjacent to regions of fibrosis, with enlarged cystic air-​spaces (honeycomb lung) and areas of milder interstitial fibrosis. A patchy chronic inflammatory cell infiltrate is variably pre- sent. Subepithelial foci of proliferating fibroblasts (‘fibroblastic foci’) are a characteristic feature, occurring occasionally and sparsely in non​specific interstitial pneumonia (NSIP) but not seen in other idiopathic interstitial pneumonias. Historically, it was believed that inflammation was the key patho- genetic process, preceding and leading to fibrotic disease, but this view has been largely abandoned. Corticosteroid and immunosup- pressive therapy, effective in primary inflammatory disorders, have now been shown in large studies to confer no treatment benefit. Indeed, far from demonstrating any benefit, immunosuppression has actually proven to be harmful in IPF. There is increasing evidence that IPF has an epithelial fibrotic pathogenesis, with initial epithelial damage leading to the forma- tion of fibroblastic foci and subsequently to more widespread thick- ening of the connective tissue matrix in advanced disease. Thus, IPF can be conceptualized as a disorder of abnormal wound healing. In established disease, lung injury, an immunological and inflam- matory response, and fibrogenesis appear to occur in parallel. It is not known whether a single key mechanism is pivotal in pathogen- esis. Oxidant-​antioxidant imbalance and the release of damaging enzymes from inflammatory cells appear to amplify injury, but a wide variety of biological mechanisms interact in the lungs of pa- tients with IPF, with up-​regulation of tumour necrosis factor-​α and chemokines (interleukin 8, and growth factors, especially trans- forming growth factor-​β; and connective tissue growth factor), and activation of the coagulation cascade, known to promote fibrogenesis. However, it is not clear whether these mechanisms are primarily pathogenetic or represent physiological responses to an up-​stream abnormality. The profusion of fibroblastic foci and Patient suspected to have IPF Yes Yes No No Potential cause/associated condition Further evaluation (including HRCT) probable UIP, indeterminate for UIP, alternative diagnosis UIP BAL Surgical lung biopsy* MDD Alternative diagnosis IPF per Figure 18.11.2.2 Not IPF MDD Chest HRCT pattern Specific diagnosis Fig. 18.11.2.1  Diagnostic algorithm for idiopathic pulmonary fibrosis (IPF). If a patient is suspected of having IPF but a specific diagnosis is not made or no potential cause for interstitial lung disease (ILD) is identified, further evaluation depends on the appearances of high resolution CT images (HRCT) of the chest and clinical input from multidisciplinary discussion (MDD). IPF is diagnosed if the appropriate combination of HRCT patterns and histopathological patterns are present (see Table 18.11.2.1). From Raghu G, et al. (2018). Diagnosis of idiopathic pulmonary fibrosis: an
official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med, 198, e44–​e68.

18.11.2  Idiopathic pulmonary fibrosis 4179 serum levels of protein markers of epithelial damage have both been linked to mortality and disease progression. Clinical features The typical presentation is progressive exertional dyspnoea without wheeze and a non​productive cough, although sputum production is present in a minority of patients. Haemoptysis should prompt investigation for lung malignancy, which is approximately 10-​fold more prevalent in IPF, after the smoking history has been taken into account. Chest discomfort, fatigue, and weight loss are oc- casional features. Digital clubbing is present in over 50% of pa- tients and has been an adverse prognostic determinant in some series. On auscultation, very fine end-​inspiratory crackles are typ- ical heard bilaterally at the lung bases and become widespread in advanced disease. Central cyanosis and clinical evidence of pul- monary hypertension, with or without right ventricular failure, are late features. Investigation Chest radiography The chest radiograph typically shows small lung volumes and pre- dominantly peripheral and basal reticulonodular shadowing, with obscuration of the heart borders and diaphragms in advanced dis- ease and overt honeycombing in 10% of cases. This profile is highly non​specific, occurring in fibrotic NSIP, asbestosis, rheumatological disorders, and other fibrotic processes. Lymphadenopathy or pleural disease should suggest an alternative diagnosis or a concurrent pathological process. Cardiomegaly may occur in the absence of cardiovascular disease as a result of reduced intrathoracic volume. High resolution computed tomography HRCT appearances are virtually pathognomonic in up to 60% of pa- tients (Fig. 18.11.2.3). The disease is predominantly postero-​basal and peripheral, becoming widespread in advanced disease, and consists of a reticular pattern, with or without honeycombing, and a minor component of ground-​glass attenuation, usually indicative of fine fibrosis (rather than inflammation). It should be stressed that HRCT appearances are atypical in at least 40% of cases, with the most frequent variant consisting of prominent ground-​glass Table 18.11.2.1  Idiopathic pulmonary fibrosis (IPF) based upon HRCT and biopsy patterns IPF suspecteda Histopathology pattern UIP Probable UIP Indeterminate for UIP Alternative diagnosis HRCT pattern UIP IPF IPF IPF Non-IPF dx Probable UIP IPF IPF IPF (Likely)b Non-IPF dx Indeterminate for UIP IPF IPF (Likely)b Indeterminate for IPFc Non-IPF dx Alternative diagnosis IPF (Likely)b
/­non-IPF dx Non-IPF dx Non-IPF dx Non-IPF dx a Clinically suspected of having IPF. b IPF is the likely diagnosis when any of the following features are present: (1) moderate-to-severe traction bronchiectasis/bronchiolectasis in a man >50 years or woman >60 years; (2) >30% reticulation on HRCT at age >70 years; (3) increased neutrophils and/or absence of lymphocytosis in BAL fluid; (4) multidisciplinary discussion makes confident diagnosis of IPF. c Indeterminate for IPF—without adequate biopsy is unlikely to be IPF; with adequate biopsy may be reclassified. Source data from Raghu G, et al. (2018). Diagnosis of idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med, 198, e44–​e68. Fig. 18.11.2.2  (a) Surgical lung biopsy from a patient with IPF shows a patchy established fibrosis with a predominantly subpleural distribution. (b) At high power there is a mild degree of associated non​specific chronic inflammation with fibroblastic foci in continuity with the established fibrosis. Note the relatively sharp demarcation between normal and abnormal parenchyma.

section 18  Respiratory disorders 4180 attenuation admixed with a fine reticular pattern and associated with traction bronchiectasis: an appearance also suggestive of NSIP (Fig. 18.11.2.4). However, IPF is also diagnosed (i.e. a histological pattern of UIP at biopsy) in occasional patients with markedly atypical HRCT appearances (Fig. 18.11.2.5 a, b). Reactive medias- tinal lymphadenopathy is usual on HRCT and is not indicative of a coexisting disease process unless also present on chest radiography. In early disease, prone HRCT sections may be required to distin- guish abnormal appearances from normal increases in density due to gravity-​related increases in perfusion in dependent areas. Other imaging modalities Ventilation–​perfusion scans show ventilation mismatch due to vascular ablation in areas of cystic lung, which typically continue to ventilate normally. These appearances simulate pulmonary thromboembolism and probably account for a widespread misper- ception that pulmonary embolism is a frequent complication of IPF. CT pulmonary angiography is required when pulmonary embolism is suspected, especially when DLco levels are disproportionately re- duced, but is usually negative in this context. Lung function tests Lung function tests reveal a restrictive ventilatory defect, as shown by reductions in vital capacity, total lung capacity, re- sidual volume, and pulmonary compliance. However, the wide range in normal premorbid lung volumes sometimes results in apparent normality (when lung volumes have fallen from the upper to the lower end of the normal range). Thus, meas- ures of gas transfer, especially DLco levels, may be reduced in isolation in early disease. Adjustment of DLco for reduced alveolar volume (Kco) has been advocated, as a more specific index of interstitial fibrosis, but Kco levels are disproportion- ately reduced by coexistent emphysema, which is present in over 30% of IPF patients. The combination of emphysema and IPF may result in spurious preservation of lung volumes, even Fig. 18.11.2.3  HRCT scan of a patient with biopsy-​proven IPF. Appearances are typical of IPF with a subpleural distribution of microcystic and macrocystic honeycomb change. Fig. 18.11.2.4  HRCT scan of a patient with biopsy-​proven IPF showing abnormalities that overlap in appearance with those seen in non​specific interstitial pneumonia. Disease is predominantly subpleural but consists of a mixture of ground-​glass attenuation and fine reticular abnormalities, without honeycombing. This appearance is seen in a significant minority of IPF patients. Fig. 18.11.2.5  (a and b) HRCT scans in patients with biopsy-​proven IPF, but in both cases the HRCT appearances are markedly atypical, with no features indicative of IPF or of any other form idiopathic interstitial pneumonia. IPF should always be suspected when disease is inexorably progressive and HRCT appearances are difficult to classify.

18.11.2  Idiopathic pulmonary fibrosis 4181 in advanced disease, and disproportionate reduction in DLco levels. Overall, the severity of disease is most accurately cap- tured by DLco levels, which correlate best with the extent of IPF, as judged by HRCT findings. In early disease, arterial gases may be normal but mild arterial hypoxia with widening of the alveolar-​arterial gradient and normal or low Paco2 levels are usual. Severe hypoxia is a late feature and increased Paco2 levels occur in terminal disease. Blood tests Blood tests contribute little to the management of IPF, except in rare cases in which an unsuspected underlying cause is identified. Mild increases in the erythrocyte sedimentation rate, serum immuno- globulins, rheumatoid factor, and antinuclear antibodies are fre- quent and in severe disease, secondary polycythaemia may occur. A high neutrophil count may be indicative of infection but a mod- erate increase is also seen in association with corticosteroid therapy. However, striking increases in autoantibodies may be indicative of a hitherto undiagnosed rheumatological disorder. Precipitin tests against fungal and avian antigens should be performed when there is suggestive exposure history, as chronic extrinsic allergic alveolitis occasionally presents with HRCT appearances suggestive of IPF and a pattern of UIP at surgical biopsy. Bronchoalveolar lavage Bronchoalveolar lavage is a useful ancillary diagnostic test when a surgical biopsy is not performed. Typically, there is an increase in total cell counts and an excess of neutrophils and/​or eosinophils is usual. A mild lymphocytosis is not infrequent but striking rises in lymphocyte counts are not generally a feature of IPF and suggest an alternative disorder such as NSIP, hypersensitivity pneumonitis, fi- brotic sarcoidosis, cryptogenic organizing pneumonia complicated by interstitial fibrosis or drug-​induced lung disease. Bronchoalveolar lavage is occasionally useful in excluding opportunistic infection in treated patients. Echocardiography Based upon recent reports of a high prevalence of pulmonary hyper- tension in IPF, routine echocardiography is warranted at presen- tation and in patients subsequently developing disproportionate hypoxia or a selective serial reduction in DLco. In some IPF pa- tients, the development of pulmonary hypertension is a feature of end-​stage disease, but in other cases, early pulmonary hypertension occurs, not associated with major functional impairment due to interstitial lung disease. Surgical lung biopsy A surgical lung biopsy is the histological diagnostic procedure of choice. Video-​assisted thoracoscopic biopsy is the most widely used procedure but mini-​thoracotomy is occasionally required in ad- vanced disease. It is strongly recommended that at least two sites are biopsied and HRCT findings should be taken into account to ensure that the full spectrum of morphological abnormalities is sampled, and to avoid areas of end-​stage disease which seldom yield diagnostic tissue. The diagnosis of IPF and other idiopathic interstitial pneu- monias cannot be based upon appearances at transbronchial biopsy, as larger biopsies are required to determine whether abnormalities are spatially heterogeneous or truly homogeneous (as in NSIP), a crucial discriminatory diagnostic feature. Diagnosis Once suspected in the symptomatic patient, IPF is usually easy to detect using lung function tests and chest radiography, but in early disease HRCT be required to confirm or exclude interstitial lung disease. However—​as discussed earlier—​clinical, chest radio- graphic features and physiological features are highly non​specific in discriminating between individual idiopathic interstitial pneu- monias, and HRCT plays a crucial role in this regard. In most pa- tients with IPF, HRCT appearances are diagnostic in an appropriate clinical setting and it is seldom necessary to confirm the diagnosis with invasive techniques, especially when a typical course of re- lentless progression is already apparent. However, in a significant number of patients diagnostic imprecision leads to major prognostic and management uncertainties, and brochoalveolar lavage and/or a diagnostic surgical lung biopsy is warranted. Thus, these investiga- tions should not be performed by protocol in all cases but should be reserved for situations in which it appears realistic that clinician perceptions of best management, including treatment and the ap- proach to monitoring, might change significantly with the addition of additional information. In less typical cases, findings at bronchoalveolar lavage may play an important ancillary role in excluding alternative disorders such as hypersensitivity pneumonitis and respiratory bronchiolitis with associ- ated interstitial lung disease (characterized by a striking lymphocytosis and a marked increase in pigmented macrophages, respectively). It should be stressed that the distinction between IPF and fibrotic NSIP (discussed in Chapter 18.11.1), based upon clinical and HRCT features, poses particular difficulty. Even when HRCT appearances are considered typical for NSIP, there is a significant likelihood that a surgical biopsy will disclose a pattern of UIP, indicative of a worse outcome. In difficult cases it is essential to review the diagnosis in a multidisciplinary meeting, with the reconciliation of clinical and radiological features, in order to confirm that a diagnostic surgical biopsy is truly required. This decision is often difficult when IPF is likely, due to patient age (typically advanced), disease severity, and the presence of comorbidity, especially cardiovascular disease. The threshold for performing a biopsy is increased in patients aged over 65 years and when DLco levels are less than 35% of predicted, as both factors are associated with a significant increase in morbidity and the latter with an increase in exacerbations following biopsy. It is also important that histological findings are no longer viewed as a diagnostic ‘gold standard’ in interstitial lung disease, although usually more diagnostically influential than clinical and HRCT fea- tures when the diagnosis is uncertain. A multidisciplinary diag- nosis, made by negotiation between clinicians, radiologists, and pathologists, is now considered optimal. A histological pattern other than UIP is considered to exclude IPF, with one important caveat: ‘sampling error’ (i.e. a biopsy taken from a non​representative site) should be kept in mind when HRCT findings and the subse- quent clinical course are strongly suggestive of IPF. Conversely, when UIP is disclosed at biopsy, the final consensus diagnosis sometimes differs from the histological diagnosis. This applies

section 18  Respiratory disorders 4182 especially to patients with clinical evidence of hypersensitivity pneumonitis or a rheumatological disorder. Prognostic evaluation Accurate diagnosis is central to prognostic evaluation. The five-​ year survival approximates 10–​15% in IPF, as compared to over 60% in fibrotic NSIP and over 90% in patients with predominantly inflammatory idiopathic interstitial pneumonias. Until recently it was believed that all patients exhibited a gradual but relentless decline in lung function reflecting the development of progressive fibrosis. However, the clinical course of individual patients with IPF is actually variable and unpredictable, with some experiencing long periods of relative stability and some a steady decline, while others rapidly deteriorate (Fig. 18.11.2.6). There is currently no way to accurately predict the clinical course, although several adverse prognostic factors have been identified (summarized in Table 18.11.2.2). Increasing age has consistently been an adverse prognostic determinant although it is not clear whether disease is, on average more progressive in older people or, as seems more likely, comorbidity (cardiac disease and malignancy) is largely responsible for an adverse outcome. Disease extent and severity at presentation is a crucial consid- eration. Increased mortality is associated with severe functional impairment, with DLco levels providing the most accurate guid- ance to likely outcome among lung function tests performed at rest. A composite physiological index, containing DLco, FVC, and FEV1 levels, has been shown to predict survival more accurately than any single lung function test in isolation. Severe resting hyp- oxia is indicative of a very poor outcome. Maximal exercise testing is advocated as a superior prognostic de- terminant by some authorities but, in reality, there are no convincing data establishing that maximal exercise data are superior to DLco levels in this regard. However, desaturation below 88% during a six-​ minute walk test has consistently identified IPF patients with a much worse outcome in several series. It is not yet clear whether desat- uration during exercise is primarily linked to incipient pulmonary hypertension. The presence of moderate to severe pulmonary hyper- tension is indicative of a very poor outcome. HRCT features have also been linked to outcome, with prom- inent honeycombing associated with a high short-​term mortality, although this finding may partially reflect an association between severe honeycombing and extensive disease. Patients with biopsy-​ proven IPF and HRCT appearances suggestive of NSIP have a better outcome than patients with HRCT appearances ­typical of IPF. Smoking status may also be important, based on the observation of a better outcome in IPF in current smokers, than in ex-​smokers and lifelong non​smokers. However, it is not clear whether this pro- vocative observation represents less progressive disease in current smokers, or merely a ‘healthy smoker effect’ (with smoking cessation linked to more advanced disease). Observed disease behaviour in patients with IPF is more prog- nostically accurate than observations made at a single point in time. Serial changes in FVC have consistently predicted mortality more reliably than baseline data: serial DLco trends have been similarly predictive in some but not all reports. Worsening fibrosis on serial imaging or increased dyspnoea both also predict an increased mor- tality. The distinction between stability and significant decline at 12 months is particularly useful. Once this information is known, in mixed patient populations with UIP or fibrotic NSIP, the histo- logical diagnosis provides no additional prognostic information. Onset of disease Onset of symptoms Diagnosis A B C D Subclinical period Prediagnosis period Death 1 yr 2 yr 3 yr 4 yr 5 yr 6 yr Time Disease progression Post-diagnosis period Fig. 18.11.2.6  The potential clinical courses of idiopathic pulmonary fibrosis (IPF). The rate of decline may be rapid (a) or slow (c and d). Acute exacerbations (indicated by the black stars) can affect either course and here creates a mixed picture (curve b). From Ley B, Collard HR, and King Jr. TE (2011). Clinical Course and Prediction of Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med, 183, 431–​40.

18.11.2  Idiopathic pulmonary fibrosis 4183 Routine monitoring Lung function tests have traditionally been used to identify treat- ment responsiveness (in inflammatory disorders) and deterioration (in IPF and other fibrotic disorders). However, measurement vari- ation is a limitation which requires the use of thresholds for ‘sig- nificant change’. A 10% change from baseline FVC levels, or a 15% change from baseline DLco levels, is required to identify definite regression or progression of disease: the greater measurement vari- ation in DLco may explain the fact that serial FVC trends are more predictive of longer-​term outcome than serial DLco trends. It is also important to recognize that the interpretation of serial lung function must be modified in some contexts. Concurrent em- physema often has a major confounding effect on lung function tests, with spurious preservation of FVC levels, but a disproportionate re- duction in DLco (which is reduced in both disorders). In this con- text, a selective serial decline in DLco levels may be seen, with no change in FVC despite significant progression of disease. A selective reduction in DLco may also be indicative of incipient pulmonary hypertension. Thus, serial lung function trends must be integrated with clinical, HRCT and (when indicated) echocardiographic infor- mation. In advanced disease with increasing hypoxia, detailed lung function tests are often impracticable and serial tests tend to be less informative than observations of changes in oxygen saturation (in the steep component of the oxygen dissociation curve). A marginal reduction in lung function indices (a 5–​10% change in FVC levels, a 10–​15% change in DLco levels) commonly causes dif- ficulties for clinicians. These changes may indicate true disease pro- gression in some patients, but lie within the measurement variation of lung function tests. Symptomatic change is sometimes a useful guide in this difficult scenario, but is sometimes misleading. Exertional dyspnoea may increase because of disease progression, loss of fitness, comorbidity, or weight gain and myopathy due to corticosteroid therapy. Serial HRCT is sometimes informative, with clear evidence of disease progression in the context of marginal lung function de- cline. However, serial HRCT should be reserved for situations in which the demonstration of disease progression is likely to influence management: it is difficult to assign significance to minor change on HRCT in the absence of lung function deterioration. In IPF, the intensity of monitoring is critically dependent upon the therapeutic goal. Regular monitoring at three to four monthly intervals is especially important in patients receiving treatment, especially novel therapies, and when referral for lung transplant- ation is contemplated. In other cases, in which no change in therapy is contemplated, less frequent monitoring may be appropriate. However, the importance of best supportive care, including the cor- rect use of oxygen in advanced disease, justifies continued moni- toring in the long term. Treatment The last decade has seen important developments in the treatment of IPF, with several well-​conducted negative randomized controlled trials reshaping the therapeutic landscape. Previous therapeutic ap- proaches based around immunosuppression have been shown to be harmful, while compounds with antifibrotic actions have been found to slow decline in lung function. Immunosuppressive agents Historically, unsuccessful treatments for IPF were targeted at redu- cing inflammation, which was incorrectly felt to be the predominant underlying disease process. Large studies have shown no benefits with corticosteroids, and similar results were seen when studying the use of the immunosuppressive agents azathioprine, ciclosporin, and cyclophosphamide. Indeed, far from demonstrating any benefit of immunosuppression with the previous mainstay of treat- ment, namely a combination of prednisone, azathioprine, and N-​ acetylcysteine, this has actually proven to be harmful compared to placebo in IPF. Immunomodulatory drugs including IFN-​γ, IFN-​β, Imatinib, and Etanercept have all been trialled, and despite initial suggestions of benefits in small pilot studies, none have gone on to show any impact on disease progression or survival in larger studies. Antifibrotic agents In contrast to negative trials targeting inflammation, two antifibrotic compounds, pirfenidone and nintedanib, have now been proven to slow functional decline in IPF. Pirfenidone, a novel antifibrotic agent with antioxidant and anti-​inflammatory effects, became the first drug to be licensed specifically for the treatment of IPF in Europe and the United States. Four randomized controlled trials have now demon- strated that treatment with pirfenidone reduces lung function decline, improves progression-​free survival, and reduces all cause mortality at 12 months. It is generally well tolerated, with most side effects related to gastrointestinal symptoms, photosensitivity, and fatigue. These all tend to be mild and easily managed with either life style modifications or dose reduction. Indeed, effective patient education prior to com- mencement can often avoid significant side effects all together. Nintedanib is a tyrosine kinase receptor antagonist that inhibits key profibrotic growth factors, platelet-​derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF). Two large phase 3 randomized trials demon- strated that, compared with placebo, nintedanib consistently slowed disease progression by significantly reducing the annual rate of Table 18.11.2.2  Features associated with a worse outcome in IPF, with evidence graded as possible but uncertain (+/​–​), definite and moderately useful in routine practice (+), or definite and highly predictive (++). Features associated with a worse outcome Grade of evidence Increasing age ++ Male gender +/​–​ Former smoking (versus current smoking) +/​–​ High profusion of fibroblastic foci at biopsy + Prominent honeycombing on HRCT ++ Presence of pulmonary hypertension ++ Moderate impairment of lung function + Resting hypoxia ++ Major desaturation on maximal exercise testing + Major desaturation during a six-​minute walk test ++ Increasing dyspnoea + Serial decline in FVC or DLco ++

section 18  Respiratory disorders 4184 decline in FVC. There is also a suggestion it may decrease the risk of acute exacerbations of IPF in subjects with more mild disease. It is generally well tolerated, with most side effects gastrointestinal. Up to 60% of subjects in clinical trials experienced diarrhoea, but this was easily managed, and tellingly almost all subjects involved elected to continue with the medication in the following open label phase. Both pirfenidone and nintedanib slow the decline in FVC in IPF and are now licensed in Europe and the United States for the treat- ment of mild to moderate IPF (FVC 50–​80% predicted). There is no head to head data, and currently little information on the potential for combination therapy. The decision as to which agent to use as first-​line treatment is therefore currently based on clinician experi- ence, patient preference, lifestyle, medical history, and concomitant medication. The availability of two agents means that patients in- tolerant of one can switch, and in the future there may be options for combination or add-​on therapy. Acute exacerbations In 10–​15% of patients each year there is an accelerated deterior- ation occurring over several weeks and often leading rapidly to a fatal outcome. Pneumonia, heart failure, and pulmonary thrombo- embolic disease are sometimes the trigger, but the cause for many of these episodes, termed acute exacerbations of IPF, remains poorly understood. Patients typically present with symptoms of worsening dyspnoea, cough, and fever, which are insidious in onset. Investigations focus on excluding known and treatable causes of deterioration, such as infection, heart failure, and pulmonary em- bolism. After these known causes of deterioration have been ex- cluded and a formal diagnosis of an acute exacerbation of IPF has been made, the treatment remains largely empirical and centred around treating the very same triggers already excluded, with al- most all patients initially receiving empirical broad-​spectrum antibiotics. If there is no response to antibiotics then patients will subsequently receive trials of high-​dose corticosteroids (e.g. 1 g/​day methylprednisolone for 3 days), which are either tapered to a lower dose or discontinued based upon clinical response. While these treatments are given, careful attention is paid to optimizing fluid balance status and providing supplementary oxygen therapy. Non-​ invasive ventilation is sometimes useful, but mechanical ventilation should be avoided due to a uniformly poor outcome. Transplantation Single lung transplantation remains the preferred procedure. As in other end-​stage lung diseases, a 3-​year survival rate of over 50% can be achieved, but a worse outcome is seen in severely deconditioned patients and over the age of 65. The rapidly progressive nature of IPF, compared to other chronic lung diseases, demands the early referral of suitable cases to a transplant centre, ideally before DLco levels fall below 30% of predicted normal. Supportive therapy Supportive therapy is central to the management of advanced dis- ease. Supplemental oxygen can be provided in the home through oxygen concentrators, and ambulatory oxygen may be beneficial in improving exercise tolerance. The prompt treatment of compli- cations, including infection and heart failure (sometimes triggered by hypoxia) is also important. In terminal disease, small dosages of opiates alleviate the distressing severe dyspnoea associated with striking reductions in lung compliance. It is difficult for patients and family members to come to terms with the chronic, relentlessly progressive nature of IPF. The input of medical and non​medical health-​care professionals is indispens- able to optimal supportive management: social workers, physiother- apists, and occupational therapists all have important roles to play. Rehabilitation programmes may benefit some patients, although less likely to be useful in preterminal disease. FURTHER READING Azuma A, et  al. (2005). Double-​blind, placebo-​controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 171, 1040–​7. Carrington CB, Gaensler EA, Coutu RE (1978). Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med, 298, 801–​9. Collard HR, King TE Jr, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK (2003). Changes in clinical and physiologic variables pre- dict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 168, 538–​42. Demedts M, et al. (2005). High-​dose acetylcysteine in idiopathic pul- monary fibrosis. N Engl J Med, 353, 2229–​42. Flaherty KR, et al. (2003). Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am J Respir Crit Care Med, 168, 543–​8. Flaherty KR, et al. (2003). Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax, 58, 143–​8. Flaherty KR, et al. (2004). Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med, 170, 904–​10. Gay SE, et al. (1998). Idiopathic pulmonary fibrosis: predicting response to therapy and survival. Am J Respir Crit Care Med, 157, 1063–​72. Heukels P, et al. (2019). Inflammation and immunity in IPF pathogen- esis and treatment. Respir Med, 147, 79–91. Hunninghake GW, et al. (2001). Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 164, 193–​6. Joint Authors Group (2000). Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med, 161, 646–​64. Katzenstein AL, Myers JL (1998). Idiopathic pulmonary fibrosis: clin- ical relevance of pathologic classification (review). Am J Respir Crit Care Med, 157, 1301–​15. King TE, et al. (2014). A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med, 370, 2083–​92. King TE, et al. (2001). Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med, 164, 1171–​81. King TE, et al. (2001). Idiopathic pulmonary fibrosis: relationship be- tween histopathologic features and mortality. Am J Respir Crit Care Med, 164, 1025–​32. Lama VN, et al. (2003). Prognostic value of desaturation during a six-​ minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med, 168, 1084–​90. Latsi PI, et al. (2003). Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am J Respir Crit Care Med, 168, 531–​7. Maher TM, Strek ME (2019). Antifibrotic therapy for idiopathic pul- monary fibrosis: time to treat. Respir Res, 20(1), 205. doi: 10.1186/ s12931-019-1161-4. Mogulkoc M, et  al. (2001). Pulmonary function in idiopathic pul- monary fibrosis and referral for lung transplantation. Am J Respir Crit Care Med, 164, 103–​8.

18.11.3 Bronchiolitis obliterans and cryptogenic o

18.11.3 Bronchiolitis obliterans and cryptogenic organizing pneumonia 4185 Vasilis Kouranos and A.U. Wells

18.11.3  Bronchiolitis obliterans and cryptogenic organizing pneumonia 4185 Raghu G, et al. (2011). An Official ATS/​ERS/​JRS/​ALAT Statement: idio- pathic pulmonary fibrosis: evidence-​based guidelines for diagnosis and management. Am J Respir Crit Care Med, 183, 788–​824. Raghu G, et al. (2012). Prednisone, azathioprine, and N-​acetylcysteine for pulmonary fibrosis. N Engl J Med, 366, 1968–​77. Raghu G, et al. (2015). An official ATS/​ERS/​JRS/​ALAT clinical prac- tice guideline: Treatment of idiopathic pulmonary fibrosis: an up- date of the 2011 clinical practice guideline. Am J Respir Crit Care Med, 192, e3–​19. Raghu G, et al. (2006). Incidence and prevalence of idiopathic pul- monary fibrosis. Am J Respir Crit Care Med, 174, 810–​16. Raghu G, et al. (2018). Diagnosis of idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med, 198, e44–e68. Richeldi L, et al. (2014). Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med, 370, 2071–​82. Seibold MA, et  al. (2011). A common MUC5B promoter poly- morphism and pulmonary fibrosis. N Engl J Med, 364, 1503–​12. Steele MP, et al. (2005). Clinical and pathologic features of familial interstitial pneumonia. Am J Respir Crit Care Med, 172, 1146–​52. Wells AU, et al. (2003). Idiopathic pulmonary fibrosis: a composite physiologic index derived from disease extent observed on com- puted tomography. Am J Respir Crit Care Med, 167, 962–​9. Wolters PJ, et al. (2018). Time for a change: is idiopathic pulmonary fibrosis still idiopathic and only fibrotic? Lancet Respir Med,
6, 154–60. 18.11.3  Bronchiolitis obliterans and cryptogenic organizing pneumonia Vasilis Kouranos and A.U. Wells ESSENTIALS The nomenclature of the bronchiolitides is complicated by the interchangeable use of pathological and clinical descriptions and a diversity of classification systems. The four primary histological patterns are (1)  organizing pneumonia (also termed proliferative bronchiolitis and bronchiolitis obliterans organizing pneumonia); (2) bronchiolitis obliterans (also termed obliterative bronchiolitis and constrictive bronchiolitis); (3) follicular bronchiolitis; and (4) diffuse panbronchiolitis. Organizing pneumonia—​the most characteristic abnormality is a filling of alveoli with granulation tissue and buds of loose col- lagen and connective tissue matrix cells with a uniform appearance. Presentation is typically subacute with nonproductive or minimally productive cough, insidious dyspnoea, and systemic symptoms including malaise, fever, or chills, weight loss, and myalgia. Clinical signs are nonspecific. The chest radiograph most commonly shows patchy bilateral peripheral consolidation, which is often basal, and serial radiographs often show migration of infiltrates. High-​reso- lution CT most often shows focal subpleural consolidation, with or without air bronchograms. Corticosteroid therapy is usually effective, with other immunosuppressive agents given to fulminant cases or those that do not respond. Prognosis is usually good, with overall mortality less than 5%. Bronchiolitis obliterans—​results from progressive obliteration of the terminal bronchioles with connective tissue matrix, which is cryptogenic in most cases. The usual presentation is with progres- sive breathlessness and the most characteristic physical finding is of inspiratory ‘squawks’, which are reliably indicative of small airway disease. High-​resolution CT is often diagnostic, revealing focal areas of decreased attenuation representing regional gas-​trapping and associated hypoperfusion, termed ‘mosaic attenuation’ or ‘mo- saic perfusion’. The disease is not responsive to treatment, but in cases of diagnostic uncertainty it is reasonable to institute a trial of corticosteroids. Follicular bronchiolitis—​results from polyclonal hyperplasia of lymphoid follicles with formation of germinal centres within the bronchiolar walls. Patients usually present with progressive breath- lessness, cough, and symptoms of recurrent respiratory infection. high-​resolution CT invariably reveals centrilobular nodules less than 3 mm in diameter. Prognosis is generally good. Diffuse panbronchiolitis—​is characterized by bronchiolocentric in- flammation, lymphoid hyperplasia, and an accumulation of intersti- tial foam cells in the lungs. Patients (most typically Japanese) present with subacute symptoms of cough productive of purulent sputum, dyspnoea, and sometimes weight loss. Survival has been transformed by the use of long-​term, low-​dose erythromycin therapy. Introduction The bronchioles are airways without cartilaginous support and include the terminal bronchioles and the respiratory bronchi- oles which lead to the alveolar ducts. The nomenclature of the bronchiolitides is complicated by the interchangeable use of patho- logical and clinical descriptions and a diversity of classification systems. The four primary histological patterns are organizing pneumonia (also termed proliferative bronchiolitis and bronchio- litis obliterans organizing pneumonia), bronchiolitis obliterans (also termed obliterative bronchiolitis and constrictive bronchio- litis), follicular bronchiolitis, and diffuse panbronchiolitis. All four disorders may ablate or obstruct the bronchioles. Organizing pneu- monia and bronchiolitis obliterans may be associated with other disease processes (Table 18.11.3.1). The terminological similarity between bronchiolitis obliterans and an unrelated acinar disorder, bronchiolitis obliterans organizing pneumonia (BOOP), causes particular confusion as the terms are commonly but incorrectly re- garded as synonymous. Because of this widespread confusion bron- chiolitis obliterans and BOOP are covered in the remainder of this chapter, as are follicular bronchiolitis and diffuse panbronchiolitis, although BOOP is properly an idiopathic interstitial pneumonia, as recently reclassified by an American Thoracic Society/​European Respiratory Society nomenclature committee. The term ‘cryptogenic organizing pneumonia’ is preferable to BOOP, but it is likely that both terms will continue to appear in the medical literature for the foreseeable future. Cryptogenic organ- izing pneumonia/​BOOP also involves the bronchioles, but these are not truly obliterated and instead are filled with loose intraluminal

section 18  Respiratory disorders 4186 fibrous tissue. The clinical presentation, radiological features, physiological features, and responsiveness to treatment differ rad- ically between bronchiolitis obliterans and cryptogenic organizing pneumonia (Table 18.11.3.2). Essentially, bronchiolitis obliterans is an irreversible disorder of small airways whereas cryptogenic organizing pneumonia is a largely reversible disorder of the lung interstitium. Bronchiolitis obliterans In common with other forms of bronchiolitis, bronchiolitis obliterans is associated with certain triggers but is cryptogenic in most cases. A viral pathogenesis is often proposed based on the fact that the dis- ease often presents following an apparent respiratory infection, but this is unproven. Occasionally, bronchiolitis obliterans precedes the development of an overt rheumatological disorder. The disease results from progressive obliteration of the terminal bronchioles with connective tissue matrix. In early reports it was found to progress relentlessly to a fatal outcome. With the advent of CT and the detection of less advanced disease, it is now clear that the natural history is highly variable. Although inexorable progression occurs in some patients, especially those with rheum- atological disease, an indolent course is probably more frequent, and some patients who appear to develop the disease after a se- vere viral insult do not progress even when there is severe airflow obstruction. Histopathology The terminal bronchioles are predominantly affected, with vari- able involvement of the proximal respiratory bronchioles. There is fibrotic obliteration of the airway lumen with an occasional inflammatory component, especially in rheumatological disease (Fig. 18.11.3.1). Diagnostic appearances may be lost in advanced disease as a result of airway occlusion by dense connective tissue matrix, which may render the airways invisible. Clinical features The usual presentation is with progressive breathlessness. Wheeze and a sensation of chest tightness are occasionally present as non-​ specific consequences (respectively) of constriction of small airways and hyperinflation. Nonproductive cough is frequent, but haem- optysis is not a feature. On examination an expiratory wheeze is occasionally heard, but the more characteristic finding is of inspira- tory ‘squawks’, which are reliably indicative of small airway disease. There may be subtle evidence of rheumatological disease, especially rheumatoid arthritis. Investigations Imaging Chest radiography is normal until disease is advanced. The typical findings are nonspecific, consisting of large lung fields with vari- able loss of vascular markings (indicative of hyperinflation) but no interstitial abnormalities. High-​resolution CT is often diagnostic (Fig. 18.11.3.2). There are focal areas of decreased attenuation representing regional gas-​trapping and associated hypoperfusion, termed ‘mosaic attenuation’ or ‘mosaic perfusion’. Such an appear- ance is occasionally present in pulmonary vascular disease, but mo- saicism on CT is enhanced on expiration in bronchiolitis obliterans as density contrasts due to regional gas-​trapping are exaggerated. Bronchiectasis and bronchial wall thickening are usually present, hence it is sometimes difficult to distinguish bronchiolitis obliterans from bronchiectasis (in which ‘mosaic attenuation’ indicative of small airways involvement is generally present). Lung function tests Lung function tests show fixed airflow obstruction with an increase in residual volume and total lung capacity. Preservation of the total Table 18.11.3.1  Causes of bronchiolitis obliterans and organizing pneumonia Cause Bronchiolitis obliterans Organizing pneumonia Infection Viral, mycoplasma Viral, bacterial, fungal, parasites Rheumatological disease Especially rheumatoid arthritis, Especially dermato/​polymyositis, rheumatoid arthritis Transplantation Bone marrow, heart/​lung, lung Bone marrow, lung Drugs E.g. penicillamine E.g. amiodarone, sulphasalazine, gold, minocycline Other Toxicity from inhaled gases, smoke Radiotherapy Malignant haematological disorders Immunodeficiency syndromes Cryptogenic Cryptogenic Cryptogenic Table 18.11.3.2  Contrasting features of bronchiolitis obliterans and organizing pneumonia Bronchiolitis obliterans Organizing pneumonia Histology Obliteration of bronchioles Bronchioles filled with loose fibrous tissue Chest radiography Hyperinflation Consolidation High-​resolution CT Mosaic attenuation Consolidation, with occasional reticular elements Pulmonary function tests Airflow obstruction Restrictive defect Response to therapy Invariably poor Good in most cases

18.11.3  Bronchiolitis obliterans and cryptogenic organizing pneumonia 4187 gas transfer for carbon monoxide (DLco), except when the forced expiratory volume is 1 s (FEV1) is less than 1 litre, is a useful an- cillary feature distinguishing between intrinsic airway disease and emphysema. The gas transfer index (total gas transfer corrected for alveolar volume) is preserved even when airflow obstruction is se- vere. Arterial gases at rest remain normal until disease is advanced. Other investigations Blood tests show no diagnostic features except when autoantibodies are indicative of unsuspected rheumatological disease. In mild to moderate disease bronchoalveolar lavage shows a characteristic neutrophilia, and absence of eosinophilia may help to distinguish between bronchiolitis obliterans and refractory asthma. Lavage should not be performed in advanced disease as it may cause re- spiratory decompensation. Differential diagnosis The chronic airflow obstruction of bronchiolitis obliterans is indistin- guishable from the chronic airflow obstruction seen in emphysema, bronchiectasis, in some patients with asthma, and in bronchiolitis obliterans complicating other disorders. The diagnosis can gener- ally be made with confidence by reconciling patterns of functional impairment with high-​resolution CT appearances. Preserved gas transfer distinguishes intrinsic airways disease from emphysema. The appearances on high-​resolution CT are often diagnostic of small airways disease and help exclude emphysema as a cause of airflow obstruction. The auscultatory finding of inspiratory ‘squawks’ is also strongly indicative of the diagnosis. In early disease the clinical and radiological features may overlap with those of bronchiectasis, but the obstructive defect tends to be much more severe in bronchiolitis obliterans. A surgical biopsy is seldom required to make the diag- nosis and is contraindicated in severe airflow obstruction. Treatment The disease is not responsive to treatment. In cases of diagnostic un- certainty it is usual to institute a trial of corticosteroids (e.g. pred- nisolone 40 mg/​day for 4 weeks). A significant objective response, based on an improvement in lung function tests, is suggestive of an alternative bronchiolar disorder. Following any response the cortico- steroid dosage should be tapered and the minimum maintenance dose should be established. Inhaled steroid therapy and long-​acting β2-​adrenoceptor agents such as salmeterol or eformoterol are occa- sionally efficacious in this context. However, in irreversible disease there is no proven role for long-​term corticosteroid or immunosup- pressive therapy. Supportive measures play a crucial role. Patients with bronchio- litis obliterans have difficulty in clearing infective secretions, and in indolent disease prolonged infection may be associated with irre- versible worsening of the functional defect. A policy of early anti- microbial therapy for respiratory infection is essential. Enrolment in a pulmonary rehabilitation programme is appropriate in advanced disease. For younger patients with inexorably progressive disease, lung transplantation is the only treatment known to improve life ex- pectancy. There is no evidence that post-​transplantation obliterative bronchiolitis, the most common lethal complication of lung trans- plantation, is more prevalent in patients transplanted for bronchio- litis obliterans. Organizing pneumonia Introduction Organizing pneumonia is a disorder of unknown cause originally described as a clinicopathological entity by Davidson in 1983. Epler and colleagues described a larger series of patients with similar clinical and histological abnormalities which they referred to as ‘bronchiolitis obliterans organizing pneumonia’ (BOOP) in 1985. Cryptogenic organizing pneumonia is the preferred term because it better describes the clinical and pathological findings, which are Fig. 18.11.3.1  A case of bronchiolitis obliterans showing virtual occlusion of the bronchiole by a mixture of fibrosis and a chronic inflammatory cell infiltrate that includes scattered eosinophils. Fig. 18.11.3.2  High-​resolution CT scan in a patient with severe bronchiolitis obliterans. There is extensive decreased attenuation, indicative of severe gas-​trapping, with small areas of increased density representing normal interstitium. There is also severe bronchiectasis, a frequent ancillary finding in advanced bronchiolitis obliterans.

section 18  Respiratory disorders 4188 those of an acinar rather than an airway disease, and because the term BOOP is often confused with bronchiolitis obliterans. Organizing pneumonia can be associated with several other disorders (listed in Table 18.11.3.1) and is then called ‘secondary organizing pneumonia’. The clinical features of cryptogenic and sec- ondary disease are very similar, but the distinction is important be- cause the prognosis of secondary disease is often worse. Histopathology The most characteristic abnormality is a filling of alveoli with granu- lation tissue and buds of loose collagen and connective tissue ma- trix cells with a uniform appearance (Fig. 18.11.3.3). Fibroblasts are embedded in a myxoid matrix containing a variable infiltrate of inflammatory cells forming characteristic polypoid masses known as Masson bodies or ‘bourgeons conjunctifs’. The distribution is peribronchial, and airways distal to the terminal bronchiole are also involved. There is variable surrounding chronic inflammation. Supervening interstitial fibrosis, an occasional feature, usually has a pattern of nonspecific interstitial pneumonia. Clinical features The incidence and prevalence are unknown. The disease most com- monly presents in the sixth and seventh decade, but the age range (20–​80 years) is wide. In young adults, underlying rheumatological disease should be suspected. There is no gender predilection. Most patients are non-​ or ex-​smokers. Presentation is typically subacute with nonproductive or minim- ally productive cough, insidious dyspnoea, and systemic symptoms including malaise, fever, or chills, weight loss, and myalgia. Wheeze and haemoptysis are rare. Symptoms usually develop over several months and may be preceded by a suspected respiratory tract in- fection. Rarely, the condition may present as a fulminating illness with acute respiratory failure, and by contrast the disorder can pre- sent (5–​20% of cases) as an incidental radiological abnormality in an asymptomatic patient, most typically a solitary pulmonary nodule, usually in the upper lobes. Clinical signs are nonspecific: focal or more widespread crackles are usually, but not always, present. Digital clubbing does not occur. Systemic abnormalities suggestive of rheumatological disease are often subtle and easily overlooked. Investigations Imaging The chest radiograph most commonly shows patchy bilateral per- ipheral consolidation, which is often basal. Serial radiographs often show migration of infiltrates, a useful diagnostic feature. Extensive reticulonodular abnormalities predominate in occasional cases with extensive supervening interstitial fibrosis. Presentation with a soli- tary pulmonary nodule is sometimes termed ‘unifocal organizing pneumonia’. Pleural abnormalities are rare. High-​resolution CT scans most often show focal subpleural consolidation, with or without air bronchograms (Fig. 18.11.3.4). Ground-​glass attenuation is commonly present and sometimes pre- dominates, especially in patients with immune deficiency. Other occasional abnormalities include small (<10 mm) nodules along the bronchovascular bundles, larger nodules, and peripheral re- ticular abnormalities, denoting supervening fibrosis. The most frequent atypical variant consists of consolidation surrounding bronchovascular bundles, often associated with fibrotic abnormal- ities and more prevalent in organizing pneumonia complicating polymyositis/​dermatomyositis. Lung function tests Lung function tests show a restrictive ventilatory defect without coexisting airflow obstruction, and reduced gas transfer. Disproportionate hypoxia may occur due to shunting through di- lated vessels within consolidated lung even in apparently limited disease. Fig. 18.11.3.3  A case of organizing pneumonia showing intra-​alveolar buds of granulation tissue, the typical features of cryptogenic organizing pneumonia when identified in an idiopathic setting. Fig. 18.11.3.4  High-​resolution CT scan in a patient with organizing pneumonia. There is bilateral multifocal consolidation which is most prominent subpleurally.

18.11.3  Bronchiolitis obliterans and cryptogenic organizing pneumonia 4189 Other tests Blood tests show nonspecific inflammatory changes, including a markedly raised ESR, raised C-​reactive protein, and periph- eral blood neutrophilia. Increased autoantibody titres, including antinuclear antibodies, rheumatoid factor, and extractable nuclear antigens, may disclose underlying rheumatological disease that is not clinically overt. Bronchoalveolar lavage Abnormalities in bronchoalveolar lavage fluid are nonspecific. However, the usual cell profile of a lymphocytosis (with a low CD4:CD8 ratio) associated with foamy macrophages reduces the likelihood of bacterial infection, vasculitis, or solid cell malignancy. A neutrophilia and/​or eosinophilia is not infrequent, and a prom- inent neutrophilia is reported in patients who progress to extensive fibrosis. Mast cells and plasma cells are occasionally present. Differential diagnosis If serial imaging demonstrates that infiltrates are migratory, alter- native immunologically mediated abnormalities should be con- sidered, including eosinophilic pneumonia, vasculitis (especially Churg–​Strauss vasculitis and Wegener’s granulomatosis) and allergic bronchopulmonary aspergillosis. However, fixed consolidation is seen in many patients with cryptogenic organizing pneumonia and in other cases imaging has not been performed before presentation. In this context the differential diagnosis includes infection, alveolar cell carcinoma and other solid malignancies, lymphoma, and alveolar proteinosis. Lung cancer is the usual differential diagnosis in cases that present as a solitary pulmonary mass. When the clinical and radiological features are typical, the diag- nosis may be made if the histological features of organizing pneu- monia are evident on a transbronchial biopsy. A bronchoalveolar lavage should also be performed, both to exclude infection and be- cause a compatible cellular profile provides useful diagnostic sup- port, especially when transbronchial biopsies are inconclusive. In some cases, a surgical biopsy is required and this should be of suf- ficient size to ensure that organizing pneumonia is the main histo- logical finding and not secondary to another pathological process such as infection, vasculitis, or malignancy. It should be stressed that areas of organizing pneumonia may be seen at biopsy in infection, vasculitis, eosinophilic pneumonia, and malignancy. Thus ‘sampling error’ at transbronchial biopsy occasionally leads to misdiagnosis and the diagnosis should always be reconsidered when the presen- tation or disease course are atypical. Moreover, histological appear- ances do not distinguish between cryptogenic disease and secondary organizing pneumonia. Treatment There are no controlled studies of treatment, but corticosteroid therapy is usually efficacious, with complete remission in over 60% in published series and a partial response in most of the remaining cases. Response is often rapid, with symptomatic improvement re- ported within days, although chest radiographic and pulmonary function responses tend to be slower, sometimes requiring up to 3 months of treatment. It is essential that alternative diagnoses be considered in cases that fail to respond. Until recently initial treatment has generally consisted of oral prednisolone at a dose of 0.75 mg/​kg per day, with intravenous methyl prednisolone sometimes used at doses of 500–​1000 mg daily for three days in severe disease, followed by prednisolone at 20 mg daily with further reductions tailored according to the clinical course. However, no single recommendation covers all patients and regimens should be adjusted according to initial disease severity and the rapidity and degree of responsiveness. Good response rates were seen in one series with much lower corticosteroid doses (pred- nisolone 0.75 mg/​kg for 4 weeks; 0.5 mg/​kg for 4 weeks; 20 mg daily for 4 weeks; 10 mg daily for 6 weeks; 5 mg daily for 6 weeks), relapse rates were not excessive, and the long-​term outcome was not ad- versely affected by rapid withdrawal of prednisolone prior to re- lapse. Rigorous adherence to traditional regimens in patients with limited disease or a good initial response may therefore result in steroid overtreatment. Disease which is refractory to corticosteroids may respond to immunosuppressive therapy, such as azathioprine or cyclophos- phamide (given orally or intravenously). However, in other cases nonresponsiveness indicates supervening interstitial fibrosis, seen more often in secondary organizing pneumonia, especially that of drug-​induced or rheumatological disease. Treatment goals must be adjusted accordingly: once an organizing pneumonia component has been suppressed, prevention of disease progression may become the main therapeutic goal. Acute fulminating organizing pneumonia rarely presents as the adult respiratory distress syndrome, but with typical organizing pneumonia at biopsy or autopsy. Mechanical ventilation is often re- quired. Such patients are treated with high doses of corticosteroids, with cyclophosphamide most commonly added in those who fail to respond. Rapid progression to death may occur and the overall mor- tality rate in this group exceeds 50%. Prognosis In typical cryptogenic organizing pneumonia the prognosis is usu- ally good, with an overall mortality of less than 5%. Relapses occur in up to 60% of cases as corticosteroids are reduced or stopped, but such relapses respond well to reinstitution of high-​dose treatment. A few cases have a poor outcome, with adverse prognostic deter- minants including a reticular imaging pattern suggestive of pul- monary fibrosis, a prominent neutrophilia, or lack of lymphocytosis on bronchoalveolar lavage, associated connective tissue disease, and histological features of interstitial fibrosis with architectural remodelling of lung parenchyma. Treatment is usually effective in preventing progression of supervening pulmonary fibrosis, but in occasional cases the disease progresses inexorably to a fatal outcome. This is seen more commonly in organizing pneumonia occurring secondary to other disorders, which had a 5-​year survival of only 44% in one series. Unifocal organizing pneumonia presenting as a solitary pul- monary nodule has a uniformly good outcome, with no reported recurrences. The diagnosis is usually made following resection for suspected malignancy. Follicular bronchiolitis Follicular bronchiolitis results from polyclonal hyperplasia of lymphoid follicles with formation of germinal centres within the bronchiolar walls. These cause airway obstruction by encroaching

section 18  Respiratory disorders 4190 upon or obliterating the bronchiolar lumen. Follicular bronchio- litis may occur as an isolated or primary phenomenon, but more commonly arises secondary to a variety of other conditions such as chronic aspiration or infection (bronchiectasis, cystic fibrosis, lung abscess), tumours, and immune deficiencies including HIV. It is also frequently associated with collagen vascular diseases such as rheumatoid arthritis, systemic sclerosis, and Sjögren’s syndrome. When a secondary phenomenon, its clinical presence may be masked by concomitant bronchial or alveolar disease. Patients usually present with progressive breathlessness, cough, and symptoms of recurrent respiratory infection. They usually have inspiratory crackles, but no finger clubbing. The chest radiograph shows diffuse small nodular or reticulonodular infiltrates but may be normal. High-​resolution CT invariably reveals centrilobular nodules less than 3 mm diameter. Peribronchial and subpleural nodules may also occur and patchy, nonsegmental ground-​glass opacification is common. Lung function tests may show a restrictive, obstructive, or mixed pattern. Diagnosis of primary follicular bronchiolitis often requires a surgical lung biopsy. Treatment involves optimum management of any underlying condition. Primary follicular bronchiolitis usually improves with corticosteroids, but other immunosuppressive agents such as azathioprine or methotrexate may be required. The prognosis is gen- erally good, although in younger patients the disease may progress. Diffuse panbronchiolitis Diffuse panbronchiolitis is a chronic obstructive pulmonary dis- ease of unknown aetiology that was first described in 1969. The pathological features are a triad of bronchiolocentric inflammation, lymphoid hyperplasia, and an accumulation of interstitial foam cells in the walls of respiratory bronchioles, adjacent alveolar ducts, and alveoli. There may also be luminal collection of neutrophils, but the typical concentric submucosal fibrosis of obliterative bronchiolitis is not a feature. Diffuse panbronchiolitis is relatively common in Asia, particularly among the Japanese and to a lesser extent Chinese and Koreans, al- though occasional cases have also been described in Europe and the United States of America. In Japan it is associated with HLA Bw54, an antigen unique to east Asian ethnic groups, while in Korea the association appears to be with HLA A11. This suggests the gene or genes conferring susceptibility lie in the class 1 region between the HLA-​A and HLA-​B loci. Any age may be affected, but the mean is around 50 years, and most patients have never smoked. There is a male preponderance of over 2:1. There have been reports of diffuse panbronchiolitis complicating ulcerative colitis and adult T-​cell leukaemia. Patients present with subacute symptoms of cough productive of purulent sputum, dyspnoea, and sometimes weight loss. Up to 75% have chronic sinusitis, which often predates chest symptoms. On auscultation there are widespread coarse crackles and wheeze, but finger clubbing is unusual. Common features on chest radiography are ill-​defined nodules up to 5 mm in diameter, symmetrically distributed, and most prominent in the lung bases. There may also be hyperinflation and in the later stages changes of bronchiectasis become evident. On high-​resolution CT centrilobular nodules are evident, often with distal branching structures giving a ‘tree in bud’ appearance. Thickened, ectatic bronchioles are also seen, and in more advanced disease there is bronchiectasis and air trapping. Pulmonary func- tion tests show an obstructive or mixed picture, and transfer factor is normal or sometimes reduced. Most patients show resting hyp- oxaemia. Laboratory investigations are nonspecific, but there may be elevated IgA, IgG, and cold agglutinins, and low titres of rheumatoid factor and antinuclear antibodies. In early disease sputum cultures grow Haemophilus influenzae or Streptococcus pneumoniae, but later Pseudomonas aeruginosa predominates. Diagnostic lung biopsy is rarely necessary in countries where the prevalence is high, but may be required elsewhere in the world where the condition is rare. Without treatment, patients with diffuse panbronchiolitis run a deteriorating course punctuated by episodic superinfections and have 50% mortality at 5 years. However, survival has been trans- formed by the use of long-​term, low-​dose erythromycin therapy (400–​600 mg daily), which improves lung function and CT appear- ances and extends 10-​year survival to 90%. This improved survival is independent of the presence of Pseudomonas infection, suggesting that macrolide therapy works by an anti-​inflammatory effect. FURTHER READING Cordier J-​F (2000). Organising pneumonia. Thorax, 55, 318–​28. du Bois RM, Geddes DM (1991). Obliterative bronchiolitis, crypto- genic organizing pneumonitis and bronchiolitis obliterans organ- izing pneumonia:  three names for two different conditions. Eur Respir J, 4, 774–​5. Epler GR, et al. (1985). Bronchiolitis obliterans organizing pneumonia. N Engl J Med, 312, 152–​8. Howling SJ, et al. (1999). Follicular bronchiolitis: thin-​section CT and histologic findings. Radiology, 212, 637–​42. Kudoh S, et  al. (1998). Improved survival in patients with diffuse panbronchiolitis treated with low-​dose erythromycin. Am J Respir Crit Care Med, 157, 1829–​32. Lazor R, et al. (2000). Cryptogenic organizing pneumonia: character- istics of relapses in a series of 48 patients. Am J Respir Crit Care Med, 162, 571–​7. Lohr RH, Boland BJ, Douglas WW (1997). Organizing pneumonia. Features and prognosis of cryptogenic, secondary and focal variants. Arch Intern Med, 157, 1323–​9. Muller NL, Miller RR (1995). Diseases of the bronchioles: CT and histopathologic findings. Radiology, 196, 3–​12. Myers JL, Colby TV (1993). Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med, 14, 611–​12. Ryu JH (2006). Classification and approach to bronchiolar diseases. Curr Opin Pulmon Dis, 12, 145–​51. Verleden SE, Vos R, Verleden GM (2019). Chronic lung allograft dys- function: light at the end of the tunnel? Curr Opin Organ Transplant, 24, 318–23. Wells AU (2001). Cryptogenic organizing pneumonia. Semin Resp Crit Care Med, 22, 449–​59. Worthy SA, et al. (1997). Mosaic attenuation pattern on thin-​section CT scans of the lung: differentiation among infiltrative lung, airway, and vascular diseases as a cause. Radiology, 205, 465–​70.

18.11.4 The lung in autoimmune rheumatic disorders

18.11.4 The lung in autoimmune rheumatic disorders 4191 M.A. Kokosi and A.U. Wells

18.11.4  The lung in autoimmune rheumatic disorders 4191 18.11.4  The lung in autoimmune rheumatic disorders M.A. Kokosi and A.U. Wells ESSENTIALS Lung complications occur in all rheumatological disorders, but their frequency and type vary strikingly between different systemic diseases. All components of the lungs can be affected, including the interstitium, airways, pleura, and pulmonary vasculature. Multicompartment involvement of the lung is characteristic. The distinction between subclinical involvement and clinically sig- nificant disease is a significant challenge with regard to treatment decisions. Particular autoimmune disorders Systemic sclerosis—​pulmonary function is abnormal in up to 90% of cases. The most prevalent pattern of lung disease is nonspecific inter- stitial pneumonia. Both isolated pulmonary vascular disease and sec- ondary pulmonary hypertension occur. Lung cancer is increased in prevalence. Lung and pulmonary vascular disease are now the main cause of morbidity and mortality. Polymyositis/​dermatomyositis—​interstitial lung disease, usually with organizing pneumonia or nonspecific interstitial pneumonia, is the commonest pulmonary complication. Aspiration pneumonia is a frequent feature of advanced disease and a common cause of death. Rheumatoid arthritis—​is associated with a wide range of pleuropulmonary complications, including interstitial lung dis- ease (with usual interstitial pneumonia the most frequent pattern, followed by nonspecific interstitial pneumonia), organizing pneu- monia, bronchiolitis obliterans, bronchiectasis, pleural effusion, pul- monary vasculitis (rarely), and pulmonary rheumatoid nodules. Sjögren’s syndrome—​interstitial lung disease takes the form of fi- brotic nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia. Tracheobronchial disease can be in the form of loss of mucus secretion in the trachea (xerotrachea), bronchi and bronchi- oles, or (less frequently) lymphocytic bronchiolitis. Systemic lupus erythematosus—​clinically significant interstitial lung disease affects about 10% of patients, with nonspecific inter- stitial pneumonia the usual form. Acute lupus pneumonitis is an uncommon life-​threatening disorder. Diffuse alveolar haemorrhage due to capillaritis can occur. The ‘shrinking lung syndrome’ is thought to be due to respiratory muscle weakness. Pulmonary hypertension is increasingly recognized. Pleural disease is common, affecting 50% of patients at some time. Pleuroparenchymal fibroelastosis—​a newly recognized entity with dense intra-​alveolar fibrosis and dense fibrous thickening of the vis- ceral pleura and adjacent lung, which has been described in rheum- atic disorders but its prevalence and clinical significance has yet to be defined. Management Is treatment required on account of lung disease?—​it is critical that high-​resolution CT findings and lung function tests are reconciled, with clear definition of all complications and deconstruction of the functional defect. Most clinicians regard DLco levels below 65% of predicted normal as indicative of clinically significant dis- ease. Maximal exercise testing is often useful in marginal cases. Careful monitoring with regular pulmonary function tests should be performed. Introduction of treatment for lung disease—​the threshold for introducing therapy is reduced by three considerations: (1) the risk of progression of lung disease appears to be greatest early in the course of systemic disease; (2)  severe functional impairment has consistently been associated with a higher mortality because it is indicative of a previously progressive course and an increased likeli- hood of future disease progression, also because loss of pulmonary reserve implies that the symptomatic consequences of a further pre- ventable loss of lung function may be substantial; and (3) observed disease progression is a major indication for treatment. Therapeutic options—​ immunomodulation remains the corner- stone of therapy. The intensity of the treatment depends on the disease phenotype and behaviour. Treatment decisions are less straightforward in rheumatoid arthritis-​associated UIP. The place of antifibrotic drugs such as pirfenidone and nintedanib has yet to be established. Introduction Lung complications occur in all rheumatological disorders, but their frequency and type vary strikingly between different systemic diseases. Interstitial lung disease (ILD) and pulmonary vascular disease are now increasingly recognized, although the detection of limited abnormalities poses difficulties for clinicians who must now distinguish between subclinical involvement and clinically sig- nificant disease. The presence or absence of exertional dyspnoea is often misleading as musculoskeletal limitation may mask respira- tory symptoms or, alternatively, may cause exercise intolerance without lung pathology, due to the increased work associated with inefficient locomotion. Furthermore, ILD precedes the onset of sys- temic disease in some cases, although typical autoantibody profiles are often diagnostic. The range of lung histological patterns in rheumatological disease mirrors that seen in the idiopathic interstitial pneumonias, but pro- cesses are frequently admixed, with interstitial disease commonly associated with prominent lymphoid follicles (Fig. 18.11.4.1) or pleural thickening (Fig. 18.11.4.2). Nonspecific interstitial pneu- monia (NSIP), usual interstitial pneumonia (UIP), and organ- izing pneumonia are the most frequent findings, with lymphocytic interstitial pneumonia (LIP), acute interstitial pneumonia, and smoking-​related disorders (desquamative interstitial pneumonia, respiratory bronchiolitis with associated interstitial lung disease) occurring in occasional cases. However, unlike the idiopathic inter- stitial pneumonias (see Chapters 18.11.1 and 18.11.2), NSIP is the most frequent pattern, especially in systemic sclerosis and polymyo- sitis/​dermatomyositis, partly accounting for the better prognosis consistently reported in lung involvement in rheumatological dis- orders compared to idiopathic disease in which UIP predominates. The outcome is usually better than in idiopathic fibrotic interstitial pneumonias. Of note, a UIP pattern in connective tissue disorders

section 18  Respiratory disorders 4192 has been suggested to have a better prognosis than idiopathic pul- monary fibrosis. Rheumatoid arthritis-​associated UIP has had a worse prognosis than NSIP in recent series, but overall it seems that UIP does not have a uniformly poor outcome in rheumatoid arthritis. The clinical features of lung disease in particular rheumatological disorders will now be discussed, followed by consideration of key problems and treatments. Systemic sclerosis The diagnostic criteria for systemic sclerosis are detailed in Chapter  19.11.3. Pulmonary involvement (Tables 18.11.4.1 and 18.11.4.2), whether due to lung or pulmonary vascular disease, is now the major source of morbidity and mortality. Interstitial lung disease Lung disease (Table 18.11.4.2), which consists of NSIP in most cases (Fig. 18.11.4.3), occasionally precedes systemic symp- toms. Exertional dyspnoea (reported by over 50% of patients at some stage of disease) is the commonest presenting feature. Non-​ productive cough is less frequent and pleuritic chest pain is un- common. Digital clubbing is rare and should raise the suspicion of underlying malignancy. Fine, predominantly basal ‘Velcro’ crackles are present. Raynaud’s phenomenon is a useful clue to the underlying systemic diagnosis, which—​in limited disease—​is confirmed by capillaroscopy, digital thermography, strongly posi- tive antinuclear antibodies and, in most cases, the presence of the Scl 70 anti-​DNA topoisomerase autoantibody. ILD is present on chest imaging at some stage in most patients and may be associ- ated with oesophageal dilatation. Lung function is abnormal in up to 90% of cases, but reduction in carbon monoxide diffusing capacity (DLco), the most frequent functional defect, does not in isolation discriminate between interstitial lung disease and pul- monary vasculopathy. Bronchoalveolar lavage is often performed to exclude underlying infection but does not have prognostic value. In NSIP and UIP, granulocytes and lymphocytes are often present in excess, whereas a lymphocytosis is the rule in organizing pneumonia, with a granulocytosis usually indicative of supervening fibrosis. Pulmonary vascular disease Both isolated pulmonary vascular disease and secondary pulmonary hypertension (complicating extensive interstitial lung disease) occur. Isolated pulmonary vascular disease takes the form of con- centric fibrosis, with ablation of arteriolar intima and media but no vasculitic element. This mainly complicates limited systemic scler- osis (including the CREST syndrome—​calcinosis, Raynaud’s phe- nomenon, oesophageal dysmotility, sclerodactyly, teleangiectasia) and is typically associated with the anticentromere autoantibody. There is usually no evidence of interstitial lung disease on chest radi- ography, high-​resolution CT, or bronchoalveolar lavage, and lung function tests generally show an isolated fall in DLco or a dispropor- tionate reduction in DLco in patients with coexisting lung involve- ment. Doppler echocardiography is often diagnostic and is widely used as a screening test, but is insensitive in early disease because of the large reserve in the pulmonary vascular bed. Isolated pulmonary vascular disease is a common cause of mortality and is partly re- sponsible for the very poor prognosis associated with marked reduc- tion in DLco in clinical series. Other pulmonary complications Lung cancer is increased in prevalence, even in nonsmokers, with adenocarcinoma more frequent than other histological subtypes. Extrapulmonic restriction due to severe cutaneous involvement is an Fig. 18.11.4.1  A case of rheumatoid arthritis involving the lung, with diffuse interstitial fibrosis (fibrotic nonspecific interstitial pneumonia) and prominent lymphoid follicles (reactive germinal centres): an association that is typical of rheumatoid lung. Fig. 18.11.4.2  A case of systemic lupus erythematosis showing thickening of the visceral pleura in association with fibrotic nonspecific interstitial pneumonia.

18.11.4  The lung in autoimmune rheumatic disorders 4193 extremely rare finding. Pleural disease and organizing pneumonia have been reported occasionally. Despite the fact that oesophageal dysfunction is common, aspiration pneumonia seldom occurs. Polymyositis/​dermatomyositis Diagnostic criteria for polymyositis and dermatomyositis are de- scribed in Chapter 19.11.5. Pulmonary disease (Table 18.11.4.1), occurring in up to 60% of patients, is the most frequent cause of death. Pleural and airways involvement are rare. Interstitial lung disease Interstitial lung disease is the commonest pulmonary complication of polymyositis/​dermatomyositis (Table 18.11.4.2). Although the presentation is usually with organizing pneumonia or NSIP, a rap- idly progressive form of acute pneumonitis occurs more frequently than in other rheumatological disorders. Lung disease (usually or- ganizing pneumonia) precedes systemic disease in up to one-​third of patients. Acute exacerbation can occur and manifests as acute or subacute diffuse alveolar damage. Pulmonary capillaritis resulting in haemoptysis has occasionally been reported. Exertional dyspnoea is a common presenting symptom and orthopnoea is occasionally prominent, especially when myopathy is severe. Cough is a frequent feature, especially in organizing pneu- monia, but is seldom severe. Haemoptysis and pleuritic chest pain are rare. In fibrotic disease, fine basal ‘Velcro’ crackles are usual, and these are variably present in organizing pneumonia. Organizing pneumonia is often obvious on chest radiography, but high-​resolution CT is usually diagnostic and demonstrates the characteristic combination of patchy consolidation and fi- brotic disease with bronchocentric and lower zone distribution (the classic form of admixed NSIP and organizing pneumonia). Lung function tests usually show a restrictive ventilatory defect with a reduction in DLco. When reduced lung volumes are associ- ated with preservation of DLco and an increase in the gas transfer index (Kco), extrapulmonic restriction due to respiratory muscle weakness should be suspected. Bronchoalveolar lavage is useful in discriminating between infection and autoimmune organiz­ ing pneumonia, especially when immunosuppressive therapy has previously been instituted for systemic disease, but has little value in prognostic evaluation. Autoantibodies to aminoacyl-​tRNA synthetase, especially Jo-​1 (antihistidyl tRNA synthetase) are often present when prominent inflammatory myopathy coexists with dif- fuse lung disease, but are found in less than 5% of patients without diffuse lung disease. Other pulmonary manifestations Aspiration pneumonia, a very frequent feature of advanced disease and a common cause of death, should also be considered in earlier disease if there is upper airway/​pharyngeal or oesophageal muscle weakness, especially when the dependent lung regions are select- ively involved. Respiratory muscle weakness, occurring in up to 5% of patients, may occasionally lead to hypercapnic respiratory failure but requires muscle function testing for confirmation in milder cases. Mild pulmonary hypertension is increasingly recognized, al- though the exact prevalence is uncertain, but vascular involvement is generally self-​limited. Lung cancer has increased incidence in polymyositis/​dermatomyositis, which in these cases might represent a paraneoplastic feature. Table 18.11.4.1  Pulmonary complications in autoimmune rheumatic disorders, with the range in prevalence, from rare (±) to frequent (++), indicated semiquantitatively (?, unknown prevalence) Rheumatoid arthritis Systemic sclerosis Polymyositis/​ dermatomyositis Systemic lupus erythematosus Sjögren’s syndrome Constrictive (obliterative) bronchiolitis + ± ± + + Bronchiectasis ++ ± ± + + Pleural disease ++ ± ± ++ ± Respiratory muscle weakness ? ? ++ ± ? Pulmonary hypertension ± ++ ± ++ ± Diffuse alveolar haemorrhage ± ? ± + ? Table 18.11.4.2  Histological patterns of interstitial lung diseases in autoimmune rheumatic disorders, with the range in prevalence, from rare (±) to frequent (++), indicated semiquantitatively (?, unknown prevalence) Lung pattern Rheumatoid arthritis Systemic sclerosis Polymyositis/​ dermatomyositis Systemic lupus erythematosus Sjögren’s syndrome Usual interstitial pneumonia ++ + + + ± Nonspecific interstitial pneumonia ++ +++ ++ ++ ++ Organizing pneumonia + ± ++ ± ± Lymphocytic interstitial pneumonia ± ± ± ± ++ Pleuroparenchymal fibroelastosis ? ? ? ? ? Desquamative interstitial pneumonia and/​or RB-​ILD ± ± ± ± ± Diffuse alveolar damage + ± + + ±

section 18  Respiratory disorders 4194 Rheumatoid arthritis Diagnostic criteria for rheumatoid arthritis are detailed in Chapter  19.5. Pleuropulmonary complications (Table 18.11.4.1) are more variable than in other rheumatological disorders. Interstitial lung disease Interstitial lung disease (Table 18.11.4.2) has a male predominance (male:female 3:1) and is associated with high titres of rheumatoid factor, the presence of rheumatoid nodules, a history of smoking, and HLA B8 and HLA Dw3 positivity. UIP is the most preva- lent histologic pattern in rheumatoid arthritis, followed by NSIP. Interstitial lung disease precedes the onset of systemic disease in about 15% of cases. Exertional dyspnoea is the most frequent presenting symptom, with nonproductive cough also common, especially in patients with sicca symptoms. Bilateral, predominantly basal ‘Velcro’ crackles are usual and digital clubbing is more prevalent than in other rheum- atological diseases. Acute exacerbations of underlying interstitial lung disease can occur and have poor prognosis, similar to that of acute exacerba- tions in idiopathic pulmonary fibrosis. Drug reactions and infec- tions should be considered in the case of acute deterioration. Radiologically overt interstitial lung disease, usually with a basal predominance, was present in less than 5% of cases in three large chest radiographic series. High-​resolution CT often shows limited interstitial abnormalities when chest radiographs are normal, al- though the significance of ‘subclinical’ disease has yet to be as- certained. In established disease, a restrictive ventilatory defect is associated with reduced DLco levels, but an isolated reduction of DLco is seen in up to 40% of unselected rheumatoid arthritis patients. As in other rheumatological disorders, bronchoalveolar lavage may be very useful when opportunistic infection is sus- pected, but it has limited routine value when disease is overtly fibrotic. Organizing pneumonia Organizing pneumonia more commonly mimics infectious pneu- monia in rheumatoid arthritis than in polymyositis/​dermatomyo- sitis. Cough and exertional dyspnoea are commonly accompanied by fever and weight loss. There is multifocal consolidation on chest radiography and high-​resolution CT. Lung function tests show a restrictive defect and reduced DLco, often associated with disproportionate hypoxia due to shunting through consolidated lung. A lymphocytosis is usual on bronchoalveolar lavage, with a granulocytosis usually indicative of underlying fibrotic disease. Organizing pneumonia responds well to corticosteroid therapy in most cases. Bronchiolitis obliterans This rare but often lethal bronchiolar disorder usually presents with exertional dyspnoea, often with a component of wheeze and non-​ productive cough. The breath sounds are usually quiet, with inspira- tory ‘squawks’ a very specific sign of small-​airways disease. An association with the use of penicillamine was postulated in the first descriptions of obliterative bronchiolitis 20 to 30 years ago. Based on subsequent case reports and small series this is probably a true association, but it should be stressed that more cases of oblit- erative bronchiolitis are seen in patients with rheumatoid arthritis who have not used penicillamine than in those who have. The chest radiograph is normal or shows hyperinflation. High-​ resolution CT shows a ‘mosaic’ pattern which is more obvious on expiratory images and represents regional gas trapping. In most cases the lung function defect is obstructive, although there is oc- casionally a mixed obstructive/​restrictive pattern. Measures of gas transfer (DLco and Kco) are preserved provided the forced ex- piratory volume in 1 s (FEV1) exceeds 1 litre. Preservation of gas transfer is especially useful in discriminating between oblitera- tive bronchiolitis and emphysema, in which both DLco and Kco are significantly reduced. Bronchiolitis obliterans is characterized histologically by fibrous destruction and ablation of the terminal bronchiolar wall by granulation tissue. Although a fatal outcome was almost invariable in early reports, the increasing use of high-​resolution CT has disclosed many pa- tients with milder disease in whom the course is often indolent. Bronchiectasis Bronchiectasis is more prevalent in rheumatoid arthritis than in other rheumatological diseases. From a definitive literature re- view of 289 rheumatoid arthritis patients with associated bron- chiectasis reported since 1928, it is clear that the condition precedes the onset of systemic disease in some cases. Before the routine use of high-​resolution CT bronchiectasis was generally diagnosed in patients presenting with chronic purulent sputum production. However, it is increasingly apparent that asymptom- atic (‘dry’) bronchiectasis is extremely common, being present on high-​resolution CT in 30% of 50 rheumatoid arthritis patients with normal chest radiographs on prospective evaluation. The high-​resolution CT overlap between bronchiectasis and oblitera- tive bronchiolitis should be stressed. Bronchiectasis and a ‘mo- saic’ pattern may coexist in both disorders, and bronchiectasis is often present in rheumatoid arthritis patients with interstitial lung disease. Fig. 18.11.4.3  High-​resolution CT scan in a patient with systemic sclerosis. There is prominent ground-​glass attenuation, admixed with fine reticular abnormalities: these appearances are typical of nonspecific interstitial pneumonia.

18.11.4  The lung in autoimmune rheumatic disorders 4195 Pleural disease Pleural involvement is present at autopsy in about 50% of cases, but only 20% of patients experience pleuritic pain at some stage and most pleural effusions are found incidentally on chest radiography. Clinically overt pleural effusions occur in less than 5% of patients, usually in males, but evidence of pre-​existing pleural disease is found on screening chest radiography in up to 20%. Pleural disease has been linked to the presence of rheumatoid nodules but not to more severe systemic disease. Symptoms are confined to a minority of cases and generally con- sist of pleuritic pain and prominent fever, often necessitating the ex- clusion of empyema. Effusions may occasionally develop acutely in association with pericarditis or exacerbations of arthritis. Dyspnoea may result from pulmonary compression when effusions are large, especially when there is underlying interstitial lung disease. The fluid is exudative, with a low glucose level, a low pH, and usually a predominant lymphocytosis. The most frequent histological finding is replacement of the normal mesothelial cell covering by a pseudostratified layer of epithelioid cells, with focal multinucleated giant cells and regular small papillae containing branching capil- laries, but no necrosis or granulomata. These findings are pathog- nomonic for rheumatoid pleuritis when present, but histological appearances are often nonspecific. Some cases respond well to corticosteroid therapy, but more often remission is at best partial. Pulmonary vasculitis Pulmonary vasculitis is a surprisingly uncommon complication of rheumatoid arthritis given the relatively high prevalence of systemic vasculitis in the disease. However, it is likely that pulmonary vas- culitis is not detected in many cases as the diagnosis is often elu- sive. Diffuse alveolar haemorrhage has been reported in a handful of cases. Pulmonary rheumatoid nodules These are present on chest radiography in less than 1% of patients and are usually associated with subcutaneous rheumatoid nodules. Caplan’s syndrome consists of the association of pulmonary nodules, especially cavitating nodules, with coal miner’s pneumoconiosis. Single nodules in cigarette smokers often require histological con- firmation of the diagnosis (by means of percutaneous needle or surgical biopsy) as malignancy cannot be excluded noninvasively. Nodules may fluctuate in size, waxing and waning with variations in underlying rheumatoid activity, and can reach 5–​10 cm in diam- eter. Usually nodules are asymptomatic and found incidentally on chest radiography, but they often cavitate (50%) and can rupture, giving rise to haemoptysis, pneumothorax, or bronchopleural fis- tula. Multiple nodules occasionally occur, with respiratory failure a reported complication of intense nodular infiltration. Other pulmonary manifestations Nonproductive cough due to secondary Sjögren’s syndrome is not uncommon in rheumatoid arthritis and may result from either im- paction of viscid secretions within small airways or from a lympho- cytic bronchiolitis, often associated with enlargement of lymphoid follicles. Full-​blown follicular bronchiolitis is a rare disorder (see Chapter  18.11.3), in which reticulonodular chest radiographic appearances are often suggestive of interstitial lung disease and lung function tests may be restrictive or obstructive. Unlike obliterative bronchiolitis, follicular bronchiolitis often responds to cortico- steroid therapy. Lymphocytic interstitial pneumonia is a rare benign lymphoproliferative disorder which may be limited or extensive, presents as an interstitial lung disease, and is variably responsive to corticosteroids. Desquamative interstitial pneumonia is rare. Lower respiratory tract infection is increased in fre- quency in rheumatoid arthritis, especially in advanced disease. Bronchopneumonia is a common terminal event, accounting for 15 to 20% of deaths. Pulmonary hypertension occurs in up to 20% of patients with rheumatoid arthritis and is usually mild and secondary to inter- stitial lung disease, but occasionally it can result from a primary vasculopathy. Sjögren’s syndrome The diagnostic criteria for Sjögren’s syndrome are detailed in Chapter  19.11.4. There is evidence of pulmonary abnormalities (Table 18.11.4.1) in about one-​quarter of cases, but disease is usu- ally self-​limited and seldom progresses to severe disability or death. Interstitial lung disease Parenchymal disease (Table 18.11.4.2), once thought to consist ex- clusively of lymphocytic infiltration (lymphocytic interstitial pneu- monia) based on historical series, occurs in up to 10% of patients. However, it is increasingly recognized that clinically significant disease more often consists of fibrotic NSIP (with UIP very seldom reported). Interstitial lung disease is often asymptomatic but may declare it- self with cough or exertional dyspnoea. The findings are nonspecific, consisting of crackles on auscultation, reticular or reticulonodular abnormalities on chest radiography, and a restrictive ventilatory defect associated with a reduction in DLco. High-​resolution CT discriminates usefully between these processes. Fibrotic NSIP is characterized by reticular abnormalities and traction bronchiectasis and in some occasions ground glass. LIP is characterized by ground glass and cystic changes. LIP can evolve to pulmonary lymphoma occasionally. Extrapulmonary lymphoma is also increased in preva- lence in Sjögren’s syndrome and is probably as frequent as pulmonary lymphoma. Lymphoma often mimics organizing pneumonia, which has occasionally been reported in Sjögren’s syndrome. Tracheobronchial disease Tracheobronchial disease may take two forms. The more fre- quent disorder consists of loss of mucus secretion in the trachea (xerotrachea), bronchi, and bronchioles. Xerotrachea occurs in up to 25% of patients with primary Sjögren’s syndrome in older series, but may be less prevalent with the increasing recognition of milder variants of the syndrome. The histological picture con- sists of atrophy of tracheobronchial mucous glands, with or without a lymphoplasmacytic infiltrate. Less frequently, airway disease is due to a lymphocytic bronchiolitis, and occasionally there is con- siderable enlargement of lymphoid follicles (follicular bronchio- litis). Both xerotrachea and lymphocytic bronchiolitis present with an unremitting dry cough. Endobronchial inflammation is often

section 18  Respiratory disorders 4196 obvious at bronchoscopy and there is an increased prevalence of bronchial hyperresponsiveness, reported in 40 to 60% of patients with Sjögren’s syndrome, and studies of airflow at low lung volumes in unselected patients disclose a high prevalence of small-​airway disease. The increased viscidity of secretions results in a high preva- lence of secondary infection and in some patients the predominant feature is recurrent episodes of bronchopneumonia. Lymphocytic bronchiolitis usually responds to oral or inhaled corticosteroid therapy, but the increased risk of oral candidiasis in Sjögren’s syn- drome needs to be kept in mind. Xerotrachea responds variably to nebulized saline. Systemic lupus erythematosus The diagnostic criteria for systemic lupus erythematosus (SLE) are detailed in Chapter  19.11.2. Pleuropulmonary manifestations are listed in Table 18.11.4.1. Diffuse lung disease Although limited interstitial fibrosis is found at autopsy in up to 70% of patients, it is likely that this represents post-​inflammatory sequelae in most cases. Clinically significant interstitial lung dis- ease is present in less than 5% of patients at the onset of systemic disease, and develops in a further 5% during follow-​up. The clin- ical presentation closely resembles that of interstitial lung disease in other rheumatological disorders and typically includes dyspnoea, cough, predominantly basal crackles and a restrictive lung func- tion defect or isolated reduction in DLco, and predominantly basal reticulonodular abnormalities on chest radiography. There are no definitive reports of typical high-​resolution CT appearances, al- though there is a high prevalence of limited subclinical interstitial abnormalities. The most common histological pattern is NSIP, al- though UIP has also been reported (Fig. 18.11.4.2). Acute lupus pneumonitis is an uncommon life-​threatening dis- order, seen in less than 2% of patients, but with a mortality rate des- pite treatment of up to 50% once respiratory failure has developed. It may resemble organizing pneumonia, which is very infrequent in SLE. It is believed by some that acute lupus pneumonitis represents an aberrant immunological response to infection, facilitated by the intrinsic immune defect of the systemic disease. Extrapulmonary restriction Extrapulmonary restriction in SLE takes the form of the ‘shrinking lung syndrome’, consisting of a marked reduction in lung volume on chest radiography in association with a restrictive functional de- fect, preservation of DLco, and a marked increase in Kco. The lung interstitium is normal and the disorder is thought to represent re- spiratory muscle weakness, especially diaphragmatic weakness. The syndrome is usually self-​limited, although producing severe exer- cise limitation in more advanced cases. Improvements have been reported with corticosteroid or immunosuppressive therapy, but these appear to be unpredictable and there is no other efficacious treatment. Diffuse alveolar haemorrhage Diffuse alveolar haemorrhage due to capillaritis occurs more fre- quently than in other rheumatological conditions but is still rare in SLE. It occurs in 1.5% of cases, and is the initial presenta- tion in 10–​20% of these. Typically, patients present with subacute or acute dyspnoea and extensive infiltrates on chest radiography. Haemoptysis is occasionally torrential but is more often minimal or absent, even when there is extensive intra-​alveolar haemorrhage. The presentation is similar to those of acute lupus pneumonitis and opportunistic infection, especially in the absence of haemoptysis. The diagnosis is best made by bronchoalveolar lavage, when in- creasingly heavy blood-​staining is typical as the distal airways are lavaged in cases without overt endobronchial haemorrhage. Diffuse alveolar haemorrhage is life-​threatening with a mortality of up to 50% in patients with respiratory failure. There are no definitive treat- ment data, but empirical treatments have included intravenous cor- ticosteroid therapy, intravenous cyclophosphamide, rituximab, and plasmapheresis. Pulmonary hypertension Pulmonary hypertension, once regarded as rare, is encountered with increasing frequency. In early reports, largely containing pa- tients with severe disease, the 2-​year mortality approached 50%. However, with the increasing use of echocardiography, subclin- ical pulmonary vascular abnormalities are detected in 10% of pa- tients. In some cases associated with Raynaud’s phenomenon it appears that vasoconstriction with secondary irreversible damage is the dominant pathophysiological mechanism. In other cases vasculitis predominates, and this may respond strikingly to cor- ticosteroid therapy or intravenous cyclophosphamide, even in ad- vanced disease. Thromboembolism or microthrombosis in small intrapulmonary arterioles also occur in many cases, especially when antiphospholipid antibodies are present. It is often impossible to determine which mechanism predominates as surgical biopsy is contraindicated by severe pulmonary hypertension. Treatment is empirical, consisting of immunosuppression, anticoagulation, and a variety of vasodilator agents. Pleural disease Pleural disease is common in SLE. There is clinical or radiographic evidence of pleural involvement in 20% of patients at the onset of systemic disease, and at least 50% have overt pleural involvement at some time. Pleural disease is often detected on incidental chest radiography in asymptomatic patients, but in other cases pleur- itic pain is recurrent or intractable. The pleural fluid is usually serosanguinous and exudative, with a high neutrophil content in patients with pleurisy, but a predominant lymphocytosis is the rule in chronic disease and in some cases, effusions are haemorrhagic. Corticosteroid therapy is usually much more efficacious than in rheumatoid arthritis. Relapsing polychondritis Relapsing polychondritis is described in Chapter  19.11.9. Respiratory involvement accounts for about 10% of deaths and takes the form of obstruction of the glottis, trachea, and bronchi, leading to airway stricture, collapse, and distal infection. Pulmonary vas- culitis is common but often subclinical, and pulmonary hyperten- sion is rare. Parenchymal disease seldom occurs in isolated relapsing polychondritis, but many other autoimmune conditions, including

18.11.4  The lung in autoimmune rheumatic disorders 4197 most rheumatological disorders, are associated with relapsing polychondritis and may be complicated by interstitial lung disease. Lung function tests typically show severe airflow obstruction due to airway collapse, with reduced maximal inspiratory and expiratory flow representing extrathoracic and intrathoracic airway involve- ment, respectively. Airway abnormalities are prominent on chest radiography, with bronchiectasis and bronchial wall thickening evident on high-​resolution CT. Bronchoscopy has been reported to trigger fatal airway obstruction and should be undertaken with caution. The diagnosis may be made using dynamic CT scanning showing collapse of the larger airways on inspiratory manoeuvres. However, definitive diagnosis requires biopsy, which often shows characteristic features in extrapulmonary cartilaginous areas. Immunosuppression is sometimes effective in preventing disease progression, and mechanical stenting may be life-​saving in advanced destructive disease. Traditionally, flares of relapsing polychondritis have been treated with corticosteroid therapy or immunosuppres- sants, but—​based on recent accumulated experience—​anti-​TNF agents are increasingly used, and they are advocated by some as first-​ line treatment. Ankylosing spondylitis Ankylosing spondylitis is described in Chapter  19.6. Interstitial lung disease is a rare complication, identified on chest radiography in less than 2% of cases, although subclinical interstitial abnormal- ities are highly prevalent on high-​resolution CT, including fibrotic abnormalities and paraseptal emphysema. Fibrobullous lung dis- ease is largely or entirely confined to the upper zones and is usually symmetrical. Fibrotic abnormalities may be more extensive in occa- sional patients with severe long-​standing spinal disease. Interstitial lung disease does not respond to corticosteroid therapy and immunosuppressive therapy has no recognized role and may predispose to chronic infection. Cavities tend to develop within distorted fibrotic apical tissue and are often colonized by myco- bacteria or fungi, especially Aspergillus fumigatus. Life-​threatening haemoptysis is an occasional complication of intracavitary myce- toma formation. Bronchial artery embolization is sometimes ef- fective, but surgical resection of a mycetoma is generally held to be contraindicated and carries a high mortality due to postoperative bronchopleural fistula formation and empyema. Extrapulmonary restriction is more frequent than interstitial lung disease and results from immobilization of the chest wall due to fu- sion of the costovertebral joints. This complication is often asymp- tomatic and the lung function defect is mild, perhaps because the diaphragm is able to compensate for chest-​wall immobility. Exercise tolerance is seldom impaired, provided that an active lifestyle is maintained. Chest-​wall fixation increases in prevalence and severity in long-​standing disease and does not respond to anti-​inflammatory treatment. Management is confined to spinal extension exercises and the maintenance of general fitness with exercise programmes. Mixed connective tissue disease In this syndrome there are variable features of SLE, systemic scler- osis, and polymyositis/​dermatomyositis in association with high titres of autoantibody directed against the extractable nuclear antigen U1-​RNP. However, the diagnosis is often elusive because clinical features evolve as disease progresses and individual criteria may be ephemeral. Pulmonary involvement encompasses the full spectrum of disease seen in systemic sclerosis, polymyositis/​dermatomyositis, and SLE, the three most frequent disorders being pleural effusions, interstitial lung disease, and pulmonary hypertension. Pleuritic pain is reported by up to 40% of patients, but effusions are typically small and generally remit spontaneously. Interstitial lung disease is even more prevalent and usually mimics the inter- stitial fibrosis of systemic sclerosis: organizing pneumonia is sur- prisingly infrequent and, when present, is generally self-​limited. Pulmonary vascular disease is well recognized and is occasion- ally fatal:  reported mechanisms include, most commonly, vaso- constriction in association with arteriolar obliteration, as in systemic sclerosis, but also pulmonary vasculitis and pulmonary thromboembolism. Other rare pulmonary complications are those of the dominant rheumatological picture and include respiratory muscle weakness, severe diffuse alveolar haemorrhage, aspiration pneumonia due to pharyngeal dysfunction, and opportunistic infection in patients receiving immunosuppressive therapy. The investigation and man- agement of pulmonary complications is as for the individual rheum- atological diseases. Long-​term outcome has not been quantified with any precision. Undifferentiated connective tissue disease Many patients with an idiopathic interstitial pneumonia have clin- ical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease. Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus recently led to the proposal of interstitial pneumonitis with autoimmune features (IPAF). The clas- sification criteria are organized around the presence of a combin- ation of features from three domains: a clinical domain consisting of specific extrathoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic, or pulmonary physiologic features. The definition of IPAF requires that the patient fulfils two of the three domains. The clinical significance of IPAF needs to be further studied. Key clinical problems in interstitial lung disease in patients with rheumatological disorders Detection of disease The reported prevalence of interstitial lung disease is critically de- pendent on which diagnostic modality is used. Rheumatoid arthritis patients without overt lung involvement were found to have inter- stitial fibrosis in almost one-​half of cases in an early biopsy study, yet abnormalities are present on chest radiography in less than 5%. Chest radiography is now known to be insensitive and symptoms are often misleading. There is an increasing tendency to screen patients with rheuma- toid arthritis, systemic sclerosis, and polymyositis/​dermatomyositis

section 18  Respiratory disorders 4198 for interstitial lung disease as lung involvement is most prevalent in these disorders. However, lung function tests are often difficult to interpret, as minor abnormalities, especially isolated reduc- tions in DLco, occur in most patients. Even normal lung function tests may be misleading: the normal range is wide and may con- ceal substantial loss of lung function in some cases. Moreover, pul- monary function variables are affected by several pulmonary and extrapulmonary comorbidities, including airway disease (such as obliterative bronchiolitis or bronchiectasis), concurrent smoking-​ related emphysema, pulmonary vascular disease, pleural disease, respiratory muscle weakness, and other forms of extrapulmonary limitation. Bronchoalveolar lavage was once widely advocated as a means of detecting underlying alveolitis, but abnormalities are present in most patients with systemic sclerosis, ankylosing spondyl- itis, and Sjögren’s syndrome, and are probably equally prevalent in the other rheumatological diseases. Subclinical alveolitis has never been shown to evolve into clinically significant intersti- tial lung disease and hence this use of bronchoalveolar lavage is largely discredited. High-​resolution CT is the most sensi- tive and reliable means of detecting interstitial lung disease but should probably be reserved for patients with symptoms, chest radiographic abnormalities, lung function impairment, or high-​ risk patients (e.g. patients with systematic sclerosis (SSc) who are positive for anti-​topoisomerase or anti-​RNA polymerase III antibodies). Determination of clinically significant disease The advent of high-​resolution CT has undoubtedly helped clin- icians greatly in identifying interstitial lung disease, but has led to a separate problem: the identification of limited subclinical abnormalities. Severe interstitial fibrosis is rare in Sjögren’s syn- drome, SLE, and ankylosing spondylitis, but high-​resolution CT abnormalities are present in many patients. In unselected patients with rheumatoid arthritis, interstitial lung disease is evident in 25% of cases, but clinically overt pulmonary fibrosis develops in less than 10%. It is inappropriate to base treatment decisions on high-​resolution CT findings in isolation, but the interpretation of lung function tests is often complicated by the coexistence of interstitial lung disease and other processes, especially pul- monary vascular disease and pleural disease. High-​resolution CT findings and lung function tests must be rec- onciled, with a clear definition of all complications and deconstruc- tion of the functional defect. In this way, the degree of functional impairment ascribable to parenchymal lung disease can usually be approximately apportioned. Except in patients with a severe restrictive ventilatory defect, DLco levels provide the best overall guide to disease severity. Although there is no exact consensus, most clinicians regard DLco levels below 65% of predicted normal as indicative of clinically significant disease. In marginal cases, max- imal exercise testing is often useful, as respiratory symptoms may be shown to result from musculoskeletal limitation (i.e. there is no desaturation or widening of the alveolar–​arterial oxygen gradient at the limits of exercise). However, there is lingering doubt as to whether abnormalities are clinically significant in many cases and in this situation, there is no substitute for careful monitoring, with regular repetition of pulmonary function tests if treatment is not in- stituted immediately. Prognostic evaluation and when to treat The decision as to whether to start treatment is often a very close call. Many patients have intrinsically stable disease and hence the introduction of immunosuppressive therapy in attempt to prevent disease progression is often unnecessary and may result in avoidable drug toxicity. Accurate prognostic evaluation is essential, with treatment ideally reserved for patients at higher risk of progression, but this goal is not straightforward. It is important that the few patients with predom- inantly inflammatory disease be identified, with a view to therapy aimed at reversing disease and restoring lung function. High-​ resolution CT plays a significant role in this regard: patients with organizing pneumonia and other forms of inflammatory cell infil- tration are readily identifiable from characteristic high-​resolution CT patterns. However, most patients have underlying irreversible interstitial fibrosis, most commonly taking the form of fibrotic NSIP. The pattern of disease at surgical biopsy can be an invaluable aide to management in the idiopathic interstitial pneumonias, but has little to offer in this respect in the rheumatological disorders, in which the distinction between NSIP and UIP seems to be less important (except, possibly, in rheumatoid arthritis). The morphological defin- ition of interstitial fibrosis using high-​resolution CT has yet to lead to reliable therapeutic recommendations. The presence of a bronchoalveolar lavage neutrophilia in sys- temic sclerosis was viewed as prognostically important in patients with SSc-​ILD. However, data from two large patient cohorts failed to confirm links between disease progression and neutrophilia of the bronchoalveolar lavage (BAL) fluid. Similarly, despite the fact that the prevalence of SSc-​ILD is much higher in SSc subgroups positive for anti-​topoisomerase antibody and anti-​RNA polymerase III anti- body, there is no evidence that progression of ILD differs materially according to autoantibody status. Biomarkers can be promising prognostic tools, but for the mo- ment no biomarker has been shown to reliably identify an increased risk of progression in CTD-​ILD in a prospective study. Serum levels of KL-​6 (a glycoprotein marker of lung epithelial cell turnover) cor- relate with the extent of systemic sclerosis-​ILD and are higher in patients with active lung disease than in the remaining patients, but the prognostic value of KL-​6 levels has yet to be quantified. A staging system based on assessment of disease severity has been proposed for the identification of systemic sclerosis-​ILD associated with a poorer outcome. Patients with significantly worse survival can be identified by the rapid semi-​quantitative assessment of extent of disease on CT, integrated with forced vital capacity (FVC) levels. Given the aforementioned, treatment must be based on general principles. The threshold for introducing therapy is reduced by the following three considerations: • The risk of progression of lung disease appears to be greatest early in the course of systemic disease. In systemic sclerosis this has long been recognized, with the risk of deterioration being highest in the first 4 years. In polymyositis/​dermatomyositis acute life-​ threatening progression of disease is much more prevalent in the first year, especially when lung disease precedes systemic disease. The same principle applies to other rheumatological disorders, although there is a paucity of data. • Severe functional impairment has consistently been associated with a higher mortality in clinical series of rheumatological

18.11.4  The lung in autoimmune rheumatic disorders 4199 disorders. This is best documented in systemic sclerosis, with se- vere reduction in DLco and severe lung restriction both being ma- lignant prognostic determinants. The severity of disease becomes an increasingly important therapeutic consideration as DLco levels fall below 60% of predicted normal values. Severe disease requires treatment for two reasons. (1) it is indicative of a previ- ously progressive course and an increased likelihood of future dis- ease progression. (2) Loss of pulmonary reserve implies that the symptomatic consequences of a further preventable loss of lung function may be substantial. • Observed disease progression is a major indication for treatment, even when the systemic disease is long-​standing and the func- tional defect is mild to moderate. In systemic sclerosis, decline in gas transfer over 1 to 3 years is associated with a substantially increase in mortality, although it is sometimes necessary to con- firm progression of lung disease (as opposed to worsening of pulmonary vascular disease) using serial high-​resolution CT scanning. This is especially the case when the reduction in gas transfer is disproportionate. In view of the absence of a definitive evidence base, management strategies can usefully be built around the recently proposed ‘disease behaviour classification’, developed initially for the management of unclassifiable disease (Table 18.11.4.3). More specifically, treatment decisions are informed by the designation of disease into one of five categories, based on severity, cause (if present), the predominance of reversible or irreversible disease (as judged by high-​resolution CT or biopsy appearances), and the combination of this information with the observed disease behaviour. Treatment The treatment of interstitial lung disease in rheumatological dis- orders has until recently been largely empirical, consisting of trad- itional immunomodulation, with corticosteroid monotherapy often used in mild disease and combination therapy with low-​dose corticosteroids and immunosuppressive agents (such as cyclophos- phamide, azathioprine, methotrexate and mycophenolate mofetil) in more severe or progressive disease. When inflammatory dis- ease predominates, as in organizing pneumonia or lymphocytic interstitial pneumonia, it is appropriate to treat for a therapeutic response with high-​dose steroid therapy, or intense immunosup- pressive therapy in refractory cases. Following a response it has been usual to gradually reduce treatment to establish the minimum dose required to prevent relapse, and in many patients with organ- izing pneumonia it is eventually possible to withdraw treatment al- together, although continuation of careful monitoring is advisable in the long term. There is now ample evidence from several clinical series that this approach works well in most patients with polymyositis/​ dermatomyositis, with corticosteroid monotherapy often highly efficacious, although it should be stressed that high-​dose cortico- steroid therapy is associated with a greatly increased risk of renal crisis in systemic sclerosis and is strongly contraindicated in that disease. Treatment decisions are less straightforward in predominantly fibrotic disease. There is lack of controlled data on treatment of these disorders, with the only current placebo-​controlled trials conducted in lung disease associated with systemic sclerosis. A placebo-​controlled trial of oral cyclophosphamide therapy has shown a definite treatment effect, although the inclusion of many patients with mild disease makes it difficult to draw conclusions on its clinical significance. Intravenous cyclophosphamide, given at monthly intervals, is less toxic and may be equally efficacious, based on the amplitude of the treatment effect in a placebo-​con- trolled evaluation (although the study was underpowered). In both studies the greater part of the effect was prevention of dis- ease progression, with regression of disease relatively infrequent. A Cochrane systematic review published in 2018 concluded that ‘small benefit may be derived from the use of cyclophosphamide’. The same broad principles are applicable in rheumatological disorders other than polymyositis/​dermatomyositis and systemic sclerosis, but data remain sparse. The exception is rheumatoid arthritis-​associated ILD, which is less responsive to immunosup- pression. The prominent UIP pattern in this entity raises the pos- sibility of the use of antifibrotic drugs (pirfenidone, nintedanib), as is the case in idiopathic pulmonary fibrosis, but this potential needs to be tested in clinical trials. In a large recent retrospective series of patients with CTD-​ILD, mycophenolate mofetil therapy was associated with stabilization of disease for at least 2 years in most cases. More recently a ran- domized control trial of cyclophosphamide versus mycophenolate mofetil in systemic sclerosis associated ILD, showed similar effi- cacy of the two drugs on FVC, but a greater treatment effect on gas transfer levels with mycophenolate. Table 18.11.4.3  Disease behaviour classification Clinical behaviour Monitoring strategy Treatment goal Reversible and self-​limited To remove possible triggers Short-​term (3–​6 months) observation to confirm disease regression Reversible with risk of progression To achieve complete or partial regression of disease and then to rationalize longer-​term therapy Short-​term observation to confirm treatment response; long-​term observation to ensure that gains are preserved Stable with residual disease To maintain status, with or without therapy Long-​term observation to assess disease course Progressive, irreversible with potential for stabilization To stabilize disease Long-​term observation to assess disease course Progressive, irreversible despite treatment (i.e. a pattern of progression mimicking that of IPF) To slow progression Long-​term observation to assess disease course and need for transplantation or effective palliation IPF, idiopathic pulmonary fibrosis.

18.12 Sarcoidosis 4208 Robert P. Baughman and Elys

18.12 Sarcoidosis 4208 Robert P. Baughman and Elyse E. Lower

ESSENTIALS Sarcoidosis is a disease of unknown cause that is characterized by the presence of noncaseating granulomas in at least two organs. It can present in a wide variety of ways. Differential diagnosis is most com- monly from tuberculosis or lymphoma. Clinical features Respiratory involvement—​described in more than 90% of patients and staged according to the chest radiograph appearance: stage 1, hilar adenopathy alone; stage 2, adenopathy and parenchymal disease; stage 3, parenchymal disease alone; and stage 4, fibrosis. Such sta- ging predicts outcome (resolution in 2–​3 years—​stage 1, 90%; stage 3, 30%) but not the degree of extrapulmonary disease. Pulmonary function studies typically demonstrate a restrictive pattern. Skin involvement—​the second most commonly affected organ: manifestations include hyperpigmentation; hypopigmentation; ke- loid reaction; waxy, maculopapular lesions, which when present on face are called lupus pernio and diagnostic of sarcoidosis; erythema nodosum. Other organ involvement—​eye:  uveitis and lacrimal glands; neurological: cranial nerves (especially VII), central nervous system (lymphocytic meningitis, hypothalamic involvement) and periph- eral nerves; liver: abnormal liver function tests in more than 25%; hypercalcaemia/​hypercalciuria; heart: involvement is rare but can be serious with arrhythmic death. Acute vs. chronic disease—​acute disease (which lasts for <2 years) is associated with erythema nodosum, hilar adenopathy, anterior uveitis, and cranial nerve VII paralysis. Chronic disease includes such manifestations as lupus pernio, stage 4 chest radiograph, posterior uveitis, urolithiasis, and bone cysts. Investigations and management Investigations—​those of particular note include: (1) serum angiotensin converting enzyme levels—​elevated in 60% of patients with acute and one-​third of those with chronic disease; (2) bronchoalveolar lavage—​revealing increased lymphocytes, especially an increased CD4:CD8 ratio; (3)  transbronchial biopsy—​noncaseating granu- lomas found in greater than 60% of stage 1 and 80% of stage 2 or 3 disease; (4) gallium scan—​uptake in the parotid and conjunctiva (the ‘panda’ sign) and/​or in the hilar nodes (the ‘lambda’ sign) are fairly characteristic and useful confirmation of diagnosis in difficult cases; (5) characteristic changes on CT scan of chest or positive emission tomography scan. Management—​there is no single treatment for all patients with sarcoidosis. Key issues are to determine (1) whether the patient re- quires treatment, this usually being based on symptoms, and then (2) the extent of symptomatic disease, and (3) whether this is acute or chronic. First line treatment is usually with corticosteroids, often prednisolone 20–​40 mg/​day (initial dosage, followed by gradual re- duction) if topical administration is not possible, although it is not universally accepted that steroids change the course of the disease. If the dose of steroid cannot be reduced to an acceptable level, or if the patient is not responding, then other agents (e.g. chloro- quine/​hydroxychloroquine, methotrexate, leflunomide, infliximab) are added. Prognosis—​most patients with sarcoidosis will experience disease resolution within 2–​5 years; about 25% will develop residual fibrosis in the lungs or elsewhere; in a few the disease will become chronic and persist for more than 5 years. Most series from referral centres report 5% disease-​related mortality, usually from respiratory failure. Introduction Sarcoidosis was first recognized in 1869 by Jonathan Hutchinson, who treated a man with skin lesions that appeared unrelated to tuberculosis. Over the next few decades most case reports of sar- coidosis described patients with skin lesions, and pathological information was scarce since the disease is often self-​limiting. Schaumann in Sweden was one of the first to recognize the multiorgan features of the disease combined with common patho- logical feature: his original thesis was written in 1914, but not pub- lished until 1936. After the Second World War, the use of routine screening chest radiographs identified patients with asymptomatic abnormalities. Löfgren described a group with erythema nodosum, uveitis, and hilar adenopathy. Others began to appreciate the unique aspects of sarcoidosis compared to tuberculosis. Interestingly, as tubercu- losis becomes less frequent in a country, sarcoidosis becomes more obvious, which may reflect the observation that sarcoidosis is a 18.12 Sarcoidosis Robert P. Baughman and Elyse E. Lower

18.12  Sarcoidosis 4209 disease of industrial nations and temperate climates, although sev- eral groups have reported series of patients with sarcoidosis in India, Thailand, and China. Pulmonary sarcoidosis can be evaluated by chest radiography, with Scadding in Scotland and Wurm in Germany independently developing a staging system based on the chest radiograph pattern that has become a useful method of describing the extent of and characterizing lung involvement, and which also provides prog- nostic information. Newer radiological techniques have been evaluated in sarcoidosis. The chest CT scan provides more detailed information regarding adenopathy, but has not replaced the prognostic information available from the chest radiograph. Gallium scanning will reveal increased uptake in areas of inflammation such as lung and medi- astinum. MRI and positron emission tomography (PET) scanning have brought new methods for evaluating extrapulmonary disease. Bronchoalveolar lavage provides a sample of lower airway se- cretions, with lavage findings from patients with sarcoidosis being distinctly different from those without disease, this window into the lung providing insights into the true inflammatory response of the lung. Aetiology The cause of sarcoidosis remains obscure, one hypothesis being that it is an inflammatory response to an environmental agent (including infection) which occurs in a susceptible host, susceptibility being determined by genetic predisposition. Several potential infectious agents have been proposed as causes of sarcoidosis. The granulomatous reaction reminds many of tuber- culosis, and much effort has been made to identify a mycobacterial cause of sarcoidosis. Several studies using polymerase chain reaction and similar molecular biological techniques have been employed, but there is still no convincing evidence that Mycobacterium tuber- culosis causes most cases of the condition, which may lead to an oc- casional case of sarcoid-​like reaction. Other mycobacteria have been identified in some cases, and cell-​wall-​deficient mycobacteria have been grown from the blood of patients with sarcoidosis. However, a controlled trial failed to demonstrate a difference in the incidence of cell-​wall-​deficient mycobacteria between sarcoidosis patients and controls. Another potential pathogen is Propionibacterium acnes. There is increasing evidence supporting nontuberculous mycobac- teria as the cause if sarcoidosis in at least some patients. Epidemiology Sarcoidosis is a worldwide disease. It has been reported to have a higher prevalence in Scandinavian countries and in Ireland. Table 18.12.1 summarizes the relative frequency of sarcoidosis per 100 000 population around the world. In the United States of America, a higher incidence of sarcoidosis has been reported in African-​Americans. The disease presentation differs in different parts of the world, with Table 18.12.1 listing some of the more frequent patterns seen in various ethnic groups. For example, lupus pernio is common among African-​Americans and West Indians who have migrated to the United Kingdom, whereas erythema nodosum is common among Scandinavians. Cardiac disease has been re- ported at a higher frequency in Japanese sarcoidosis patients than for other groups. There is evidence that there is a link between genetic predispos- ition and environmental exposure, but genetic studies regarding the cause of sarcoidosis are hindered while the cause remains unknown. However, once a patient has sarcoidosis it is clear that genetic background may affect clinical outcome, for example, most patients who present with Löfgren’s syndrome (erythema nodosum and hilar adenopathy) resolve their disease within a few years, and about 10% have chronic disease; resolution occurs in almost everyone with the human leucocyte antigen (HLA) alleles DRB10301/​DQB10201, but only 55% of those without. Several occupations have been associated with sarcoidosis, including healthcare workers, firefighters, and seamen aboard air- craft carriers. In a detailed study of exposures of over 700 patients with recently diagnosed sarcoidosis compared to unaffected age-​, race-​, and sex-​matched controls from the same geographic area, those with sarcoidosis were more likely to have been exposed to mouldy environments or insecticides, although one-​half of them had no known exposure to these factors. Occupational exposures can lead to reactions mimicking sar- coidosis. Beryllium—​a metal used in certain industries (ceramics, Table 18.12.1  Sarcoidosis around the world Scandinavia Ireland Japan USA West Indies African-​American White Prevalence per 100 000 1200 213 20 140 50 180 Female predominant No Yes No Yes No No Erythema nodosum +3 +3 Rare Rare +2 Rare Lupus pernio Rare Rare Rare +1 Rare +1 Hypercalcaemia +3 +2 Rare Rare +2 Rare Cardiac Rare Rare +3 +1 +1 +1 Neurological +1 +1 +1 +1 +1 +1 Hypergammaglobulinaemia +1 +1 +1 +4 Rare +1 Rare, <1%; +1, 1–​5%; +2, 5–​10%; +3, 10–​30%; +4 >30%.

section 18  Respiratory disorders 4210 nuclear processing, dental)—​can cause a reaction in the lung and skin indistinguishable from sarcoidosis. Besides clinical history, the distinguishing feature about berylliosis is the lymphocyte’s sen- sitivity to beryllium salts, and the lymphocyte stimulation test of blood, or the more sensitive bronchoalveolar lavage, is a reliable way of detecting which patients are reacting to the metal. None of the infectious, occupational, and environmental expos- ures encompass all cases of sarcoidosis, one possible explanation being that the condition is a common reaction to several agents. Pathogenesis Sarcoidosis is defined by its immunological reaction, the granuloma. Original immunological studies stressed a lack of systemic immune response by the sarcoidosis patient, including anergy, which is a common feature of active sarcoidosis. A reduction in circulating leucocytes, especially lymphocytes, is an important feature of the disease. In the 1970s, new techniques helped us understand sarcoid- osis better. The most important tool introduced at the time was bronchoalveolar lavage, which provided a sampling of the inflamma- tory cells in the lower respiratory tract. Alveolar macrophages are the usual resident inflammatory cell retrieved by lavage, with lympho- cytes and neutrophils much less frequent in normal lavage fluid. The T lymphocyte is usually increased in the lavage fluid from patients with active sarcoidosis: these are often T helper/​inducer lymphocytes (CD-​4+), and the ratio of CD4/​CD8 lymphocytes is increased from that normally found in the blood, often to greater than 3.5. T lympho- cytes can mount either a Th1 or Th2 response, the Th1 response being associated with granuloma formation, whereas Th2 is associated with an eosinophilic response and fibrosis. The initial response of sarcoid- osis follows a Th1 pattern, with lymphocytes releasing interleukin (IL)-​2 spontaneously, and γ-​interferon being released by lympho- cytes and macrophages. Increase in IL-​12 and reduced levels of IL-​10 have also been described, both consistent with a Th1 response. The resolution of sarcoidosis has also been studied with serial lavages: the T lymphocytes remain elevated for some time, but the proportion of CD4 to CD8 decreases to the ratio found in blood (0.8–​2.2), and the amount of cytokines released also decreases. This normalization of the inflammatory response has been shown to occur during treat- ment of sarcoidosis with corticosteroids or methotrexate. The alveolar macrophage is also activated in sarcoidosis. Increased levels of IL-​1, tumour necrosis factor (TNF) and oxygen free rad- icals are released by macrophages retrieved by bronchoalveolar lavage. For those patients with chronic disease, the macrophages and other resident cells may continue to release proinflammatory cytokines, especially TNF, which has become a target for some ther- apies. Alveolar macrophages from patients may also begin releasing profibrotic factors such as IL-​8 and endothelin. Clinical features Patients with sarcoidosis may have a variety of presentations. Commonly affected organs include the lung, skin, and eyes. Less commonly the liver, heart, and brain are affected by the disease. Individual organ involvement can be proven by a biopsy showing noncaseating granuloma; organ involvement is presumed if certain criteria are met. Table 18.12.2 lists some of the criteria suggested for definite or probable organ involvement for some of the more com- monly affected organs in sarcoidosis. Table 18.12.2  Organ involvement in patients with biopsy-​confirmed sarcoidosisa Organ Definite Probable Lung Positive biopsy of lung Chest radiograph characteristic for sarcoidosis (hilar adenopathy.
diffuse infiltrates, or upper lobe fibrosis) Pulmonary function tests showing restriction Lymphocytic alveolitis by bronchoalveolar lavage Any other pulmonary infiltrate Isolated reduction of DLco (carbon monoxide transfer factor) Skin Positive biopsy of skin Lupus pernio Erythema nodosum Annular lesion Macular/​papular lesion New nodules (including subcutaneous) Eyes Positive biopsy of eye Lacrimal gland swelling Uveitis Optic neuritis Blindness Liver Positive biopsy of liver Liver function tests >3 times normal Compatible CT scan Elevated alkaline phosphatase Neurological Positive biopsy of nerve tissue MRI with gadolinium uptake in meninges, brainstem, or mass lesion Cerebrospinal fluid with increased lymphocytes or protein Diabetes insipidus Cranial nerve VII paralysis Other cranial nerve dysfunction Other abnormalities on MRI Unexplained neuropathy Positive electromyogram Cardiac Positive cardiac biopsy Treatment responsive cardiomyopathy ECG showing intraventricular or nodal block Positive PET, MRI, or gallium scan Cardiomyopathy or ventricular arrythmias and no other cardiac problems Positive thallium scan DLco, carbon monoxide transfer factor. a Patients with documented sarcoidosis and no other explanation for organ specific abnormality.

18.12  Sarcoidosis 4211 Commonly affected organs and systems Respiratory system Respiratory involvement has been described in more than 90% of patients, including both the lymph nodes and the lung paren- chyma. Scadding and Wurm independently described stages of the chest radiograph, the commonly used stages being: stage 1, hilar adenopathy alone; stage 2, adenopathy and parenchymal disease (Fig. 18.12.1); stage 3, parenchymal disease alone; and stage 4, fi- brosis. The interstitial disease usually has a diffuse reticulonodular appearance, but confluent patches of disease (alveolar sarcoid- osis) have been described. Fibrotic changes due to sarcoidosis are usually in the upper lobe, with retraction. The staging system has proved useful both in standardizing the reports of pulmonary level of involvement, also as a prognostic measure. Patients with stage 1 disease have a 90% rate of resolution within 2 to 3 years, whereas stage 3 patients possess only a 30% chance of resolution. However, ‘staging’ by chest radiograph appearance does not predict the degree of extrapulmonary disease, hence the choice of the term ‘stage’ is un- fortunate, although it is so standard that it will not be easily replaced. Table 18.12.3 lists the other diseases to be considered in the differential diagnosis based on the chest radiographic pattern. The presence of mediastinal adenopathy alone (stage 1 disease) is cer- tainly consistent with lymphoma or metastatic cancer, although it has been pointed out that symmetrical bilateral adenopathy with right paratracheal adenopathy in an asymptomatic individual is almost always sarcoidosis. Asymmetrical adenopathy raises the question of lymphoma, and a tissue diagnosis is usually required. For patients with diffuse infiltrates, adenopathy points one toward sarcoidosis. However, several other conditions may have some adenopathy, including hypersensitivity pneumonitis and idiopathic pulmonary fibrosis. The use of the CT scan has changed the evaluation of many inter- stitial lung diseases, when the larger the adenopathy, the more likely the patient has sarcoidosis (Fig. 18.12.2). Nodularity may be more obvious on high-​resolution CT than on plain chest radiography, and peribronchial thickening is often seen in the upper lobe in sar- coidosis (Fig. 18.12.3). The CT scan is also useful in patients with more advanced disease, since it can identify honeycombing, trac- tion bronchiectasis, and superimposed mycetomas (Fig. 18.12.4). It must, however, be appreciated that increased adenopathy is much more frequently recognized on CT scan than on chest radio- graphs, making the staging system only applicable for plain radi- ography. But if the CT scan identifies adenopathy in a patient with possible extrapulmonary sarcoidosis, then this may help in deciding where to proceed to obtain a tissue diagnosis (e.g. brain biopsy vs. mediastinoscopy). Pulmonary function studies in patients with sarcoidosis classic- ally demonstrate a restrictive pattern, with reduction of lung vol- umes. The transfer factor is usually reduced out of proportion to the loss of lung volume, as one would expect in an interstitial lung disease. In advanced cases, the oxygen level will be reduced, es- pecially during exercise. Obstructive disease can also occur due to airway involvement by sarcoidosis or associated with cough, a common complaint in sarcoidosis. Fig. 18.12.1  Chest radiograph showing stage 2 involvement with sarcoidosis. Enlarged hilar lymph nodes and lung infiltrates are seen. Table 18.12.3  Differential diagnosis of sarcoidosis according to the stage on chest radiography Stage 1 Stage 2 Stage 3 Stage 4 Pattern Hilar adenopathy Adenopathy plus lung infiltrates Lung infiltrates alone Fibrosis Diseases that can commonly cause similar appearances on chest radiography Tuberculosis Lymphoma Enlarged pulmonary arteries Metastatic carcinoma Histoplasmosis Lymphangitic carcinoma Pneumocystis jirovecii Pneumoconiosis Histoplasmosis Berylliosis Lymphangitic carcinoma Pneumocystis jirovecii Pneumoconiosis Histoplasmosis Idiopathic pulmonary fibrosis Berylliosis Hypersensitivity pneumonitis Bronchoalveolar cell carcinoma Pneumonia Congestive heart failure Collagen vascular disease associated lung disease Eosinophilic granuloma Lymphangitic carcinoma Pneumoconiosis Histoplasmosis Idiopathic pulmonary fibrosis Berylliosis Hypersensitivity pneumonitis Bronchoalveolar cell carcinoma Pneumonia Congestive heart failure Collagen vascular disease associated lung disease Eosinophilic granuloma Diseases that can rarely cause similar appearances on chest radiography Leukaemia Infectious mononucleosis Alveolar proteinosis Idiopathic hemosiderosis α1-​Antitrypsin disease Bronchoalveolar cell carcinoma Sjögren’s syndrome Haemosiderosis Alveolar proteinosis Sjögren’s syndrome Haemosiderosis Alveolar proteinosis

section 18  Respiratory disorders 4212 The skin The skin is the second most commonly affected organ in sarcoid- osis. Hyperpigmentation, hypopigmentation, and keloid reaction may demonstrate granulomas on biopsy, but their appearance is not always specific. Waxy, maculopapular lesions, which occur on the extremities, back, and face, are usually raised with most less than 2 cm in diameter. When the lesions occur on the face, especially on the cheeks and nose, they are called lupus pernio (Fig. 18.12.5). Erythema nodosum—​red nodular lesions on the extremities—​ usually involves the legs. The constellation of erythema nodosum, arthritis (in the ankles), and hilar adenopathy is referred to as Löfgren’s syndrome, which as noted earlier usually has a good prog- nosis. Interestingly, the skin lesions from erythema nodosum do not contain granulomas, but are thought to be due to circulating im- mune complexes from the disease. The eyes The eye is affected in more than 20% of patients with sarcoidosis. The most common findings are uveitis and lacrimal gland involve- ment. Anterior uveitis is often self-​limiting and can be treated top- ically, but posterior uveitis is a more chronic form of the disease and may require injections of corticosteroids or systemic therapy. Sicca (dry eyes) and glaucoma are long-​term complications which are en- countered in patients often years after other sarcoidosis symptoms have resolved. They are consequences of the fibrotic changes in the lacrimal glands and eye and do not respond to anti-​inflammatory therapy. Optic nerve involvement can be seen with sarcoidosis, with idiopathic disease and multiple sclerosis being the other major causes of this sight-​threatening complication. Retinal disease has also been reported. Blindness from sarcoidosis is fortunately rare, and it is usually a consequence of untreated uveitis, retinitis, or optic neuritis. Neurological disease from sarcoidosis can affect the cranial nerves, central nervous system (CNS), and peripheral nerves. Cranial nerve involvement, especially of the nerve VII, is a common complaint in neurosarcoidosis. CNS lesions can lead to a lymphocytic meningitis. Fig. 18.12.2  High-​resolution CT scan of the chest demonstrating both interstitial infiltrate as well as significant hilar adenopathy in sarcoidosis. Fig. 18.12.3  High-​resolution CT scan of the chest demonstrating peribronchial thickening, which is more prominent in the right lung. Fig. 18.12.4  High-​resolution CT scan of the chest from the upper lobe area, which is more commonly affected in sarcoidosis, demonstrating fibrotic changes including traction bronchiectasis and honeycombing. Fig. 18.12.5  Lupus pernio due to sarcoidosis. The plaque-​like lesions can be seen on forehead and both cheeks; the nasal area is also affected and can be associated with sinusitis, as it was in this case. Reproduced with permission.

18.12  Sarcoidosis 4213 Hypothalamic involvement is a characteristic pattern, with diabetes insipidus as a resulting complaint. Contrast-​enhanced MRI is the most sensitive method for detecting CNS disease (Fig. 18.12.6). The lumbar puncture is complementary, with increased protein and lymphocytes often seen in active disease. Detection of angiotensin converting enzyme (ACE) in the spinal fluid is suggestive but not diagnostic of neurosarcoidosis. Liver and spleen Liver and spleen involvement may be found in over one-​half of patients with sarcoidosis, but symptomatic disease occurs in less than 10% of cases. Liver function tests are often elevated, espe- cially the alkaline phosphatase, suggesting an obstructive pat- tern. Hyperbilirubinemia is relatively rare, but implies extensive disease and is usually an indication for therapy. Massive spleno- megaly can occur, and occasionally splenectomy is performed to avoid rupture. Hypercalcaemia and hypercalciuria can be seen with sarcoidosis. One mechanism is the granuloma converting 25-​hydroxyvitamin D3 to the biologically active form 1,25-​dihydroxyvitamin D3, which is also increased by sunlight exposure. In the Unites States of America, hypercalcaemia is far more common in whites than in African-​ Americans. Because of the effect of increased calcium absorption, urolithiasis may be also seen in patients with sarcoidosis. A less common but serious complication of sarcoidosis is car- diac involvement. Direct involvement of the heart can lead to arrythmias such as heart block and ventricular ectopy, which can lead to sudden death. Once the problem is recognized, the use of an implanted defibrillator may reduce the risk of death. Cardiomyopathy is also seen, and cardiac sarcoidosis should be considered in a young patient who presents with unexpected heart failure. Endomyocardial biopsy rarely makes a diagnosis because the granulomas are patchy. Cardiac MRI and PET scanning are the most commonly used imaging techniques to identify cardiac involvement. Sarcoidosis granulomas can involve virtually any organ of the body. Rare manifestations of sarcoidosis include bone cysts, usually in the distal portion of the fingers, sinus invasion, pleural disease, breast disease, and ovarian or testicular masses. Fatigue is a major complaint of over half of patients with sarcoid- osis. This may be related to sleep apnoea, which occurs in about one-​ third of patients with the condition, although other factors may also be involved. The multiorgan involvement of sarcoidosis distinguishes it from other diseases, with lymphoma and tuberculosis the two that are most often considered in the differential diagnosis. Table 18.12.4 summarizes the common features in all three of these diseases and points out features that can be used to separate them. Pathology The noncaseating granuloma is the characteristic pathological fea- ture of sarcoidosis. The centre of the granuloma includes macro- phages and giant cells which are of the Langerhans’ type and can contain more than 10 nuclei. This core of cells is surrounded by Fig. 18.12.6  Brain MRI with gadolinium contrast. There is uptake in multiple areas (white areas) indicating inflammatory lesions within the brain due to neurosarcoidosis. Table 18.12.4  Comparison of features of sarcoidosis, tuberculosis, and lymphoma Feature Sarcoidosis Tuberculosis Hodgkin’s lymphoma Bilateral hilar adenopathy Very common Rare, except in HIV patients Common Skin lesions Common Rare Rare Lupus pernio Diagnostic None None Erythema nodosum Common Rare Very rare Hypercalcaemia Can occur Very rare Rare Eye disease Common Rare Very rare Pleural disease Very rare Common Common Cranial nerve VII paralysis Common Very rare Very rare Elevated ACE Very common Rare None Tuberculin skin test Anergic Positive Anergic BAL lymphocytes Very common Common Very rare ACE, angiotensin converting enzyme; BAL, bronchoalveolar lavage.

section 18  Respiratory disorders 4214 lymphocytes. Immunohistochemical studies have shown that the lymphocytes present two rings of cell types: the larger component is the CD4 lymphocyte, while the outer ring usually includes CD8 lymphocytes. The granulomas tend to be well formed, and in lung biopsies they are often well demarcated from normal tissue. The central area will occasionally contain a Schaumann body, which is formed of crystallized material (calcium phosphate) and different in appearance from the foreign bodies or caseation that can be seen in other granulomatous diseases. Occasionally the granuloma will have a necrotic area, but most are bland. The diagnosis of sarcoidosis is always one of exclusion, but the finding of noncaseating granulomas in two or more organs is—​for practical purposes—​considered diagnostic. Cultures and special stains for tuberculosis and deep-​seated fungal infections should be taken to rule out infection as the cause of granulomas. Close exam- ination should also be made for foreign bodies and malignancy, both of which could lead to a granulomatous reaction. Investigation Serum ACE levels In 1976, Lieberman reported that serum ACE was elevated in the blood of some patients with sarcoidosis, and it has subsequently be- come clear that this can also occur in a few other conditions. Only 60% of patients with acute sarcoidosis and less than one-​third of pa- tients with chronic disease will have elevated levels of ACE. Patients with infectious granulomatous diseases such as tuberculosis, histo- plasmosis, and coccidiomycosis occasionally have an elevated ACE level. Mild elevations have also been reported in diabetes mellitus and osteoarthritis, and high levels have been detected in Gaucher’s disease, leprosy, and hyperthyroidism. ACE levels are usually lower than normal in patients with Hodgkin’s lymphoma, and because ACE is measured using a biological assay, patients on ACE inhibitors have low functional levels. In sarcoidosis the ACE level will decrease in response to treatment or disease resolution with time. It has been proposed as a marker for disease activity, but corticosteroids inde- pendently suppress ACE levels, and reducing the dose of cortico- steroids may lead to a rise in ACE level without a clinical worsening of disease. There is a genetic polymorphism for ACE, with an insertion (I) or deletion (D) of a nonsense DNA fragment. ACE levels are higher in DD patients, which needs to be considered when interpreting the serum ACE level, but there appears to be no difference in the distri- bution of the alleles in patients with sarcoidosis versus the general population. Serum lysozyme is also elevated in the same way as ACE. Unfortunately, it is elevated in a smaller number of patients with sar- coidosis. Most clinicians will only determine ACE levels. Tests of the lung Bronchoalveolar lavage findings have proved to be fairly character- istic in sarcoidosis. The finding of increased lymphocytes, especially an increased CD4:CD8 ratio, has been interpreted by some groups as enough evidence to make a diagnosis of sarcoidosis, and lavage findings may be considered sufficient in a patient with a compatible clinical history and no evidence for infection or malignancy. A more definitive answer from bronchoscopy includes a transbronchial biopsy showing noncaseating granulomas. In over 60% of patients with a stage 1 chest radiograph the biopsy should be positive, rising to 80% in patients with stage 2 or 3 disease. Transbronchial needle aspiration can sample mediastinal and hilar lymph nodes, but un- fortunately incomplete sampling of the lymph node in a granuloma- tous response to malignancy can occur. Endobronchial ultrasound (EBUS) has been shown to be superior to blind transbronchial needle aspiration in identifying granulomas in lymph nodes of sar- coidosis patients. Mediastinoscopy and video assisted thoracoscopy provide minimally invasive methods to obtain more tissue and are usually definitive. Imaging Aside from chest radiography and CT scanning, which have already been discussed, gallium and PET scans can demonstrate active in- flammation in lymph nodes and other active areas in sarcoidosis. However, the uptake is nonspecific and the level of uptake can be the same as seen with malignancy. This can lead to confusion in patients undergoing PET scan for possible lymphoma, when the activity will be the same for both sarcoidosis and lymphoma. In the gallium scan, which is the older-​established procedure, uptake in the parotid and conjunctiva (the ‘panda’ sign), and uptake in the hilar nodes (the ‘lambda’ sign), are fairly characteristic for sarcoidosis and are useful confirmation in difficult cases. PET scan, when available, has replaced gallium scan to detect active inflammation. PET scan and MRI have been found particularly helpful in detecting myocardial involvement in sarcoidosis. Other tests The Kviem–​Siltzbach agent is a suspension of spleen tissue from a patient with confirmed sarcoidosis. Six weeks after an intradermal injection of the agent, the site is inspected for a reaction, which will occur in over 60% of patients with acute sarcoidosis. On biopsy the reaction will show noncaseating granuloma, consistent with sar- coidosis. Properly prepared Kviem–​Siltzbach agent has a less than 1 in 500 chance of causing a false positive, however, because of the difficulties in preparing the agent and concerns regarding transmis- sion of an infectious agent, the test is rarely used except in centres with a well-​established reagent. Other laboratory tests may support the diagnosis of sarcoidosis or the level of disease activity. For example, the sedimentation rate and C-​reactive protein can be elevated in sarcoidosis and may be useful for disease monitoring, but in over half of patients these in- flammatory markers are normal, hence they are neither specific nor sensitive diagnostic tests. Serum calcium is elevated in 10% of patients with sarcoidosis and is supportive of the diagnosis, but hypercalcaemia can be seen in other conditions which mimic the condition, such as malignancy. Hypercalcaemia due to sarcoidosis should be associated with a normal to low serum phosphate. Renal failure may occur in those with significant hypercalcaemia, which is usually reversible with treatment of the hypercalcaemia. Hypergammaglobulinemia is also a feature of sarcoidosis, with activated T lymphocytes in the lung capable of stimulating circu- lating peripheral blood B cells to produce the polyclonal γ- globulin response found in the condition. Serological markers for some diseases may be falsely elevated as a result of this nonspecific re- action, including antifungal and antinuclear antibodies. The

18.12  Sarcoidosis 4215 hypergammaglobulinemia is more common in African-​Americans than in whites. As stated previously, liver involvement occurs in over one-​half of patients with sarcoidosis, although in some cases there is no serum chemistry test indicating involvement. However, most patients with liver involvement will have elevated serum enzymes, and usually the pattern is obstructive with a rise in the serum alkaline phosphatase. In some patients an elevation of the transaminases is seen. Elevation of the serum bilirubin is less frequent and associated with more ex- tensive liver involvement. Rarely, lymphadenopathy at the porta hepatis can lead to biliary obstruction. Haematological abnormalities are common in sarcoidosis. Lymphopenia is frequently seen, and is probably due to seques- tration of the lymphocytes into the area of inflammation, such as the lung. Anaemia has been reported in about 20% of cases: the mechanism is multifactorial, including a high proportion with iron deficiency. Other causes include direct bone marrow invasion by granulomas and suppression of the bone marrow by cytokines such as IL-​2. Treatment The natural course of sarcoidosis is unclear because corticosteroids are normally used to treat symptomatic patients. The prognosis is often good for the patient with no symptoms on presentation, with spontaneous resolution of the disease often occurring within a year or two of diagnosis. However, the disease can also take a chronic form, with symptoms for many years. The concept of acute disease, which lasts for less than 2 years, vs. chronic disease has been a useful method of discussing pa- tients, especially in terms of therapy. Table 18.12.5 lists several factors associated with resolution within 2 to 5 years, as well as those predicting chronic disease. Acute disease is associated with erythema nodosum, hilar adenopathy, anterior uveitis, and par- alysis of cranial nerve VII. Chronic disease includes such manifest- ations as lupus pernio, stage 4 chest radiograph, posterior uveitis, urolithiasis, and bone cysts. Most chronic disease is controllable by therapy, but there are refractory patients. Mortality from sar- coidosis occurs, but is less than 5% in most series, with the most common causes of death being from lung, cardiac, and neurological disease refractory to therapy. The main indication for therapy in sarcoidosis is symptoms, al- though hypercalcaemia should be treated even if the patient is asymptomatic. An eye examination should be performed in all pa- tients with sarcoidosis: uveitis may be misdiagnosed as sicca (dry eyes), but the former will require anti-​inflammatory agents, while the latter will only need a wetting agent. Corticosteroids If possible, treatment should be topical. Corticosteroid topical creams and eye drops are effective if the inflammation is superficial. The effectiveness of inhaled steroids is less clear cut. The higher-​ potency steroids such as budesonide appear to have a role in redu- cing the dosage of systemic corticosteroids, and randomized trials have indicated a role for this drug as maintenance therapy for a pa- tient who has received systemic therapy for 3 months to induce a remission. It is not clear whether corticosteroids change the course of the disease. Early randomized trials found no difference in the long-​ term outcome of patients who received corticosteroids versus con- trols. A British Thoracic Society randomized study demonstrated a small benefit for corticosteroids over placebo for patients with per- sistent, but not severe disease. However, in this study—​as in most of the early studies—​patients with symptomatic disease were excluded and always treated with corticosteroids, which could lead to a limit in the observed response to therapy. Several groups have looked at the need for treatment and the dur- ation of therapy. The genetic background of these groups varies, from mostly white northern European descent, where 60% never required systemic therapy, to African-​Americans, where 70% were treated. In general, about one-​half of sarcoidosis patients will require systemic therapy for their disease, and after 2 to 5 years, 18–​53% of the patients could not be withdrawn from therapy. In patients who were tapered off corticosteroids, one group found that 80% eventu- ally relapsed and required reinstitution of therapy. The differences in rate of continued therapy and relapse between the centres could be due to either the genetic background of the patients or the bias of the treating physicians. Interestingly, two studies demonstrated that if the patient did not require initial systemic therapy, there was a less than 10% chance that they would require treatment after 2–​5 years. The toxicities of corticosteroids are well known. These include weight gain, diabetes mellitus, hypertension, and mood swings, and with prolonged use avascular necrosis and osteopenia are significant problems. Some patients with sarcoidosis will have lost weight as part of their disease, but the weight gain with treatment often sur- passes the amount of weight lost. The longer a patient is on cortico- steroids, the more problematic, and unfortunately most patients will require more than a year of treatment. Several alternatives to systemic corticosteroids have been pro- posed over the years. These are summarized and compared to corticosteroids in Table 18.12.6, which includes the usual doses, commonly encountered toxicities, an estimate of response rate, and the usual indications for use. Other agents The commonly prescribed antimalarial agents chloroquine and hydroxychloroquine possess anti-​inflammatory activity, with the major toxicities being eye and gastrointestinal. Hydroxychloroquine has been associated with less eye toxicity and therefore it is more Table 18.12.5  Features predictive of the clinical course of sarcoidosis Organ Acute Chronic Chest radiograph Stage 1 Stage 4 Skin Erythema nodosum Lupus pernio Eyes Anterior uveitis Posterior uveitis Pars planitis Joint involvement Bone cysts Calcium metabolism Hypercalcaemia Urolithiasis Cardiac Cardiomyopathy Neurological Cranial nerve VII palsy Central nervous system mass Sinus Sinus involvement

section 18  Respiratory disorders 4216 frequently prescribed, although some experts feel chloroquine is a more effective agent. The drugs concentrate in the skin and have been most efficacious for skin disease and hypercalcaemia: they are less successful for treating pulmonary disease. Methotrexate is an antimetabolite chemotherapy used for various solid tumours. In a double-​blind randomized placebo-​controlled trial of acute pulmonary sarcoidosis it was found to be steroid sparing, but required 6 months to be effective. The response rate for chronic sarcoidosis is 60–​80% and methotrexate is usually used in this context. Most patients who respond can be treated with metho- trexate alone, but about 20% of patients will require low-​dose cor- ticosteroids in addition. The usual dose is 10 to 15 mg orally each week, which may need to be adjusted for toxicity. We have success- fully treated patients with doses as small as 2.5 mg of methotrexate a week. Acute toxicity, including mucositis and nausea, can be min- imized with supplements of folic acid at 1 mg/​day. Leucopenia can also occur, but is usually insignificant unless the patient is already leucopenic from sarcoidosis or the patient has renal insufficiency. The long-​term toxicity of methotrexate can include hypersensitivity pneumonitis and cirrhosis, the latter being a concern because 50% of chronic patients will have sarcoidosis granulomas in a liver bi- opsy, hence we recommend liver biopsies every 2 years for patients requiring prolonged treatment with methotrexate. Leflunomide is an antimetabolite similar to methotrexate but with less pulmonary and gastrointestinal toxicity. It appears to be as effective as methotrexate and has also been given in combination with methotrexate, when the two drugs appear to be synergistic. Azathioprine has been used as an immunosuppressant for solid organ transplant patients and patients with idiopathic pulmonary fi- brosis for many years. However, its use in sarcoidosis has been more sporadic, and it is usually reserved for chronic cases. Other drugs have been used for refractory sarcoidosis. Cyclophosphamide, a cytotoxic agent used in the treatment of many vasculitic diseases, has been reported as very useful in neurological and cardiac sarcoidosis, but it has more gastrointes- tinal, haematological, and bladder toxicity than methotrexate or azathioprine. Ciclosporin has been used with limited success in some neurological cases, but a randomized trial failed to show additional benefit over corticosteroids alone in patients with pul- monary sarcoidosis. Table 18.12.6  Treatments for sarcoidosis Drug Dosage Efficacy (%) Toxicity Usage Prednisone/​Prednisolone 5–​40 mg/​day 90 Weight gain Diabetes Hypertension Osteoporosis Psychiatric Acute Chronic Refractory Hydroxychloroquine 200–​400 mg/​day 30–​50a Gastrointestinal Retinal Acute Chronic Methotrexate 10–​25 mg once a week 60–​80 Haematological Gastrointestinal Lung Hepatic Mutagenic Chronic Refractory Leflunomide 10–​20 mg/​day 60–​80 Haematological Gastrointestinal Hepatic Mutagenic Chronic Refractory Azathioprine 50–​200 mg/​day 50–​80 Haematological Gastrointestinal Carcinogenic Mutagenic Chronic Refractory Pentoxifylline 400 mg three times a day 50 Gastrointestinal Acute Cyclophosphamide 50–​150 mg/​day orally, 500–​2000 mg every 2 weeks IV 80 Gastrointestinal Haematological Carcinogenic Bladder Teratogenic Chronic Refractory Thalidomide 50–​100 mg/​day 80a Teratogenic Somnolence Peripheral neuropathy Chronic Refractory Infliximab 3–​5 mg/​kg IV initially, 2 weeks later, then every 4–​8 weeks 90 Allergic reactions Infections Worsening heart failure Probable carcinogen Refractory Adalimumab 20–​40 mg every week to every other week 80 Infections Worsening heart failure Probable carcinogen Refractory IV, intravenous a Refers to efficacy for skin manifestations of sarcoidosis: other manifestations respond less well.

18.12  Sarcoidosis 4217 Persistent release of TNF by alveolar macrophages is a feature of patients with chronic sarcoidosis, hence the effects of drugs that block TNF release or action have been studied. These include cor- ticosteroids, methotrexate, and azathioprine, which have been dis- cussed previously. Others include pentoxifylline, which inhibits alveolar macrophage release of TNF, and can provide benefit in some cases of acute sarcoidosis, although associated with significant gastrointestinal toxicity which has limited its use. Thalidomide also has significant anti-​TNF activity and is effective at treating chronic, severe skin lesions including lupus pernio, but the drug has severe teratogenic potential such that close monitoring is required, and it also causes hypersomnolence, constipation, and a peripheral neur- opathy. The treatment of eye or pulmonary eye disease often requires high doses of thalidomide, hence the risk–​benefit ratio limits use of the drug to skin disease. Biological agents directed against TNF have been developed for various inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, and psoriasis. These include infliximab, which is a monoclonal antibody that binds TNF, and etanercept, a TNF re- ceptor antagonist. Numerous case reports and case series have dem- onstrated a rapid and sometimes dramatic response to infliximab in refractory cases of sarcoidosis. A double-​blind placebo-​controlled randomized trial of infliximab for chronic pulmonary sarcoidosis found it to be effective in further improving the vital capacity of those patients already on at least 10 mg prednisone per day and/​ or cytotoxic agents, with the study demonstrating a larger effect of therapy for those with more severe disease. The TNF receptor antag- onist etanercept has been less successful in treating sarcoidosis: in pulmonary and ocular disease less than one-​third of patients im- proved on therapy, and one-​third became worse during treatment. The difference in efficacy between infliximab and etanercept has also been noted in Crohn’s disease, where infliximab is the bio- logical agent of choice. The differences between agents may be due to mechanism of action or peak dose of the drug; infliximab is given intravenously, etanercept subcutaneously); infliximab binds TNF on the cell surface, whereas etanercept blocks soluble TNF. The interaction on the cell surface can affect the transmembrane TNF effect, and the binding has also been associated with inducing apoptosis that would lead to reduction of the number of inflam- matory cells releasing TNF and other proinflammatory cytokines. Experience with the totally humanized monoclonal anti-​TNF anti- body adalimumab has been increasing: it is effective in refractory sarcoidosis, but may require a large dose, similar to that used for Crohn’s disease. The biological agents are associated with significant toxicities and cost. Among the class toxicities are the allergic reactions, in- creased rate of infection, worsening of pre-​existing congestive heart failure, and potential carcinogenic effects. Compared to etanercept, infliximab is associated with a higher rate of reactivation of tuber- culosis, which may be a reflection of its superior antigranulomatous properties. Overall, because of the potential severe toxicities, infliximab use appears limited to refractory cases. Strategy There is no single treatment for all patients with sarcoidosis. The first step is to determine whether the patient requires treatment, the decision to treat usually being based on the patient’s symptoms. The clinician needs to determine the extent of the symptomatic disease and whether the disease is acute or chronic. Asymptomatic or minimally symptomatic patients with hypercalcaemia, cardiac, or CNS disease may require therapy to prevent life-​threatening complications. The use of systemic therapy usually means cor- ticosteroids first. If the patient is able to be successfully treated with corticosteroids, the dose is gradually reduced to minimize toxicity. If the dose cannot be reduced to an acceptable level, or if the patient is not responding to corticosteroids, then steroid sparing agents should be added. For most of these the onset of ac- tion is 6 months or more, hence the clinician should not hesitate to add these drugs early into therapy if the patient has evidence for chronic disease (Table 18.12.5) or recurrent symptoms whenever steroids are withdrawn. Prognosis Most patients with sarcoidosis will experience disease resolution within 2–​5 years; about 25% will develop residual fibrosis in the lungs or elsewhere; in a few the disease will become chronic and persist for more than 5 years. For the chronic patient, treatment can usually palliate symptoms, but organ failure—​including eye, liver, cardiac, or respiratory—​can occur as a result of disease. Most series from referral centres report 5% disease-​related mor- tality, with 1% probably the rate in nonselected patients. The most common cause for sarcoid-​related death is respiratory failure, with cardiac, neurological, and liver disease as other causes. Respiratory failure leading to death can be predicted from pulmonary function tests, for example, one study found no patient with a vital capacity of more than 1.5 litres died from respiratory failure, whereas one-​ third of those with vital capacity persistently less than 1 litre died of this complication. In patients with severe restriction the best predictor of death was presence of pulmonary hypertension and evidence of right heart failure (as associated with an elevated right atrial pressure). Recent studies, including a large retrospective study from the United States, suggest a rise in the mortality from sarcoidosis over the past 20 years. Organ transplantation has been successfully performed in sarcoidosis patients: although sarcoid- osis lesions can occur in the new organ, organ failure due to sar- coidosis is unlikely. Particular complications As stated earlier, end-​stage lung disease is the most common problem for patients with severe sarcoidosis, with fibrotic disease leading to cor pulmonale and respiratory distress. In addition, cavi- tary lesions can lead to bronchiectasis or become colonized with aspergillus. Aspergillomas can cause haemoptysis, which can be fatal, and treatment is difficult because most patients are not good surgical candidates: embolization has been used for life-​threatening bleeding. In studies of patients who are persistently dyspnoeic due to sar- coidosis, up to 50% have pulmonary hypertension. Factors associ- ated with this are stage 3 or 4 chest radiograph, hypoxia, and reduced DLco. A right heart catheterization is an important part of their evaluation because they may have coincident left ventricular disease. Precapillary pulmonary hypertension in sarcoidosis has a higher risk of mortality than patients with similar advanced pulmonary sarcoidosis without pulmonary hypertension. In case reports of

section 18  Respiratory disorders 4218 patients with sarcoidosis associated pulmonary arterial hyperten- sion, both epoprostenol and bosentan have been reported as useful, working independently of any anti-​inflammatory drugs used to treat the underlying condition. Steroid-​induced osteopenia is a significant problem with long-​ term corticosteroid therapy. Patients are often not treated initially with calcium supplements because of the risk of hypercalcaemia, but calcium supplementation should be considered if a patient requires long-​term systemic steroids, with monitoring serum calcium during therapy usually sufficient to avoid complications. The use of nasal calcitonin or bisphosphonates should also be considered if the pa- tient requires prolonged therapy. Cardiac sarcoidosis can lead to sudden death, hence arrythmias must be evaluated in patients with sarcoidosis. Continuous elec- trocardiographic monitoring is useful to identify episodes, and we use electrophysiological studies in patients with symptomatic arrythmias to determine their source. Treatment of the sarcoid- osis alone may be insufficient to control rhythm disturbances in patients with ventricular arrythmias:  an implanted defibrillator may be required, particularly for those with refractory ventricular tachyarrthymias. Areas of uncertainty/​controversy Some clinicians have proposed the use of bronchoalveolar lavage as the exclusive diagnostic test for sarcoidosis: this is based on the rationale that, in the appropriate clinical setting, findings of in- creased lymphocytes and a CD4:CD8 ratio greater than 3.5 repre- sents a granulomatous process. In patients with cultures negative for tuberculosis and fungal infection, sarcoidosis is most likely and no further diagnostic testing may be needed. However, the per- centage of patients with increased lymphocytes and CD4:CD8 ratio varies from centre to centre: in our institution at least 50% will meet these criteria, but the use of bronchoalveolar lavage does not provide an absolute diagnosis of sarcoidosis. As previously noted, transbronchial needle aspirate may also be useful in making a diagnosis, but the finding of a granuloma does not assure the diagnosis. The use of corticosteroids for the treatment of sarcoidosis remains controversial. In the patient with minimal symptoms, treatment can be withheld or topical. If the disease spontaneously resolves, no therapy is indicated. However, if the patient becomes symp- tomatic, corticosteroids will probably be useful. The best treatment of the patient with persistent, mild disease is unclear: the British Thoracic Society study suggests that these patients should receive corticosteroids; others argue that the differences are small and do not justify treatment. Possible future developments The cause of sarcoidosis remains unknown. Newer molecular bio- logical techniques may provide further insight into a causative agent and/​or an underlying genetic predisposition for the disease, and study of causality may provide better answers to other questions in the disease process as well. The patient with chronic disease represents a disproportionate number of cases with increased morbidity and need for medical services, and the use of corticosteroids alone is not adequate for many of these. Research is still required into whether other agents are truly steroid sparing and associated with improved clinical out- come, and pulmonary arterial hypertension and its treatment have to be studied in these chronic cases. The quality of life of patients with sarcoidosis is affected by both the disease and its treatment. Corticosteroids may cause more prob- lems than benefit, and steroid-​sparing drugs also have their toxicity. Fatigue is a major complaint for the patient and not well treated by our current drugs: new agents such as modafinil and methylphenidate are being developed to treat fatigue and may be applicable in sarcoidosis. FURTHER READING Baughman RP, et al. (2001). Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med, 164, 1885–​9. Baughman RP, et al. (2006). Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med, 174, 795–​802. Baughman RP, et al. (2011). A concise review of pulmonary sarcoid- osis. Am J Respir Crit Care Med, 183, 573–​81. Baughman RP et  al. (2013). Established and experimental medical therapy of pulmonary sarcoidosis. Eur Respir J, 41, 1424–​38. Baughman RP, Wells A (2019). Advanced sarcoidosis. Curr Opin Pulm Med, 25, 497–504. Keijsers RG, et al. (2013). Imaging the inflammatory activity of sar- coidosis. Eur Respir J, 41, 743–​51. Song Z, et  al. (2005). Mycobacterial catalase-​peroxidase is a tissue antigen and target of the adaptive immune response in systemic sar- coidosis. J Exp Med, 201, 755–​67. Spagnolo P, et al. (2018). Pulmonary sarcoidosis. Lancet Respir Med, 6, 389–402. Valeyre D, et al. (2014). Sarcoidosis. Lancet, 383, 1155–​67.

18.13 Pneumoconioses 4219 P.T. Reid

18.13 Pneumoconioses 4219 P.T. Reid

ESSENTIALS Pneumoconiosis describes the pathological reaction of the lung to inhaled dust, most often, but not exclusively, related to exposures occurring at work. It may be defined as a permanent alteration of lung structure due to the inhalation of mineral dust and the tissue reactions of the lung to its presence, excluding bronchitis and emphysema. The causes of pneumoconiosis are many and varied, but coal worker’s pneumoconiosis, asbestosis, and silicosis are most common. Many epidemiological studies have shown an exposure–​response relationship between the total mass of respirable dust to which workers have been exposed and their risk of developing disease. These form the basis of regulations specifying limits to permitted levels of exposure. Workers who develop pneumoconiosis as a con- sequence of their employment may be entitled to compensation in some countries. Coal worker’s pneumoconiosis Caused by inhalation of coal-​mine dust. Now uncommon in the United Kingdom and other Western countries, but in China the disease is widespread, and in India it affects about 1–​2% of the coal industry workforce. Simple coal worker’s pneumoconiosis causes no respiratory symptoms or physical signs and is recog- nized by the detection of coal macules on chest radiography. Complicated pneumoconiosis is characterized by the appearance of progressive massive fibrosis, which may be diagnosed when any radiographic lesion exceeds 1 cm in diameter. This condi- tion often progresses, causing mixed airflow obstruction and restriction, and—​when severe—​leads to respiratory failure, cor pulmonale, and death. Asbestosis Exposure to asbestos fibres can cause a range of respiratory con- ditions, including benign pleural plaques, acute effusion, dif- fuse fibrosis of the visceral pleura, asbestosis, and mesothelioma. Asbestosis occurs only in people working regularly with asbestos over several years and not in those with occasional or incidental ex- posure. Disease is usually progressive, with radiological appearance identical to idiopathic pulmonary fibrosis (i.e. predominantly basal and peripheral irregular linear shadowing, progressing to honeycombing). The risk of lung carcinoma is related to asbestos exposure, interacting multiplicatively with smoking. Silicosis Caused by inhalation of crystalline silicon dioxide, usually in the form of quartz. Crystalline silica is highly fibrogenic, causing fibrous pleural adhesions, enlarged lymph nodes that contain fibrotic nodules and often calcify, and grey nodules throughout the lung with a typical whorled appearance when cut across. The clinical presentation ranges from acute silicosis, which is very rare, but leads to death within months, to slowly progressive lung fibrosis, to asymptomatic radiological abnormalities. The progression of silicosis may be complicated by tuberculosis, lung cancer, chronic obstructive pulmonary disease, and rarely by connective tissue
disease and renal damage. Introduction The inhalation and clearance of inhaled particles and fibres Respiration involves the inhalation of a variety of airborne dusts and fibres, which may be in the environment. Airborne dusts may be defined as small, solid particles, conventionally taken as those particles below 75 microns in diameter, which settle out under their own weight, but which may remain suspended for some time. Particle behaviour also depends on the aerodynamic properties (size, shape, and density), and the anatomical, clear- ance, and immune mechanisms of the lung into which they are inhaled. Most inhaled particles with a diameter greater than 7 mi- crons are trapped by the nose and expelled forcibly by sneezing or more gently by the nasal mucociliary escalator. However, physical activity, as often occurs during manual work, increases mouth breathing. Particles inhaled by the oral route impact on the vocal cords and may be expelled by coughing or pass into the 18.13 Pneumoconioses P.T. Reid

section 18  Respiratory disorders 4220 trachea and major bronchi, where they are trapped by airway mu- cous and transported caudally by the cilia to the upper airway, to be either expectorated or swallowed. Mucociliary clearance operates from the trachea to the terminal bronchioles. Cilia beat with a synchronous motion causing the mucous layer to have a continued upward movement of 5–​10  mm/​min. Ciliary clearance may be significant impaired by cigarette smoke and ‘dust overload’. Particles that escape entrapment by airway mucus may be engulfed and digested by macrophages and neutrophils. Soluble particles may enter the body by dissolution. Very small particles, usually taken to be between 0.5 and 7 microns may travel as far as the alveolar regions and these are termed respirable particles. In common with larger particles, the aerodynamic characteris- tics of fibres are also affected by their size and shape. Short thick fibres are deposited in the upper respiratory tract and cleared by mucociliary action to the pharynx where they are expectorated, whereas longer and thinner fibres may transit to the alveolar regions. On reaching the alveolar units, most inhaled particles are cleared by alveolar macrophages either by the airways to the pharynx or via the lymphatic system to the regional lymph nodes. Macrophages are avidly phagocytic and engulf, among other things, bacteria, surfactant, cell debris, and respirable particles. Increased numbers of alveolar macrophages, derived from per- ipheral blood monocytes, are recruited to the lungs of individ- uals exposed to dust and become resident in both the pulmonary interstitium and the alveolae. Ultrafine dust particles may directly traverse the epithelium entering the pulmonary interstitium. Free particles that are not ingested by macrophages enter the peri- vascular lymphatic channels to be translocated to the draining mediastinal lymph nodes as free particles or within macro- phages. Ciliary clearance operates rapidly; for example, around 12 hours, but clearance by macrophages takes place over days to months. Longer fibres (over 100 μm in length) are cleared at a much slower rate, thereby being retained in the lung for longer periods. For any individual, there is an important relationship between the cumulative amount of dust inhaled and the ability of the lung to clear this dust. Lung damage occurs when respirable dusts reach the acinus in sufficient quantity to overwhelm the normal phagocytic and clearance mechanisms. The pathophysiology of pneumoconioses Most dust accumulates in the upper lobes and hence, with the not- able exception of asbestosis, pneumoconiosis has a predilection for these. Slightly more dust is deposited in the right than the left lung, although this is seldom clinically apparent. Some dusts, such as carbon or tin, are relatively inert, but most others initiate the recruitment and activation of inflammatory cells and the release of pro-​inflammatory and pro-​fibrotic medi- ators. Commonly described tissue reactions include the forma- tion of macules, nodules, interstitial fibrosis, granulomata, and emphysema. The tissue reaction may be confined to the lung, or—​as is the case with asbestos—​involve the pleura. Silica-​exposed workers may develop autoantibodies which, in some cases, precede the development of connective tissue disease. Systemic toxicity may follow the inhalation of lead, cadmium, beryllium, and manganese. Several inhaled particles and fibres, notably asbestos, silica, hexa- valent chromium, certain chromates, arsenic (elemental and organic compounds), particles containing polycyclic aromatic hydrocar- bons and certain nickel-​bearing dusts, act in a synergistic manner with tobacco to trigger carcinogenesis. Most inhaled particles known to cause pneumoconiosis do so through altering macrophage function. The inability of macro- phages to effectively phagocytose crystalline silica and amphibole asbestos is invariably accompanied by necrosis and disintegration of the cell, accompanied by the liberation of the ingested silica, which may be re-​ingested and cause death of other macrophages. The biopersistence of silica and asbestos in the lung leads to a self-​ perpetuating inflammatory response and the progressive deposition of collagen. Beryllium acts via a CD4 + T cell-​mediated inflammatory mechanism. The positively charged metal is internalized by major histocompatibility (MHC) class  II peptides, resulting in a con- formational change on the surface of the cell. Beryllium specific toll-​like receptors do not recognize beryllium itself, but the change in the surface of the complex induced by internalization of the metal. Thus, the mechanisms underpinning chronic beryllium dis- ease are believed to lie on the border between allergic hypersensi- tivity and autoimmunity. The radiology of pneumoconioses The presence of pneumoconiosis is usually heralded by a profu- sion of rounded and irregular opacities, most often, but not always, predominating in the upper lobes. Complications such as emphy- sema, tuberculosis, and malignancy may also be observed on plain chest radiographs. Chest radiograph In 1950, the International Labour Office (ILO) issued guidance on how best to describe the radiographic abnormalities produced by the inhalation of dust. The system has undergone several iterations and was most recently updated in 2011, with the current edition pro- viding advice on the acquisition, display, and storage of digital chest images. The reporting of films is undertaken by certified readers who compare the image they are reporting with a standard set of films. Following a comment on the technical quality, readers record their opinion on the presence of any abnormalities in the parenchyma and pleura. Each lung field is divided into three zones (upper, middle, lower) by horizontal lines drawn at approximately one-​third and two-​thirds of the vertical distance between the lung apices and the domes of the diaphragm. The profusion of small opacities, which refers to the concentration of opacities per unit area of lung, is de- termined by considering the profusion as a whole over the affected zones. Should the reader encounter marked (three subcategories or more) difference in profusion between different zones, then the zone or zones showing the least degree of profusion is/​are ignored for the purpose of classifying the overall profusion. Parenchymal abnormalities may be classified according to their size and shape. Opacities up to 1.5 mm, 1.5–​3 mm, and 3–​10 mm,

18.13  Pneumoconioses 4221 are called ‘p’, ‘q’ and ‘r’ respectively if rounded in appearance and ‘s’, ‘t’ and ‘u’ respectively if irregular in appearance. A large opacity is de- fined as an opacity having the longest dimension exceeding 10 mm and may be further categorized as A B or C. Category A refers to one large opacity having the longest dimension up to about 50 mm, or several large opacities with the sum of their longest dimensions not exceeding about 50 mm. Category B refers to one large opacity having the longest dimension exceeding 50 mm, but not exceeding the equivalent area of the right upper zone, or several large opacities with the sum of their longest dimensions exceeding 50  mm but not exceeding the equivalent area of the right upper zone. Finally, category C refers to one large opacity which exceeds the equiva- lent area of the right upper zone, or several large opacities which, when combined, exceed the equivalent area of the right upper lobe. Finally, the reader comments on pleural abnormalities such as pleural plaques, costophrenic angle obliteration, and diffuse pleural thickening. The category which best describes the radiographic appearances under consideration is recorded as the first choice. In cases where a reader gives serious consideration to an alternative, then the first and second choices are separated by a slash. For example, if the first choice was category 1, but category 2 was seriously considered, the reading 1/​2 is recorded. If no other category was given serious con- sideration, the number is listed twice (e.g. 1/​1). The application of the ILO classification represents an attempt to standardize descriptions and facilitate international compari- sons of data on pneumoconioses, providing a tool for epidemio- logical investigation and research reports. It is not intended as a diagnostic tool and limited inference may be made as to the causative agent. It should not be used when forming an opinion on working capacity, and the system is not intended for compen- sation purposes. High-​resolution computed tomography The greater sensitivity and specificity of high-​resolution com- puted tomography (HRCT) overcomes many of the limitations of the chest X-​ray. Its significantly greater sensitivity allows the pres- ence of pneumoconiosis to be detected at a much earlier stage, even when the chest X-​ray is normal, and the ability to observe both the extent and the pattern of distribution affords the radiologist a greater opportunity to comment on the likely differential diagnosis. For example, diseases causing nodules such as pulmonary tubercu- losis (which may complicate silicosis), sarcoidosis, hypersensitivity pneumonitis, and respiratory bronchiolitis–​interstitial lung disease may be more readily discriminated from a pneumoconiotic reac- tion by HRCT. Furthermore, the extent of radiological abnormality shown on HRCT correlates with the physiological or functional outcome, which is particularly helpful when the interpretation of lung function testing is confounded by a combination of pul- monary and pleural pathologies. Positron emission tomography Positron emission tomography (PET) exploits the avid ability of malignant tissue to absorb and metabolize glucose and have become central to staging malignant disease. In patients with pneumoconioses, the use of PET/​CT may assist in the differenti- ation between the appearance of benign lesions such as progressive massive fibrosis (PMF) and lung cancer, and benign and malignant pleural lesions in asbestos-​exposed workers. Coal worker’s pneumoconiosis Coal worker’s pneumoconiosis (CWP) describes the reaction of the lung to the inhalation of coal and coal dust. It may be classified as simple or complicated. Coal is a complex chemical structure derived from peat. The principal constituent is carbon, which is present in varying pro- portions depending on the grade or rank of the coal. Lignite, the lowest rank coal contains the least carbon, whereas anthracite con- tains the highest rank; bituminous coal is intermediate rank. Higher rank coals have a greater calorific value. Coal also contains minerals originating from the rock in which it was formed, the most im- portant of these being silica. Coal worker’s pneumoconiosis rose to prominence in the United Kingdom shortly after the Second World War, when around 3000 men per annum were identified with the condition. Cooperation be- tween the Medical Research Council and the National Coal Board led to an increased understanding of the condition, which in turn led to improvements in occupational hygiene controls. This, together with the decline of the mining industry, has resulted in the condi- tion becoming of largely historical interest in the United Kingdom. By contrast, in China the disease is widespread and in India it affects about 1–​2% of the current coal industry workforce of 800 000. The strategic importance of coal as a long-​term source of fuel supply and as a chemical feedstock means that it will continue to be needed, and any relaxation of dust control in mines for any reason will be followed by the reappearance of pneumoconiosis, such as has been described in young coal miners from West Virginia, United States. Aetiology and pathology The incidence and clinical manifestations following the inhalation of coal dust vary from mine to mine reflecting the influence of both the rank of coal and the constituency of the respirable dust. As a general rule, the higher the rank, the more likely the dust will cause pneumoconiosis (Fig. 18.13.1). In addition, the presence of Dust concentration (mg/m3) 1 2 3 4 5 6 7 8 0 Probability 20 15 10 5 0 High rank (91%) Low rank (83%) Fig. 18.13.1  Relationship between risk of category 2 or 3 radiological simple pneumoconiosis and daily exposure over a working lifetime to different concentrations of coal dust. The greater risk in association with exposure to dust from coals of higher combustibility (rank) should be noted.

section 18  Respiratory disorders 4222 different minerals in coal dust may modify the biological potency; for example, mining in areas with siliceous rock leads to the de- velopment of a condition more closely resembling silicosis. Some forms of clay may reduce the overall toxicity, probably by blocking the surface activity of the toxic fraction. An increased susceptibility to coal worker’s pneumoconiosis is conferred by polymorphisms in genes regulating the inflammatory response such as glucocorticoid-​ induced tumour necrosis factor receptor-​related protein (GITR), NOD-​like receptor family, pyrin domain-​containing 3 (NLRP3), and mucin 5B gene (MUC5B). The earliest manifestation of coal worker’s pneumoconiosis is the formation of the coal macule, an aggregation of dust-​laden macro- phages and free dust in a centriacinar distribution (Fig. 18.13.2). Macules are loosely bound by a reticulin framework and assume a stellate appearance. The absence of collagen renders them soft and impalpable to the pathologist and their presence does not equate to a formal diagnosis of CWP. However, if the response involves greater deposition of collagen, the more easily palpable nodule may develop. If these are less than 10 mm in dimension then this is pathologically regarded as CWP. Macules have no effect on lung function and simple CWP only a limited effect. The coal macule is often surrounded by enlarged air spaces referred to as focal emphysema, which differs only from classical centriacinar emphysema by virtue of the presence of retained dust. Complicated CWP includes cases were the fibrous nodules ex- ceed 10 mm size, up to an including the presence of PMF. PMF con- sists of irregular masses of fibrous tissue that, by definition, exceed 1 cm in diameter (Fig. 18.13.3). It most often occurs against a back- ground of simple pneumoconiosis and is most common in the upper lobes. The condition occurs either by aggregation of several, usually collagenous, smaller nodules, or through a more diffuse accumula- tion of dust associated with dead cells and ischaemic necrosis of lung tissue. The former mechanism is less common and occurs particu- larly in relation to relatively high quartz exposures, while the latter seems more frequent with exposure to high-​carbon dusts. With ei- ther type there is a tendency for the lesions to grow and become associated with surrounding bullous emphysema. Central necrosis is common, and when cut the lesions may contain black fluid and cholesterol crystals. High-​carbon or high-​quartz dusts are particu- larly liable to cause the condition, and the higher the dust exposure the greater is the risk (Fig. 18.13.4). Clinical features CWP is most often described in underground coalminers, but anyone who inhales sufficient quantities ought to be considered at risk and the condition has been described in surface workers. Simple coal worker’s pneumoconiosis Simple CWP is asymptomatic and usually detected by chest radio- graph performed for the purposes of surveillance or the investi- gation of unrelated respiratory symptoms. Typical appearances include a profusion of small, discrete rounded opacities with an upper and middle zone predominance. It has been proposed that ‘p’ type opacities represent macules, ‘q’ type opacities represent stellate nodules, and ‘r’ type opacities represent rounded nodules. Fig. 18.13.2  Simple coal macules, showing accumulations of dust within macrophages but without fibrosis arranged around the centre of the acinus with associated emphysema. Fig. 18.13.3  Whole-​lung section of a coal miner’s lung showing progressive massive fibrosis. 15 10 5 0 Dust concentration (mg/m3) 1 2 3 4 5 6 7 8 0 Probability High rank (91%) Low rank (83%) Fig. 18.13.4  Relationship between risk of progressive massive fibrosis and exposure to dust over a working lifetime. Greater risk in association with exposure to dust from coals of higher combustibility (rank) should be noted.

18.13  Pneumoconioses 4223 In addition, the accumulation of dust in the alveolar septae and pleural lymphatics is reflected by the presence of small irregular and linear opacities and Kerley B lines, which are more frequently present in the lower zones (Fig. 18.13.5). As simple CWP is asymptomatic, should a miner report respira- tory symptoms or develop physical signs, some other cause should be sought, such as chronic obstructive pulmonary disease, heart failure, or asthma. Progressive massive fibrosis The development of PMF is often accompanied by the development of symptoms, including cough, sputum, and shortness of breath. Melanoptysis, the expectoration of black contents from a cavitated lesion, may be reported. PMF usually occurs during working life, but it may appear for the first time many years after dust exposure has ceased. Simple CWP is usually present, typically ILO category 2/​3. The pattern and rate of change of PMF lesions is variable but al- most always starts in the upper zone, gradually increasing in size until they may occupy up to one-​third of the lung. Such lesions are frequently multiple, often shaped like short fat sausages, with their outer border curved with the chest wall and separated from the pleura by bullous emphysema (Fig. 18.13.6). Enlarged mediastinal and hilar nodes often accompany them. Chronic obstructive pulmonary disease Detailed research undertaken by the Pneumoconiosis Field Research programme and others have consistently demonstrated that coalminers are at increased risk of reporting chronic bronchitis, developing airflow obstruction, and experiencing an accelerated de- cline in lung function, that are all broadly related to their cumulative dust exposure. Pathological studies demonstrate a relation between exposure to coal-​mine dust and emphysema, and mortality studies confirm increased deaths from chronic bronchitis and emphysema in miners. Most studies suggest that the effects of dust exposure and smoking in causing loss of lung function are additive. Caplan’s syndrome In 1953, Anthony Caplan described the high prevalence of multiple, well-​defined, round opacities, 0.5–​5  cm. in diameter, distributed throughout both lung fields, but particularly at the periphery, in coal miners who suffered from rheumatoid arthritis. In contrast to PMF, background simple pneumoconiosis was often slight or absent (e.g. ILO category 1 or 0). The opacities of Caplan’s syndrome typically appear rapidly, within months, and while they may progress, more often than not remain stable. There is rarely any associated significant pulmonary impairment. Cavitation and calcification are frequent and in many instances the lesions become confluent and may be radiographic- ally indistinguishable from PMF. The differential diagnosis includes malignancy, silicosis, pulmonary tuberculosis, and granulomatosis with polyangiitis (Fig. 18.13.7). Fig. 18.13.5  Radiograph of a coal miner showing small round lesions of simple pneumoconiosis. Some irregular shadows are also present in the lower zones. Fig. 18.13.6  CT scan of miner, showing central progressive massive fibrosis and surrounding bullous emphysema. Fig. 18.13.7  CT scan appearances in a patient with Caplan’s syndrome. Image kindly provided by Dr Arnie Debaraj, Royal Brompton and Harefield NHS Trust.

section 18  Respiratory disorders 4224 Independent immunological studies showed that many miners with these radiographic appearances, or the classical chest radio- graphic changes of the rheumatoid pneumoconiosis syndrome, had positive rheumatoid factor tests, despite their having no history, symptoms, or signs of rheumatoid arthritis. Pathological inspection of Caplan’s lesions typically reveals large necrobiotic nodules with palisaded histocytes similar to that ob- served in rheumatoid nodules. Dust may be observed in circular bands or arcs within the necrotic centres of the lesions. The appear- ance bears no relationship with the severity of extrapulmonary dis- ease activity or serological activity and, as inferred from the mild degree of background pneumoconiosis, no particular relationship with dust burden. Prognosis It is unusual for simple CWP to progress once a miner has ceased dust exposure. The exceptions to this include those in whom a sili- cotic element is present, and those in whom PMF develops. If PMF is present, the condition usually progresses and causes a mixture of restrictive and, owing to associated emphysema, obstructive venti- latory patterns. The rate of progression is variable. In general, the earlier PMF develops in a person’s life, the more rapidly progressive the condition, and thus the worse the prognosis. In severe cases, PMF may progress to cause respiratory failure, cor pulmonale, and death. Coal worker’s pneumoconiosis is not associated with an increased risk of tuberculosis or lung cancer, although obviously these diseases can occur in coal miners and should be suspected, dependent on risk (e.g. living in an endemic area or smoking), if there is unusual pro- gression of radiological changes. Prevention and management The exposure–​response relationship between the total mass of res- pirable coal dust and the risk of developing coal worker’s pneumo- coniosis has allowed standards to be set for coal-​mine dust levels that have resulted in a reduced prevalence of the disease in coal mines in developed countries. This success is dependent on adher- ence to control measures, such as regular monitoring of the respir- able dust, constant attention to dust suppression by ventilation, and the use of water at points of dust production, combined with regular radiography of the workforce to detect early signs of dust retention. Preventing miners from contracting simple pneumoconiosis, by controlling the level of dust exposure, largely controls the incidence of PMF. The present United Kingdom standard is 7 mg/​m3, meas- ured in the air returning from the coalface. If a miner develops simple pneumoconiosis late in his career, no action is normally required, apart from (in the United Kingdom) ad- vising him to apply to the Respiratory Diseases Board via the Benefits Agency for assessment of disablement and possible benefit payments. A younger man, with several years of potential dust exposure ahead, should be advised to work in an area of approved low dust conditions. In the United Kingdom the employer’s occupational health provider would usually give this advice. Men with more than the earliest stages of radiological change are entitled to disablement benefits from the Benefits Agency, the value of these depending on the extent of dis- ability. Since simple pneumoconiosis per se does not disable, these benefits are often small. Payment of benefits for airflow obstruction as an associated effect of coal dust exposure are also made in the United Kingdom if the miner has worked underground for a minimum of 20 years and his FEV1 is 1 litre below that predicted. The presence of associated radiological change is not necessary. Following a legal judgement in the United Kingdom, civil compensation through the government is now available for individuals with symptoms of chronic bronchitis or with airflow obstruction, and such workers should be referred to their trade union for advice. Asbestosis Asbestos is a generic term for a group of fibrous silicates, the most important being chrysotile (white), crocidolite (blue), and amosite (brown). Chrysotile has a serpentine configuration and breaks up into microfibrils, while the other types (amphiboles) are straight and less liable to longitudinal fracture (Fig. 18.13.8). All types are resistant to physical and chemical destruction, which gives them their commercial value in fireproofing, insulation, reinforcement of Fig. 18.13.8  Scanning electron micrographs of (a) chrysotile and (b) amosite on Millipore filters. The curly configuration and microfibrils of chrysotile should be noted. Scale bar, 4 µm.

18.13  Pneumoconioses 4225 cement, weaving into cloth, bonding in brake linings and plastics, and so on. Asbestos is mined principally in Canada, South Africa, and the former Soviet Union. The inhalation of asbestos fibres causes several separate pleuropulmonary lesions including pleural plaques, acute benign asbestos pleurisy, diffuse (visceral) pleural thickening, lung cancer, and mesothelioma (discussed in Chapter 18.19.3). Asbestosis refers to the development of diffuse pulmonary fibrosis following inhal- ation of excessive amounts of asbestos fibres. Aetiology and pathology The toxicity of asbestos fibres may be related both to their dimen- sions and their persistence in lung tissue. The amphiboles crocidolite (blue asbestos) and amosite (white asbestos), and anthophyllite ap- pear to be more fibrogenic than chrysotile (white asbestos). However, all types of asbestos increase the risk of asbestosis if a sufficient dose is inhaled. It has widely been accepted that clinical asbestosis can be in- duced by cumulative asbestos exposure amounting to an estimated 25 fibres/​ml–​yrs. However, assuming the diagnosis is correct, this depends to some extent on how the diagnosis of asbestosis is as- certained and the fibres involved. Subclinical asbestosis, which may be detected incidentally by HRCT, can result from much lower cumulative doses. The macroscopic appearances of asbestosis reflect the severity of the disease. The typical change is of grey fibrosis, more marked per- ipherally and in the lower zones (Fig. 18.13.9). In advanced disease, the lungs are shrunken and display honeycomb change. The air- ways are generally unremarkable, although traction bronchiectasis may be observed if fibrosis is severe. Lymph nodes may be enlarged but show no significant abnormalities on their cut surface. Pleural plaques or pleural thickening may be present. The microscopic features comprise both an appropriate pattern of interstitial fibrosis and the finding of asbestos bodies (Fig. 18.13.10). Fibrosis in asbestosis is always paucicellular, lacking any significant degree of inflammation, and is collagenous rather than fibroblastic. The distribution is similar to usual interstitial pneumonia, being predominantly lower lobe and peripheral, but with the temporal and spatial homogeneity of the fibrotic variant of nonspecific inter- stitial pneumonitis (NSIP). Fibroblastic foci may be observed but are uncommon. Honeycombing may be seen in advanced cases (Fig. 18.13.11). Asbestos bodies are formed when asbestos fibres are coated with a protein–​ferritin complex. They are usually readily identified in Fig. 18.13.9  Macroscopic picture of the lung from an individual with asbestosis. Photograph kindly provided by Dr Richard Attanoos, Llandough Hospital, Vale of Glamorgan. Fig. 18.13.10  Histological appearance of asbestosis, with interstitial fibrosis and asbestos bodies from a case of asbestosis. Photograph kindly provided by Dr Richard Attanoos, Llandough Hospital, Vale of Glamorgan. Fig. 18.13.11  Histological appearance of asbestos bodies. Photograph kindly provided by Dr Richard Attanoos, Llandough Hospital, Vale of Glamorgan.

section 18  Respiratory disorders 4226 haematoxylin and eosin-​stained or Perls-​stained sections as dumb-​ bell like structures. It is important to recognize that the pathologist may only detect ferruginous bodies, that is, asbestos bodies coated with, as described earlier, iron-​containing compounds, and un- coated fibres may be more frequent. The finding of asbestos bodies alone is insufficient for a histologic diagnosis of asbestosis and indi- cates only asbestos exposure. In most cases of asbestosis at least two asbestos bodies should be observed per cm2 of lung. In rare cases, fewer bodies are seen and the heavy fibre burden necessary for the diagnosis of asbestosis is only demonstrated by more sophisticated techniques involving tissue digestion. Clinical features The appearance of asbestosis follows a latent period, which is typ- ically at least 20 years from initial exposure. Shorter latent periods have been described in those with much higher exposures but are uncommon nowadays, and the typical latent period is becoming longer as the pattern of disease changes with less severe forms of asbestosis being recognized by HRCT. The symptoms of asbestosis are similar to those of other fibrosing lung diseases, with shortness of breath, initially on exertion, and dry cough. Repetitive end-​inspiratory basal crackles may precede symptoms, and finger clubbing may be observed, but this is usually a late feature. The typical chest radiographic changes are shown in Fig. 18.13.12. The classical lung function abnormalities include a restrictive ventilatory defect in the presence of reduced volumes and transfer factor, but these may not be present in those with early or limited asbestosis. The greater sensitivity and specificity of HRCT provides greater delineation of parenchymal and pleural changes and is particularly useful if the chest radiograph is normal or only minimally abnormal, as may be the case in early disease. HRCT asbestosis (Fig. 18.13.13) evolves from isolated dot-​like structures in the periphery of the lower lung, which correlate with peribronchiolar fibrosis found on histology, to pleural-​based intralobular and interlobular lines, ground-​glass attenuation, and finally honeycombing. HRCT scan- ning is also useful when emphysema or other respiratory pathology is present as it allows quantification of the relative contributions of different pathologies. The severity of asbestosis present in an individual may be classi- fied according to four grades. Grade 1 or Grade 2 asbestosis is not accompanied by clinical or radiological signs of disease and can be made only by histological examination of tissue obtained by biopsy in life or at post-​mortem. Grade 3 and Grade 4 cases have radio- logical changes and symptomatic clinical signs of the disease. There is a broad correlation between the severity of disease and the level of asbestos exposure. However, there are wide variations within that spectrum, reflecting differing individual susceptibilities. Differential diagnosis In most cases the diagnosis of asbestosis can be confidently estab- lished on the basis of the history, clinical presentation, and radio- logical features. However, the differentiation of asbestosis from other causes of pulmonary fibrosis, particularly, idiopathic pulmonary fi- brosis or the fibrotic form of NSIP, is important from the point of view of prognosis and of management, including giving advice on compensation issues. In such cases it can be helpful to focus on the Fig. 18.13.12  Radiograph of a thermal insulator (lagger) with asbestosis. The typical chest radiographic changes are those of small irregular opacities, becoming increasingly coarse as the disease progresses and eventually coalescing to form a honeycomb pattern. In advanced asbestosis the fibrosis obscures the cardiac border, giving a shaggy appearance. In this case, a calcified TB focus is present in the right upper zone. Fig. 18.13.13  CT from a patient with mild asbestosis showing a fine reticular pattern and subpleural lines. Bilateral pleural plaques are present. Image kindly provided by Dr Michael Rubens, Royal Brompton and Harefield NHS Trust.

18.13  Pneumoconioses 4227 history of asbestos exposure, the presence of pleural disease, and if follow-​up has occurred over a sufficient interval, the natural history of the condition. The development of asbestosis requires substantial exposure to asbestos, in terms of both intensity and duration and the pres- ence of a history of substantial asbestos exposure. The diagnosis should rarely be entertained in an individual with light or oc- casional exposure. If the individual has been under observation for a sufficient period, the rate of progress of the disease may be helpful. While rare cases of asbestosis with rapid progression are recognized, the clinical picture is typically one of slow change, contrasting with the more rapid progression of idiopathic pul- monary fibrosis. The presence of pleural plaques (Fig. 18.13.14) is consistent with prior asbestos exposure, but pleural plaques may develop following lower levels of asbestos exposure than those necessary to cause as- bestosis, hence on their own they are insufficient to confidently es- tablish the diagnosis of asbestosis. Investigation If the diagnosis remains uncertain on clinical and radiological grounds, tissue biopsy may be contemplated. Given the uneven distribution of asbestosis, tissue samples should be taken from more than one site. If tissue is being obtained during resection of tumour, then, in the case of pneumonectomy, peripheral and central blocks should be taken from each lobe, and in the case of lobectomy, at least one peripheral and one central section should be examined. Areas immediately adjacent to tumour should be avoided. In post-​mortem cases minimal sampling should include blocks from the peripheral and central portions of each lobe of both lungs. As just stated, the histological criteria required include both a conventional pattern of alveolar septal fibrosis and an average of at least two asbestos bodies per square centimetre of lung tissue. In most cases asbestos bodies are readily identified in haematoxylin and eosin-​stained sections, but they may be more easily identified and counted with Perl’s stain. Fibroblastic foci may be occasionally observed in cases of asbestosis, but their presence is more typical of idiopathic pulmonary fibrosis, especially when numerous. In ex- ceptional cases, where continuing diagnostic doubt exists, a more detailed fibre analysis may be undertaken by transmission electron microscopy or scanning electron microscopy. Energy-​dispersive X-​ray analysis may be used with both techniques, facilitating iden- tification of the chemical composition of individual particles con- firming fibre type. Prognosis Cases of rapidly accelerated asbestosis associated with high levels of asbestos exposure have been described, but are rare nowadays in the United Kingdom. In most individuals late onset asbestosis reflects relatively low dose asbestos exposure over a very pro- longed period of time; progression is typically slow and some- times imperceptible. As asbestos and tobacco act as synergistic carcinogens, it is particularly important to advise individuals with asbestosis who smoke tobacco to stop smoking as they are at very high risk of lung cancer. The risk of lung cancer is greatest fol- lowing exposure to amphiboles such as crocidolite and amosite, but is also present, albeit to a much lesser extent, following ex- posure to chrysotile. Prevention and management The prevention of asbestosis, as of other pneumoconioses, depends on reducing the exposure of individuals to levels that have been shown to be insufficient to cause the disease in a lifetime of exposure. Unfortunately, the difficulties of making valid measurements of air- borne fibres and the uncertainties attached to the early diagnosis of asbestosis have prevented the formulation of reliable evidence on which to base a standard. The present British standard for chrysotile of 0.3 respirable fibres/​ml has been based on work that suggests such levels would, when breathed over a working lifetime, result in asbes- tosis in less than 1% of those exposed. The corresponding standard for amphiboles is 0.2 fibres/​ml. However, it should be noted that these concentrations do not take account of the much more serious risk of mesothelioma (see Chapter 18.19.3), and for this reason use of the mineral is now banned in the United Kingdom. It should also be noted that a concentration of 0.1 fibres/​ml sounds small until it is realized that it represents 100 fibres/​litre, or many hundreds of thou- sands of fibres inhaled over a working day. The need for a material with the properties of asbestos has meant that many industries have now introduced other fibrous or crys- talline minerals in its place. The potential of such new materials to cause similar diseases depends on their fibre dimensions, solubility in tissue, and the concentrations achieved in the workplace air. It is important that they should be handled with appropriate care by industry. Regular medical and radiological examination of asbestos workers is essential for the early detection of asbestosis, and there is some evidence that removal of the worker from exposure at this stage is associated with slower progression. If asbestosis is suspected, workers in the United Kingdom should apply to the Benefits Agency for assessment for industrial injuries benefit. Fig. 18.13.14  CT scan showing extensive bilateral pleural plaques. Image kindly provided by Dr Michael Rubens Royal Brompton and Harefield NHS Trust.

section 18  Respiratory disorders 4228 Silicosis Silicosis is caused by the inhalation of crystalline silica, which exists in several forms including quartz, cristobalite, and tridymite. In in- dustry, quartz is the most commonly encountered form, being found in substantial quantities in sand, sandstone, granite, clay, shale, slate, and some concretes and mortar. The content of quartz found in different types of stone varies considerably, from some sandstones which are 100% quartz to shale and slate which may contain less than 10%. Cristobalite and tridymite may be encountered in the ceramic, refractory, and diatomaceous earth industries (which use furnaces, kilns, incinerators, and reactors). Considerable levels of respirable silica may be generated by natural phenomena such as volcanic explosions and sandstorms. Silicosis has been described in metal miners and masons since ancient times, but assumed particular importance in the cutlery and pottery trades to the United Kingdom in the nineteenth cen- tury. Today, the condition may affect anyone involved in quarrying, carving, mining, tunnelling, grinding, or sandblasting. Activities in the work place such as cutting, grinding, and polishing stone pro- duce fine dust that contains respirable crystalline silica. Working with hammers and chisels tends to produce a greater proportion of coarse dust and chippings, whereas dry cutting, grinding, and polishing produces a greater proportion of fine dust. However, both processes produce respirable dust. Power tools such as angle grinders generate far greater concentrations of airborne dusts than those produced from hand tools. Recently, colleagues in Italy, Spain, Israel, the USA and Australia have drawn attention to the occur- rence of silicosis following exposures cutting artificial stone in the construction of kitchen and bathroom finishings. Very high rates of silicosis continue to be reported from South Africa, China, Vietnam, India, Brazil, Columbia, and even the United States and Canada. Recent reports indicate that more than 23 million workers are exposed to crystalline silica in China and over 10 million in India alone. In the United States and Europe, the respective figures are 1.7 million and over 3 million. High rates of silicosis continue to be reported from South Africa, China, Vietnam, India, Brazil, Columbia, and even the United States and Canada. Outbreaks of silicosis have been reported in Spanish quartz conglomerate workers and in agate-​ grinding workers in Iran and India. In fact, recent estimates from India suggest that over 3 million workers are exposed to silica dust. Aetiology and pathology The inability of macrophages to effectively phagocytose crystal- line silica is accompanied by necrosis and disintegration of the cell, followed by the liberation of the ingested silica, which may be re-​ ingested by other macrophages fuelling a complex self-​perpetuating inflammatory response accompanied by the progressive accumula- tion of collagen and an influx of other inflammatory cells. The earliest effects of this inflammatory and fibrotic response occur in the lymph nodes. It is important, however, to recognize that the finding of an inflammatory or fibrotic response in the lymph nodes is insufficient to establish a diagnosis of silicosis. However, as these nodes become progressively blocked, impairing the normal clearance mech- anisms and promoting further retention of silica in the lung. Some silica is also transported across the alveolar epithelium by migrating macrophages and as a result of endocytosis by type 1 alveolar cells. Quartz appears to be most toxic when freshly fractured, sug- gesting that surface properties are important in toxicity. This concept is supported by experimental evidence that various clay minerals and other chemicals that occlude the surface reduce the toxicity of inhaled quartz when inhaled simultaneously in mix- tures of dust. The recognition that a coating of aluminium reduced the in vitro toxicity of quartz led to the inhalation of aluminium being trialled as a potential therapeutic agent in both the United Kingdom and Canada (MacIntyre Powder), although this was later abandoned. Macroscopic inspection of silicotic lungs shows fibrous pleural adhesions, enlarged lymph nodes that contain fibrotic nodules, often calcified, and grey nodules throughout the lung. These nodules vary from a few millimetres to several centimetres in diameter and are more profuse in the upper zones. They may rarely be calcified, and they have a typical whorled, collagenous appearance when cut across (Fig. 18.13.15). The largest lesions consist of many such nodules that have become confluent, and as in CWP, this progres- sive massive fibrosis may undergo ischaemic necrosis and cavitate. Under the microscope the silicotic nodule consists of concentric layers of collagen surrounded by a zone of refractile silica particles, macrophages, and fibroblasts. The nodule may contain the remnants of the respiratory bronchiole and arteriole, destroyed by fibrosis. Extremely high exposures to crystalline silica may be followed by the development of an alveolar lipoproteinosis-​like reaction (silicoproteinosis). In these cases the macroscopic appearance is similar to pulmonary oedema, but under the microscope the alveoli are seen to be filled with eosinophilic fluid and the alveolar walls contain plasma cells, lymphocytes, fibroblasts, and silica. The condi- tion is characterized by excessive secretion of surfactant, which the macrophages attempt to phagocytose, leading to the appearance of foamy cytoplasm that stains strongly positive with eosin and peri- odic acid-​Schiff. Clinical features There are three main clinical presentations of silicosis: classic sili- cosis, accelerated silicosis, and silicoproteinosis. Fig. 18.13.15  Silicotic nodules, showing the typical whorled appearance. Photograph kindly provided by Dr William Wallace, Consultant Pathologist, NHS Lothian.

18.13  Pneumoconioses 4229 Classic silicosis This is the most common presentation and typically appears fol- lowing 10–​20 years of continuous silica exposure, usually associ- ated with exposure to dust containing 10–​30% silica. The condition may both develop and progress in the absence of symptoms, phys- ical signs, or any demonstrable lung function abnormality, being only identified on a chest radiograph taken for surveillance pur- poses. However, as the condition progresses, increasing levels of breathlessness and lung function impairment can be anticipated. The typical pattern of lung function defect is a restrictive ventila- tory defect in the presence of reduced lung volumes and impaired gas transfer. The diagnosis of silicosis is usually based on a history of exposure and the typical radiographic appearances. The typical plain chest X-​ray appearances are similar to those of coal worker’s pneumo- coniosis, but owing to the greater fibrogenicity of silica, the nodules, which are generally between 3 and 5 mm in diameter, and concen- trate in the upper and mid-​zones, are usually more pronounced (Fig. 18.13.16). Silica cleared to the regional nodes results in hilar enlargement that eventually calcifies. Eggshell calcification in the hilar nodes (Fig. 18.13.17) is often held to be a pathognomonic fea- ture, but may be observed in sarcoidosis. HRCT provides greater diagnostic and prognostic informa- tion. The technique is considerably more sensitive at detecting the presence of nodules, whose upper lobe posterior centriacinar and subpleural bias may be more easily appreciated (Fig. 18.13.18). The presence of PMF, which may be present in the absence of symp- toms, is more readily defined and is often seen to be accompanied by cicatricial emphysema. Greater resolution of lymph node anatomy shows enlargement of the hilar and mediastinal nodes, which may show calcification as described earlier. In addition, HRCT allows an assessment of the contribution of any additional pulmonary pathology, such as emphysema, that may confound assessment of reported functional limitation and the interpretation of lung function tests. Biopsy may be considered when the diagnosis is uncertain on clinical and radiographic grounds alone. Sarcoid represents a chal- lenge for the unwary: silica exposure can be associated with bi- lateral hilar lymphadenopathy, lymphopenia, and elevated serum angiotensin converting enzyme. The typical silicotic nodule is acel- lular and consists of hyaline collagen arranged in a whorled pat- tern. Polarizing filters demonstrate birefringent crystals within Fig. 18.13.16  Chest X-​ray appearances of silicosis demonstrating upper and mid-​zone nodules and hilar lymphadenopathy. In this case, loss of volume in the upper lobes has occurred. Fig. 18.13.17  Radiograph of a hard-​rock miner, showing massive fibrosis in right mid-​zone and eggshell calcification of hilar nodes. Fig. 18.13.18  HRCT scan from a stonemason showing the presence of nodules with an upper lobe posterior bias and the occurrence of progressive massive fibrosis.

section 18  Respiratory disorders 4230 the nodules confirming the presence of silica and other silicates. Silicotic nodules develop in the lymph nodes, but silicosis should not be diagnosed unless lung involvement is present. Lung tissue between the nodules is usually normal. Occasionally, in cases of mixed dust exposure, a diffuse fibrosis may be present. Accelerated silicosis This is associated with a much shorter duration of dust exposure (typically 5–​10 years) and, as the name suggests, a faster rate of dis- ease progression. Clinical presentation may be as early as 1 year after exposure. Otherwise the clinical, radiographic, and pathological features are similar to classic silicosis. The pathology may show less established collections of macrophages, more loosely arranged than the classical silicotic nodule with relatively little collagen. Silicoproteinosis This an acute, rapidly progressive disease following very high-​level exposure. Presentation within one year of exposure and death within 5 years of exposure have been reported. The radiograph shows ap- pearances resembling pulmonary oedema. Prognosis The biopersistence of silica in the pulmonary interstitium may lead to progression of the disease, even following cessation of exposure (Fig. 18.13.19). In the most severe cases may be complicated by the development of pneumothorax, pulmonary hypertension, respira- tory failure, and cor pulmonale. In addition, those exposed to high quantifies of silica have increased risks of several other pulmonary and extrapulmonary conditions. Inhalation of respirable silica appears sufficient to increase the risk of developing pulmonary tuberculosis, but the risk is greatest when silicosis has developed and the occurrence may be termed silicotuberculosis. The prevalence of silicotuberculosis is particu- larly high among South African gold miners, who undoubtedly share other risk factors common to the contraction of pulmonary tuberculosis (TB), including a high prevalence of HIV infection. However, there are theoretical reasons to suggest that silica exposure increases the risk of contracting TB. First, silica is toxic to macro- phages that are an important defence mechanism to mycobacteria, and secondly, experimental evidence suggests silica may promote the growth of mycobacteria. The physician should be aware of this close relationship between silicosis and pulmonary tuberculosis, as both the clinical and radiological manifestations of silicosis may mask the appearance of this complication. In addition to mycobac- terium tuberculosis, individuals with silicosis are also susceptible to infection with nontuberculous mycobacteria. Crystalline silica has been recognized as a carcinogen by the International Agency for Research on Cancer since 1987. An increasing number of epidemiological studies support an increased prevalence of lung cancer in individuals with silicosis and in the Fig. 18.13.19  These images are taken from the same stonemason 8 years apart following cessation of exposure to stone dust and illustrate the progression of silicosis.

18.13  Pneumoconioses 4231 United Kingdom, the occurrence of lung cancer in individuals with silicosis is recognized as an occupational disease. In common with coalminers, epidemiological studies of workers exposed to respirable silica dust suggest that cumulative exposure to silica is related to the development of airflow obstruction and em- physema. Hence, silica exposure is a recognized cause of chronic ob- structive pulmonary disease (COPD) and potentiates the effects of cigarette smoking. Numerous publications have drawn attention to the development of hypergammaglobulinemia, rheumatoid factor, and autoanti- bodies and the association between silica exposure and scleroderma, known as the Erasmus syndrome, has been recognized since the turn of the twentieth century. Several studies have suggested that the prevalence of systemic lupus erythematosus is greater than would be expected in a comparable general population, particularly in men. Other immunologically mediated conditions, such as autoimmune haemolytic anaemia, and dermatomyositis/​dermatopolymyositis have also been described in individuals following silica exposure. Exposure to respirable silica has also been associated with the de- velopment of glomerulonephritis, even in the absence of silicosis. Prevention and management The epidemiological evidence suggests that workers exposed to levels of respirable silica in excess of 1 mg/​m3 have a high risk of silicosis, and that a risk may still exist at levels of around 0.1 mg/​m3. The United Kingdom maximum exposure limit is 0.1 mg/​m3, and industry is obliged to keep the exposure of workers as far below this level as is reasonably practicable. This is achieved by control meas- ures such as appropriate ventilation, extraction, dust-​suppression measures, and personal respiratory protection. A worker who has developed the disease should be prevented from working with silica again. In the United Kingdom, workers with sili- cosis (whether or not complicated by lung cancer) should apply to the Respiratory Diseases Board of the Benefits Agency for industrial injuries benefits. The only medical management necessary is regular sputum examination for tubercle bacilli, as tuberculosis accelerates the lung damage, but responds normally to chemotherapy. In areas where TB is particularly prevalent, it may be sensible to consider prophylaxis in individuals with silicosis. Advanced silicosis is an indication for consideration of lung transplantation. Whole-​lung lavage may be contemplated for sufferers of alveolar proteinosis, but its role in other forms of silicosis remains unclear. Silicates Silicates are complex compounds in which silicon and oxygen (combined as an anion) bond with any one of several cations. Fig. 18.13.19  Continued

section 18  Respiratory disorders 4232 While less fibrogenic than silica, many of these are believed to cause pneumoconiosis. However, as silicates are commonly contamin- ated with asbestos, silica, or both, this has confounded the under- standing of their fibrogenicity. The pathological reaction is similar to that of silicosis, but the nodules are invariably less well demar- cated. Silicates are identified on pathology as plate-​like, birefringent crystals that produce foreign body granulomata. Talc pneumoconiosis Talc (hydrated magnesium silicate) is mined as soapstone in the United States, China, Australia, Austria, and the Pyrenees. It is milled and has many uses including in cosmetics, the rubber in- dustry, paints, ceramics, and pharmaceuticals. Talc may be con- taminated with silica and asbestos (tremolite) and when these are present, talco-​silicosis and talco-​asbestosis display a clinical picture similar to silicosis and asbestosis, respectively. Talcosis refers to the inhalation of pure talc. It is an uncommon cause of pneumoconiosis, but continues to be reported in miners, millers, and soapstone artisans. ‘Samosa’ pneumoconiosis has been reported in a worker with considerable exposure to talc during prep- aration of ‘samosa’. Bronchoconstriction may occur in children fol- lowing aspiration of high concentrations of cosmetic talc, but the more usual presentation in adults is the radiological occurrence of rounded and irregular opacities in the mid-​zones, often with a perihilar distribution. Exceptionally, very small, widely dissemin- ated opacities (about 2–​3 mm in diameter), similar to the miliary lesions of sarcoidosis or tuberculosis may be observed. Talcosis may also be observed in intravenous drug abusers who crush and inject oral medications in which talc is used as a bulking agent or lubricant. The radiographic findings are more typically those of large, irregular, nodular densities, or consolidation in the upper parts of the middle lung fields. Widespread irregular nodules may appear accompanied by a permanent loss of lung volume. Lymph node enlargement is common and may be massive. Lung biopsy shows foreign body granulomata and free intracellular bi- refringent deposits and multinucleate giant cells. In particular, talc particles longer than 5 microns in length should raise suspicion of intravenous drug abuse. Kaolin pneumoconiosis Kaolin (hydrated aluminium silicate), often referred to as China clay, is quarried in southwest England, Georgia (United States of America), Japan, Egypt, Germany, and the Czech lands. Kaolin causes a pneumoconiosis similar to coal worker’s pneumoconiosis with small, discrete nodular lesions initially and a tendency to pro- duce massive fibrosis. It has been described in workers involved in the drying and milling processes in the production of china clay and in those working in the manufacture of ceramics, paper, and paint. Kaolin may also have been the component of the dust re- sponsible for pneumoconiosis in the now defunct Scottish shale oil industry. Fuller’s earth (montmorillonite) pneumoconiosis Fuller’s earth (hydrous aluminium silicates of varying composition, including altered volcanic ash, mainly calcium montmorillonite) is an adsorbent sedimentary clay, which takes its name from Fullers who trod or pounded newly woven cloth placed in large vats of water and detergent to remove grease and dirt, and to thicken and soften the cloth. Quarrying in the United Kingdom has been dis- continued on economic grounds, but it continues to be mined in the United States of America, and Germany. Nowadays it has found extensive use in cosmetic and pharmaceutical industries, but it also finds a use in special effects departments where the use of Fuller’s earth in explosions results in an impressive particle plume allowing a smaller safer charge to be used. Fuller’s earth pneumoconiosis has been described in workers extracting this clay. It is a benign nodular pneumoconiosis similar in pathological and radiological appear- ance to simple coal worker’s pneumoconiosis. Mica pneumoconiosis Mica is a complex aluminium silicate occurring in two forms, mus- covite and phlogopite. Large reserves are found in Africa, South America and India, Canada, Russia, China, and the United States. Muscovite, the most common mineral of the mica family, is mined in the United States of America and India and used in fire-​resistant windows and the manufacture of paper and paint. Other forms of mica include phlogopite, mined in Canada for use in the electrical industry because of its resistance to heat and electricity. The role of mica in the development of pneumoconiosis has recently been re- ported in muscovite miners working in a pure muscovite milling unit. Dry cough and breathlessness were accompanied by bilateral micronodular ground glass opacities and mediastinal and hilar lymphadenopathy. Histological analysis showed giant cell granu- lomas without typical silicotic nodule with high concentration of birefringent particles consistent with mica. Berylliosis Beryllium is an alkaline earth metal mined in the United States, Brazil, Russia, India, and Madagascar. The ore occurs in two forms: bertrandite, a silicate, and aluminosilicate beryl. The first descriptions of chronic berylliosis occurred in fluorescent light bulb workers who applied a beryllium oxide coating. Classically, occupational exposure to beryllium may be encountered in aero- space, nuclear, and military settings. However, its use is widespread in automotive, electronics, and telecommunications industries. Alloys may be used as tubing for oil and gas drilling, tools, jewel- lery, bicycle frames, and dental appliances. Recycling of electronics, computers, and scrap alloy to recover copper also results in beryl- lium exposure. Beryllium causes granulomatous ulcers on contact with the skin and is highly toxic when inhaled. Inhalation of high concen- trations, which is rarely seen nowadays, causes an acute pneu- monitis, which can be fatal or complicated by fibrosis in survivors. Chronic exposure to beryllium may be followed by sensitization, subclinical disease, or clinically apparent disease. The susceptible individual, who may be identified by HLA-​DP2 haplotype, typic- ally develops sensitization within two or three months following exposure. Clinical, radiological, and pathological features The clinical, radiological, and pathological presentation of chronic berylliosis is very similar to that of pulmonary sarcoid. The patient

18.13  Pneumoconioses 4233 presents with cough and shortness of breath accompanied by bi- lateral pulmonary mottling, upper lobe fibrosis, and bilateral hilar lymphadenopathy. The pathological lesion also shows noncaseating granulomata and varying amounts of interstitial fibrosis. Hence, a diagnosis of sarcoidosis may be incorrectly applied if the occupa- tional history has not been noted and awareness of the effects of beryllium exposure known. When berylliosis is suspected, the diag- nosis may be confirmed with a beryllium lymphocyte stimulation test in blood or bronchoalveolar lavage. Treatment and prognosis The progress of the disease can be controlled with corticosteroid therapy, but this needs to be continued indefinitely in most cases. The disease typically progresses to diffuse fibrosis (Fig. 18.13.20), but the rate of progression is very variable. Beryllium is a class A human carcinogen, hence individuals with beryllium sensitiza- tion or disease must be advised to stop smoking. Prevention and surveillance The risk of berylliosis is reduced by keeping exposures below the threshold limit value (2 ng/​m3), although cases have occurred in in individuals with apparently low (trivial) levels of exposure (e.g. in wives exposed to dust from their husbands’ clothes, and in people living near the factories). Efficient respiratory and skin pro- tection should also be provided for workers in these industries. Biomonitoring for beryllium by measurement of beryllium in the urine has recently become possible. However, further validation of these assays is required to remove uncertainty regarding the toxicokinetics of beryllium excretion. Aluminium The role of aluminium as a cause of pneumoconiosis remains un- certain. On the one hand, its use has been linked to a rapidly pro- gressive pulmonary fibrosis in alumina abrasive workers (Shaver’s disease) and on the other, the inhalation of aluminium powder has been advocated to ameliorate the fibrogenic potential of silica. There has been little evidence of interstitial lung disease associated with primary aluminium production (Bauxite mining, aluminium refining, and aluminium smelting) and long-​term follow-​up of China Biscuit placers from Stoke-​on-​Trent exposed to respirable aluminium found no evidence of pneumoconiosis. Nonetheless, the potential role of aluminium continues to be reported with the documentation of sarcoid-​like granulomas induced by aluminium dust and the occurrence of desquamative interstitial pneumonia in aluminium welders, the development of pulmonary alveolar proteinosis in an aluminium rail grinder and the recent reporting of pulmonary fibrosis associated with aluminium trihydrate (Corian) dust. Other pneumoconioses Siderosis occurs in workers exposed to iron oxide: iron ore miners, welders, iron foundries fettlers, steel workers, boiler scalers, haem- atite miners, and crushers. The condition is benign and is usually only detected when radiology is performed for purposes of surveil- lance. The radiological lesions often regress after exposure ceases. Pathologically, the lungs are coloured red. An increased risk of lung cancer has been reported but is probably due to radiation in mines. Baritosis occurs in workers processing barium. Although be- nign, the appearances may be dramatic owing to the radiodensity of barium. However, some resolution may occur following cessation of exposure, such as stannosis occurring in tin smelters and argyo-​ siderosis occurring in silver polishers (Fig. 18.13.21). Graphite pneumoconiosis, occurring in those exposed to graphite dust, has Fig. 18.13.20  Radiograph of a beryllium refinery worker, showing the diffuse fibrosis of berylliosis. Fig. 18.13.21  Radiograph of a worker exposed to tin oxide fume in refining. He was completely symptom-​free and had normal lung function. The radiological appearances reflect radiopaque dust in macrophages.

section 18  Respiratory disorders 4234 similar appearances to coal worker’s pneumoconiosis including mil- iary and nodular opacities, conglomerate shadows, emphysema, and Kerley B lines. Conclusion Despite being an entirely preventable condition, pneumoconioses remain common and, when standards of occupational hygiene lapse, resurgent. The continued production and use of coal, asbestos, and silica in many countries suggests that coal worker’s pneumoconi- osis, asbestosis, and silicosis will continue to dominate the literature. However, new technology creates new risks for lung disease, and the rapid increase in the nanoparticle technology has raised concern regarding nanoparticle toxicity because these particles may easily reach the alveoli. Carbon nanotubes have been shown to cause pul- monary fibrosis in rats, and the occurrence of breathlessness, pleural and pericardial effusion has been described in seven young women working in a print plant and exposed to polyacrylate consisting of nanoparticles. There is also an increasing awareness of the potential role of in- haled particles in cardiovascular disease. Concern regarding air pollution has been reflected in the cardiovascular and public health literature for some time, but more recently publications have fo- cused on the potential links between silica exposure and increased risks of cardiovascular disease and stroke. Finally, the recognition that moon dust is rich in respirable crystalline silica has prompted interest in the behaviour of particles in microgravity, and early re- sults suggest that there is increased pulmonary deposition of smaller particles in microgravity environments. Acknowledgements The author would like to acknowledge the original author of this chapter, Professor Anthony Seaton. Much of what is written con- tinues to reflect his input. In addition, I would like to acknowledge the helpful comments from Dr William Wallace, Consultant in Pathology, NHS Lothian for provision of histopathology material and helpful comments on the manuscript. Dr Richard Attanoos, Llandough Hospital, Vale of Glamorgan kindly provided several ex- amples of the histopathology of asbestosis. Dr Michael Rubens and Dr Arnie Debaraj from the Royal Brompton and Harefield NHS Trust provided images on asbestosis and Caplan’s syndrome, respectively. FURTHER READING Algranti E, Markowitz S (2017). Parenchymal disease related to as- bestos. In: Newman Taylor A, et al. (eds) Parkes’ occupational lung disorders (4th edn). CRC Press, Florida. Balmes JR, et  al. (2014). An Official American Thoracic Society statement:  diagnosis and management of beryllium sensitivity and chronic beryllium disease. Am J Respir Crit Care Med, 190, e34–​59. Clayton GM, et al. (2014). Structural basis of chronic beryllium dis- ease: linking allergic hypersensitivity and autoimmunity. Cell, 158, 132–​42. Copley SJ, et al. (2007). Asbestos-​induced and smoking-​induced dis- ease:  apportioning functional deficit by using thin-​section CT. Radiology, 242, 258–​66. Corrin B, Nicholson AG (2006). Pathology of the lungs, 2nd edition. Churchill Livingstone. Darby A, Fishwick D (2011). Beryllium: a review of the health effects and the evidence for screening or surveillance in workers exposed to beryllium. Health & Safety Executive Report RR873 research report. Halldin CN, Petsonk EL, Laney AS (2014). Validation of the inter- national labour office digitized standard images for recognition and classification of radiographs of pneumoconiosis. Acad Radiol, 21, 305–​11. International Agency for Research on Cancer (IRAC) (1997). Monographs on the evaluation of carcinogenic risks to humans. Silica, some silicates, coal dust and para-​aramid fibrils. International Agency for Research on Cancer, Lyon, France. International Labour Organization (2011). Guidelines for the use of the ILO International Classification of Radiographs of Pneumoconioses (revised edition 2011). Occupational Safety and Health Series no 22 (Rev. 2011). International Labour Office, Geneva. Prisk GK (2014). Microgravity and the respiratory system. Eur Respir J, 43, 1459–​71. Rivera-Ortega P, Molina-Molina M (2019). Interstitial lung disease in developing countries. Ann Glob Health, 85(1), pii: 4, doi: 10.5334/ aogh.2414. Roggli VL, et al. (2010). Pathology of asbestosis—​an update of the diag- nostic criteria: report of the Asbestosis Committee of the College of American Pathologists and Pulmonary Pathology Society. State of the art in clinical and anatomic pathology. Arch Pathol Lab Med, 134, 462–​80. WHO (2000). Crystalline silica, quartz:  Concise International Chemical Assessment Document (CICAD) No. 24. World Health Organization, Geneva.

18.14 Miscellaneous conditions 4235 18.14.1 Diffus

18.14 Miscellaneous conditions 4235 18.14.1 Diffuse alveolar haemorrhage 4235 S.J. Bourke and G.P. Spickett

CONTENTS 18.14.1 Diffuse alveolar haemorrhage  4235 S. J. Bourke and G.P. Spickett 18.14.2 Eosinophilic pneumonia  4238 S. J. Bourke and G.P. Spickett 18.14.3 Lymphocytic infiltrations of the lung  4241 S. J. Bourke 18.14.4 Hypersensitivity pneumonitis  4244 S. J. Bourke and G.P. Spickett 18.14.5 Pulmonary Langerhans’ cell histiocytosis  4256 S. J. Bourke 18.14.6 Lymphangioleiomyomatosis  4257 S. J. Bourke 18.14.7 Pulmonary alveolar proteinosis  4259 S. J. Bourke 18.14.8 Pulmonary amyloidosis  4261 S. J. Bourke 18.14.9 Lipoid (lipid) pneumonia  4263 S. J. Bourke 18.14.10 Pulmonary alveolar microlithiasis  4265 S. J. Bourke 18.14.11 Toxic gases and aerosols  4267 Chris Stenton 18.14.12 Radiation pneumonitis  4271 S. J. Bourke 18.14.13 Drug-​induced lung disease  4272 S. J. Bourke 18.14.1  Diffuse alveolar haemorrhage S. J. Bourke and G.P. Spickett ESSENTIALS Diffuse alveolar haemorrhage is characterized by acute respira- tory failure, diffuse air space shadowing on the chest radiograph, haemoptysis, and anaemia. There are many different causes including immune-​mediated diseases (notably pulmonary vasculitis, con- nective tissue diseases and Goodpasture’s syndrome) and non-​ immune-​mediated disease (cardiac failure, infection, coagulation disorders, thrombolytic therapy, toxins, and barotrauma). Prompt identification of the underlying cause is important in directing specific treatments. Goodpasture’s syndrome is an autoimmune disorder charac- terized by alveolar haemorrhage and glomerulonephritis due to antibasement membrane antibodies. Renal failure is usually the dominant feature, but alveolar haemorrhage can precede renal involvement. Idiopathic pulmonary haemosiderosis is a rare disorder of un- known cause with recurrent alveolar bleeding, which may provoke pulmonary fibrosis, and anaemia. Introduction Diffuse alveolar haemorrhage typically presents as a combination of acute respiratory failure, bilateral infiltrates on a chest radiograph, haemoptysis, and anaemia. It is not a distinct disease entity but a clinical pattern with many different causes. Management is cru- cially dependent on recognizing that the lung infiltrates are due to alveolar haemorrhage rather than pulmonary oedema, infection, or inflammation. Bronchoscopy with bronchoalveolar lavage is often important in demonstrating acute bleeding at the alveolar level, or haemosiderin-​ laden macrophages in chronic cases, and in excluding infection or a bronchial cause of haemorrhage. Some patents presenting in respira- tory failure may need endotracheal intubation and ventilation before bronchoscopy can be performed. Considerable amounts of blood can accumulate in the alveoli before giving rise to haemoptysis, which is therefore not always apparent at presentation. Characteristically blood in the alveoli causes an elevation of the carbon monoxide transfer factor (TLco) and transfer coefficient (Kco) as red blood cells in the alveoli bind carbon monoxide, but often patients are not suffi- ciently stable to undertake lung function tests. The causes of diffuse alveolar haemorrhage are diverse but can be broadly classified into immune-​mediated and nonimmune-​ mediated causes (Box 18.14.1.1). The clinical context is crucial in identifying the aetiology and a careful assessment is needed to iden- tify any provoking factors (drugs, tobacco smoke, inhaled toxins) 18.14 Miscellaneous conditions

section 18  Respiratory disorders 4236 or any systemic diseases (cardiac, renal, connective tissue diseases). As can be seen in Box 18.14.1.1, diffuse alveolar haemorrhage (Fig. 18.14.1.1) may be a manifestation of many diseases, but is a defining characteristic of two, Goodpasture’s syndrome and idio- pathic pulmonary haemosiderosis. Immune-​mediated alveolar haemorrhage Immune-​mediated diseases account for about 35% of cases of diffuse alveolar haemorrhage and include primary pulmonary vasculitis, vasculitis secondary to connective tissue diseases, and antibasement membrane antibody disease (Goodpasture’s syndrome). In some of these diseases both the lungs and kidneys are involved such that they present as a pulmonary-​renal syndrome. Pulmonary vasculitis Granulomatosis with polyangiitis (Wegener’s disease), eosinophilic granulomatosis with polyangiitis (Churg–​Strauss syndrome), and microscopic polyangiitis are usually associated with antineutro­ phil anticytoplasmic antibodies (ANCA). Granulomatosis with polyangiitis commonly causes a necrotizing glomerulonephritis and is associated with necrotizing inflammation of the nasopharynx, the central airways, the lung parenchyma, and the pulmonary ves- sels. Biopsy of the kidneys or nasopharynx is usually more appro- priate than lung biopsy, and the ANCA antibodies are usually of the cytoplasmic type (C-ANCA) and are directed against proteinase-​ 3. By contrast, microscopic polyangiitis does not typically involve the upper respiratory tract and is not granulomatous, and the ANCA antibodies are perinuclear (P-ANCA), directed against the myeloperoxidase of neutrophil cytoplasmic granules. In eosinophilic granulomatosis with polyangiitis there is an allergic granulomatous angiitis associated with high IgE levels and hypereosinophilia in a patient with asthma. Other vasculitic disorders rarely cause diffuse alveolar haemor- rhage, but include polyarteritis nodosa, Henoch–​Schönlein pur- pura, and Takayasu’s arteritis. Pulmonary vasculitis with alveolar haemorrhage may also rarely be secondary to connective tissue dis- eases such as systemic lupus erythematosus, rheumatoid disease, mixed connective tissue disease, IgA nephropathy, systemic scler- osis, and primary antiphospholipid syndrome. Goodpasture’s syndrome Goodpasture’s syndrome is a rare autoimmune disorder character- ized by diffuse alveolar haemorrhage and glomerulonephritis due to antibasement membrane antibodies. These antibodies are mainly directed against the α-​3 chain of type IV collagen in the alveolar and glomerular basement membranes. Damage to this domain of col- lagen may elicit an autoimmune response. Increased susceptibility is Box 18.14.1.1  Causes of diffuse alveolar haemorrhage Immune-​mediated diseases Vasculitis • Granulomatosis with polyangiitis (previously known as Wegener’s disease) • Eosinophilic granulomatosis with polyangiitis (previously known as Churg–​Strauss syndrome) • Microscopic polyangiitis • Polyarteritis nodosa • Takayasu’s arteritis • Pauci-​immune pulmonary capillaritis Connective tissue disease • Systemic lupus erythematosus • Rheumatoid disease • Mixed connective tissue disease • Systemic sclerosis • Goodpasture’s syndrome (antibasement membrane antibody disease) Nonimmune-​mediated diseases Cardiac • Left ventricular dysfunction • Valvular heart disease • Congenital cardiac anomalies • Pulmonary veno-​occlusive disease Infection • Staphylococcal pneumonia • Leptospirosis Coagulation disorders • Thrombocytopaenia • Thrombolytic therapy • Disseminated intravascular coagulation Toxic • Cannabis, cocaine, tobacco • Volatile hydrocarbon glue solvents • Drugs (penicillamine, mitomycin C, amiodarone) Idiopathic • No cause identified • Idiopathic pulmonary haemosiderosis Fig. 18.14.1.1  Radiograph showing gross alveolar shadowing following severe pulmonary haemorrhage in a 60-​year-​old man with systemic vasculitis.

18.14.1  Diffuse alveolar haemorrhage 4237 associated with HLA DRB11 501 and DRB11 502 alleles, while pro- tection is associated with HLA DR1 and DR7. Acute glomerulonephritis with renal failure is usually the dom- inant feature of antibasement membrane antibody disease, but this is sometimes associated with alveolar haemorrhage, which can rarely precede renal involvement. Alveolar haemorrhage is strongly associated with cigarette smoking, or sometimes with inhalation of other toxins such as cocaine or volatile hydrocarbon glue solvents. This suggests that inhaled toxins enhance pulmonary endothelial damage and thus allow the initiation of autoimmunity or the access of existing autoantibodies to the basement membrane. The usual respiratory presentation is with cough, breathlessness, and haemoptysis, with diffuse shadowing on the chest radiograph. Renal function may be normal initially but can deteriorate rap- idly. The diagnosis is established by the detection of antibasement membrane antibodies in the serum or as linear deposits along the basement membrane by immunofluorescence of glomeruli on renal biopsy, or rarely on lung biopsy in cases without renal involvement at presentation. Prognosis generally depends more on the renal effects than the pulmonary effects. See Chapter 21.8.7 for further discussion. Nonimmune-​mediated alveolar haemorrhage Diffuse alveolar haemorrhage can occur due to many diverse non-​ immune diseases which need to be sought and considered in the differential diagnosis. In a series of 112 consecutive patients with diffuse alveolar haemorrhage, nonimmune causes accounted for 65% of cases. These included cardiac disease in 29%, a diverse range of conditions in 23% (infection, toxins, drugs, coagulation disorders, barotrauma), and in 12% the cause was classified as idiopathic. Chronic pulmonary venous congestion is a mechanism of al- veolar haemorrhage in many cardiac diseases such as left ventricular dysfunction, valvular heart disease, pulmonary veno-​occlusive disease, and in congenital cardiac anomalies. Alveolar haemor- rhage may occur as part of severe infections, notably in patients with Staphylococcal pneumonia, but also in other infections such as leptospirosis, invasive aspergillosis, and HIV. Bleeding disorders such as thrombocytopaenia, coagulopathies, disseminated intravas- cular coagulation, and thrombolytic therapy can precipitate alveolar haemorrhage. Drugs (amiodarone, methotrexate, mitomycin C, penicillamine) or inhaled toxins (cannabis, cocaine, volatile hydro- carbon glue solvents, mycotoxins from moulds) have all been as- sociated with alveolar haemorrhage. Barotrauma with haemorrhage can occur in scuba diving or as a complication of mechanical venti- lation and general anaesthesia. A careful search for provoking fac- tors and underlying diseases is important in deciding on the best management. Idiopathic pulmonary haemosiderosis This is a rare cause of alveolar haemorrhage of unknown aetiology which particularly affects children and young adults, with recurrent episodes of haemoptysis resulting in iron-​deficiency anaemia. Recurrent alveolar haemorrhage results in cough with haemop- tysis and breathlessness, sometimes associated with fever and (in children) failure to thrive. During acute bleeds, the chest radio- graph and CT scan show a nonspecific appearance of intra-​alveolar blood. The alveolar blood may act as a fibrogenic stimulus resulting in diffuse pulmonary fibrosis, with a restrictive ventilatory defect and impaired gas transfer. Characteristically lung biopsy shows haemosiderin-​laden macrophages with varying degrees of fibrosis, but does not show vasculitis or features of any other cause of alveolar haemorrhage. Antibasement membrane antibodies are not present, and the electron microscopic appearance of the basement mem- brane shows no consistent abnormality. Some cases previously classified as idiopathic pulmonary haemosiderosis may have been a consequence of vasculitis at the pulmonary capillary level (pauci-​immune pulmonary capillaritis). Some cases may result from inhalation of toxins from moulds such as the stachybotrys mould, which may contaminate wet or damp ac- commodation, and which releases a particularly potent toxin with haemorrhagic properties. Idiopathic pulmonary haemosiderosis is also associated with cow’s milk allergy and coeliac disease. The rarity of the disease means that treatment regimens and prognosis are poorly defined and based mainly on case reports. In children with associated cow’s milk allergy or coeliac disease, avoid- ance of milk or gluten usually results in improvement. In adults the prognosis is more variable and protracted, with some patients re- sponding to corticosteroids and other immunosuppressant drugs. In longstanding cases, interstitial lung fibrosis may develop. About a quarter of patients go on to develop some form of systemic auto- immune disease. Management Treatment of alveolar haemorrhage is initially mainly supportive, with stabilization of the patient’s respiratory and haemodynamic status, and attention to any coagulation abnormalities or renal dys- function. In a large case series of consecutive patients with alveolar haemorrhage, 77% required admission to an intensive care unit, 18% needed endotracheal intubation and ventilation, and 16% renal replacement therapy. In-​hospital mortality was 24%. Prompt identi- fication of the underlying cause allows the initiation of appropriate specific treatment. For patients with vasculitis, induction of remission is usually achieved by a combination of corticosteroids (typically intravenous methylprednisolone 500–​1000 mg daily for 3–​5 days, followed by prednisolone 1 mg/​kg/​day orally) and cyclophosphamide (typically 2 mg/​kg/​day orally or 15 mg/​kg intravenously in pulses at 3-​weekly intervals). As clinical improvement occurs, the dose of immunosup- pressants is gradually reduced. Alternative immunosuppressants such as rituximab, azathioprine, or methotrexate may be used in pa- tients who are refractory to initial treatment or as steroid-​sparing agents. Goodpasture’s syndrome with pulmonary haemorrhage is usu- ally treated by a combination of plasmapheresis, corticosteroids, and cyclophosphamide. Plasmapheresis gives rapid removal of antibodies from the circulation and immunosuppressants reduce antibody synthesis. Some patients with idiopathic pulmonary haemosiderosis also appear to respond to immunosuppressants.

18.14.10 Pulmonary alveolar microlithiasis 4265 S.

18.14.10 Pulmonary alveolar microlithiasis 4265 S.J. Bourke

18.14.10  Pulmonary alveolar microlithiasis 4265 Prevention and management Prevention of lipoid pneumonia is focused on minimizing any tendency to aspiration associated with impaired swallowing, and in persuading the user of vegetable and mineral oils to adopt alternative habits. Stopping further exposure to exogenous lipids is also important in the treatment of the disease. Corticosteroids have been used where there is associated inflammation, but their effectiveness is doubtful. In acute massive lipoid pneumonia treatment is largely supportive. Therapeutic bronchoalveolar lavage has occasionally been used in an attempt to remove lipid from the alveoli. Endogenous lipoid pneumonia Lipoid pneumonia is a feature of obstructive pneumonitis, particu- larly where there is occlusion of a bronchus by a carcinoma, but also in diseases characterized by bronchiolitis or chronic interstitial in- flammation. In this situation the lipid is endogenous, consisting of cholesterol released from decaying cells and surfactant, which are taken up by macrophages. Macroscopically the area of lung shows consolidation with a characteristic yellow discolouration as a ‘chol- esterol pneumonia’ or ‘golden pneumonia’. Histologically there is an abundance of lipid-​laden macrophages with cholesterol crystals on polarized light microscopy. Excess lipid in the lungs is also a feature of Niemann–​Pick lipid-​storage disease and fat embolism to the lungs from frac- tured bones. Therefore, although lipid-​laden macrophages in bronchoalveolar lavage fluid are a characteristic feature of ex- ogenous lipoid pneumonia, endogenous causes also need to be considered. FURTHER READING Ameille J, et al. (1995). Respiratory symptoms, ventilatory impairment and bronchial reactivity in oil mist-​exposed automobile workers. Am J Indust Med, 27, 247–​56. Balakrishnan S (1973). Lipoid pneumonia in infants and children in South India. Brit Med J, 4, 329–​31. Betancourt SL, et al. (2010). Lipoid pneumonia: spectrum of clinical and radiologic manifestations. Am J Roentgol, 194, 103–​9. Borrie J, Gwynne JF (1973). Paraffinoma of lung: lipoid pneumonia. Thorax, 28, 214–​21. Brander PE, et al. (1992). Fire-​eater’s lung. Eur Respir J, 5, 112–​14. Brown AC, et al. (1994). Exogenous lipoid pneumonia due to nasal application of petroleum jelly. Chest, 105, 969–​70. Chang HY, et al. (1993). Successful treatment of diffuse lipoid pneu- monitis with whole lung lavage. Thorax, 48, 947–​8. Corwin RW, Irwin RS (1985). The lipid-​laden alveolar macrophage as a marker of aspiration in parenchymal lung disease. Am Rev Respir Dis, 132, 576–​81. Gondouin A, et  al. (1996). Exogenous lipid pneumonia:  a retro- spective multicentre study of 44 cases in France. Eur Respir J, 9, 1463–​9. Hadda V, Khilnani GC (2010). Lipoid pneumonia:  an overview. Expert Rev Respir Med, 4, 799–​807. Kiselina AM, et al. (2011). Analysis of fatty acids in ghee and olive oil and their probable causal effect in lipoid pneumonia. J Med Biochem, 30, 141–​7. Kitchen JM, et al. (2008). Perils of fire eating. Thorax, 63, 401. Lee JS, et al. (1999). Exogenous lipoid pneumonia: high-​resolution CT findings. Eur Radiol, 9, 287–​91. Miller GJ, et  al. (1971). The lipoid pneumonia of blackfat tobacco smokers in Guyana. Q J Med, 40, 457–​70. Oldenburger D, et  al. (1972). Inhalation lipoid pneumonia from burning fats. JAMA, 222, 1288–​9. Segev D, et  al. (1999). Kerosene-​induced severe acute respiratory failure in near drowning: reports on four cases and review of the literature. Crit Care Med, 27, 1437–​40. Venkatnarayan K, et  al. (2014). Diesel siphoner’s lung:  exogenous lipoid pneumonia following hydrocarbon aspiration. Lung India, 31, 63–​6. 18.14.10  Pulmonary alveolar microlithiasis S. J. Bourke ESSENTIALS Pulmonary alveolar microlithiasis is characterized by the depos- ition of calcium phosphate in the alveolar air spaces as a result of mutations of the SLC34A2 gene. The patient is often symptom-​ free when the diagnosis is made after a chest radiograph is taken incidentally and reveals calcified micronodules, but typically the disease progresses to respiratory failure over about 10–​20 years. Etidronate has led to improvement in some cases that have been detected early. Lung transplantation is the main option in ad- vanced disease. Fig. 18.14.9.1  Section of lung showing exogenous lipoid pneumonia due to aspirated paraffin. There is interstitial fibrosis containing oil vacuoles which are enclosed within multinucleated giant cells (haematoxylin and eosin stain, medium magnification). By courtesy of Dr T. Ashcroft.

section 18  Respiratory disorders 4266 Introduction Pulmonary alveolar microlithiasis is a rare lung disease in which calcium phosphate is deposited within the alveolar spaces forming microliths, as a result of mutations of the SLC34A2 gene. The diffuse microliths give a characteristic appearance of calcified micronodules on a chest radiograph, sometimes described as ‘sandstorm lung’. About 1200 patients with pulmonary alveolar microlithiasis have been reported in the medical literature since its initial description in 1918. The disease occurs worldwide, but predominantly in Turkey, Japan, India, America, and the Middle East, and about 25% of re- ported cases have been of Turkish descent. Pathogenesis The disease is an autosomal recessive condition caused by muta- tions of the solute carrier family 34, member 2 gene, SLC34A2, on the short arm of chromosome 4. Several different mutations have been described, including frameshifts, chain terminations, and amino acid substitutions. The gene has 13 exons and encodes a 690-​amino acid protein, the sodium-​phosphate cotransporter, which is primarily expressed in the apical membrane of alveolar type II cells. The recycling of surfactant releases phosphate into the alveoli, and SLC34A2 gene mutations result in impaired clear- ance of phosphate by the sodium-​phosphate transporter. The ac- cumulated phosphate binds calcium, forming calcium-​phosphate microliths, which are typically about 1 mm in diameter. Initially they are predominantly located in the lower lobes, but progress to involve all areas of the lungs and extend to fill the entire alveolar space, leading to damage to the alveolar membrane and fibrosis, with impairment of gas exchange. The diffuse micronodular calcification of pulmonary alveolar microlithiasis is very different from dystrophic or metastatic lung calcification seen in other circumstances. Dystrophic lung calcifi- cation consists of calcium deposition in tissue damaged by infec- tions such as tuberculosis, histoplasmosis, or varicella pneumonia, or diseases such as chronic sarcoidosis, silicosis, or longstanding mitral stenosis. Metastatic lung calcification refers to the phenom- enon where there is calcium deposition in the interstitium of normal lungs as a result of hypercalcaemia, primary or secondary hyper- parathyroidism, vitamin D intoxication, diffuse myelomatosis, or chronic renal failure. In pulmonary alveolar microlithiasis there is no abnormality of calcium metabolism and serum calcium and phosphate levels are normal. In most cases of pulmonary alveolar microlithiasis the lungs are the only organs affected, but the gene is expressed to a lesser extent in other tissues, and calcium deposits have been occasionally found in the kidneys, seminal vesicles, urethra, gallbladder, heart valves, and arteries. Clinical features and diagnosis The diagnosis is often made before symptoms have developed when a chest radiograph is performed for other reasons, and shows a dramatic typical ‘sandstorm’ pattern of diffuse bilateral calcified micronodules (Fig. 18.14.10.1). The dramatic radiographic appear- ances are typically out of proportion to the absence of symptoms or signs at this stage. However, the disease gradually progresses over several decades, with symptoms typically arising at about the age of 30–​40 years. Breathlessness and a dry cough are the dominant symptoms. Haemoptysis and chest pain occur occasionally. As the disease progresses lung function tests show a restriction of lung vol- umes with impaired gas diffusion. In advanced stage disease respira- tory failure develops with hypoxaemia and hypercapnia, pulmonary hypertension, and right ventricular failure. Crackles, clubbing, and signs of respiratory failure are late features. In some cases, subpleural cysts give rise to recurrent pneumothoraces, and pleural adhesions may become prominent. The diagnosis can usually be made from the characteristic radiographic appearances of profuse, small, calcified nodules (Fig. 18.14.10.1). Initially the calcified micronodules are predom- inantly situated in the mid and lower zones, but gradually these progress to all areas. The pattern is different from other causes of calcification such as chronic sarcoidosis, healed calcified varicella pneumonia, pneumoconiosis, histoplasmosis, and miliary tuber- culosis, or chronic renal failure. Computed tomography demonstrates the numerous sand-​like calcifications and sometimes also shows subpleural cysts and fi- brosis. Lung biopsy is rarely necessary for diagnosis, but typically shows numerous intra-​alveolar rounded calcified microliths. DNA sequencing of the SLC34A2 gene can be undertaken, and other family members can be tested for the disease. Serum levels of calcium and phosphate are usually normal, but elevated serum concentrations of surfactant protein SP-​A and SP-​D Fig. 18.14.10.1  A chest radiograph showing the typical ‘sandstorm’ appearances of pulmonary alveolar microlithiasis with micronodular calcific densities throughout the lungs. http://​www.ispub.com/​ostia/​index.php?xmlFilePath=journals/​ijpm/​vol9n1/​pam.xml

18.14.11 Toxic gases and aerosols 4267 Chris Stent

18.14.11 Toxic gases and aerosols 4267 Chris Stenton

18.14.11  Toxic gases and aerosols 4267 have been noted, and might be useful in monitoring the activity and progression of the disease. Treatment Etidronate, a bisphosphonate, reduces the formation of calcium hydroxyapatite crystals and has led to clinical and radiological im- provement in some cases, particularly in childhood, but seems to be ineffective in adults with advanced disease. Lung transplantation is the main treatment option to be con- sidered in advanced stage disease and has improved the prog- nosis and quality of life for the small number of patients with pulmonary alveolar microlithiasis who have undergone this pro- cedure. Transplant surgery can be difficult if there are severe ad- hesions between the lungs and the chest wall. Deaths post lung transplantation have been due to complications of transplantation such as obliterative bronchiolitis, and there has been no evi- dence of recurrence of alveolar microlithiasis up to 15  years post-​transplantation. Prognosis The severity of the disease and prognosis are variable, and this may be influenced by the specific type of gene mutation. Survival of 10–​20 years from the onset of symptoms is typical. At death, ex- tensive areas of the chest radiograph show a dense ‘whiteout’ ap- pearance due to the considerable accumulation of calcium. At post-​mortem examination, the lungs are difficult to cut and are heavy and sink in water. FURTHER READING Castellana G, Castellana G, Gentile M, Castellana R, Resta O (2015). Pulmonary alveolar microlithiasis: review of the 1022 cases reported worldwide. Eur Respir Rev, 24, 607–20. Francisco FA, et  al. (2013). Pulmonary alveolar microlithiasis. State-​of-​the-​art review. Resp Med, 107, 1–​9. Harbitz F (1918). Extensive calcification of the lungs as a distinct disease. Arch Int Med, XXI, 139–​46. Huqun SI, et al. (2007). Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis. Am J Respir Crit Care Med, 175, 263–​8. Jonsson AL, et al. (2012). Pulmonary alveolar microlithiasis: two case reports and review of the literature. Eur Resp Rev, 21, 249–​56. Jonsson AL, et  al. (2012). SLC34A2 gene mutation may explain comorbidity of pulmonary alveolar microlithiasis and aortic valve sclerosis. Am J Respir Crit Care Med, 185, 464. Ozcelik U, et  al. (2010). Long-​term results of disodium etidronate treatment in pulmonary alveolar microlithiasis. Pediatr Pulmonol, 45, 514–​17. Saito A, McCormack FX (2016). Pulmonary alveolar microlithiasis. Clin Chest Med, 37, 441–8. Shigemura N, et al. (2010). Lung transplantation for pulmonary al- veolar microlithiasis. J Thorac Cardiovasc Surgery, 139, e50–​2. Zhang XD, et al. (2018). Pulmonary alveolar microlithiasis: a case re- port and review of the literature. Exp Ther Med, 15, 831–7. 18.14.11  Toxic gases and aerosols Chris Stenton ESSENTIALS Acute exposure to noxious agents causes pulmonary effects that are determined by the size of aerosol particles and by the solubility of gases. Large particles (>10 um) and soluble agents such as CS gas, am- monia, or sulphur dioxide affect primarily the upper respiratory tract, causing lacrimation, blepharospasm, rhinitis, cough, and breath- lessness. Nitrogen oxides, ozone, and other agents of low solubility affect mainly the lungs, with pneumonitis and pulmonary oedema that can develop 24 hours or more after exposure. Smoke inhalation, intermediate solubility gases such as chlorine, and overwhelming ex- posures have effects throughout the respiratory tract. Some inhaled gases such as carbon monoxide and methane act as simple asphyxi- ants. Other reactions occur, such as metal fume fever with zinc and cadmium, and pulmonary haemorrhage with crack cocaine. Management is essentially supportive. Carboxyhaemoglobin and lactate levels should be measured with smoke inhalation. Consideration should be given to the possibility of delayed pul- monary oedema even if the patient is well initially. Chronic effects such as asthma, pulmonary fibrosis, and bronchi- ectasis can follow acute inhalation injuries. These can occur without any obvious acute injury, and may be difficult to detect as the radio- logical and lung function abnormalities are subtle. Introduction The inhalation of toxic chemicals following accidents or through routine use is one of the commonest forms of workplace injury. There has been a resurgence of military and paramilitary exposure to toxic substances such as sulphur mustard in recent decades. Long term effects of these and other exposures is increasingly recognized, with disease of the small airways (constrictive bronchiolitis) the commonest outcome. Smoke inhalation from domestic fires in- volves exposure to numerous toxic agents and remains common. Acute toxic injury to the respiratory tract The acute effects of inhaled gases are determined largely by their solubility in water (Table 18.14.11.1). Soluble gases such as am- monia or sulphur dioxide dissolve in the secretions lining the upper respiratory tract and cause acute irritant effects there. The symptoms usually force the affected individual to withdraw from exposure and that limits adverse effects. Poorly soluble gases such as nitrogen oxides and ozone have little or no effect in the upper airways but penetrate to the alveoli and cause pneumonitis and pulmonary oedema, which often becomes apparent only several hours after exposure. The effect of aerosols (airborne suspensions of substances that are normally solid or fluid) is largely determined by their particle size. Particles of more than 10 μm diameter are deposited chiefly in

section 18  Respiratory disorders 4268 the nose and oropharynx. Smaller particles penetrate to the alveoli. Gases of intermediate solubility such as chlorine, massive exposures, or mixed exposures (e.g. with smoke inhalation), are likely to have effects at all levels of the respiratory tract. Clinical features Acute airway effects Soluble irritant gases Aerosols of the riot control and antipersonnel agents CS ‘gas’ (2-​chlorobenzylidene malononitrile), mace (CN; 2-​chloroaceto­ phenone), and pepper (capsaicin) are employed because of their acute irritant effects on the eyes and upper respiratory tract. Exposures to soluble irritant gases and other large particle aerosols cause similar symptoms. A burning sensation develops in the eyes, nose, throat, and large airways within seconds, usually with lacrimation, blepharospasm, rhinitis, cough, and breathlessness. Symptoms generally settle within 30 minutes, although some effects may persist for up to 24 hours. With more marked exposure there may be laryngeal oedema and upper airway obstruction with progressive coughing, wheezing, and stridor. Full recovery remains the rule, but acute bronchospasm can be fatal and tracheobronchitis can lead to secondary infection. If consciousness is lost then there is likely to be greater penetration to the alveoli, and pulmonary oedema may develop. Some individuals are left with asthma that persists for months, or even indefinitely. The latter is known as acute irritant asthma or the reactive airways dysfunction syndrome. Sulphur mustard Sulphur mustard (C4H8Cl2S) caused injury to many Iranians during the 1980–​1988 Iran–​Iraq war. It affects mainly the skin, eyes, nose, and upper respiratory tract. Symptoms progress over several hours to days with lacrimation, rhinorrhoea, and coughing. Airway oedema and inflammation can lead to the development of pseudomembranes that can slough and cause airflow obstruc- tion. Pulmonary oedema, and secondary infection is common. Pulmonary problems are the principal cause of mortality within the first few weeks of exposure. Burns Between 20% and 30% of burn victims suffer from pulmonary com- plications. Improvements in the treatment of shock and sepsis have rendered inhalation injury the main cause of mortality. Thermal in- jury affects the upper airways causing oedema and narrowing. Soot particulates and toxic gases including ammonia, sulphur dioxide, chlorine, phosgene, nitrogen dioxide, aldehydes affect all levels of the respiratory tract. Carbon monoxide and hydrogen cyanide act as chemical asphyxiants. If fat or oil is involved, a lipoid pneumonia may ensue, particularly if combustion (or explosion) leads to oil nebulization (see Chapter 18.14.9). Acute pneumonitis/​ pulmonary oedema Gases of low solubility such as oxides of nitrogen, ozone, or phos- gene have little if any effect in the upper airways. They penetrate readily to the gas-​exchanging tissues, where they cause pneumon- itis and pulmonary oedema. The effects are exemplified by nitrogen dioxide generated by stored grain. Farm workers can develop silo-​ filler’s lung when they enter or decap a contaminated silo. Typically breathlessness caused by pulmonary oedema develops several hours after exposure though presentation may be delayed for 24 hours or more. Nitrogen dioxide can also be generated by thermal oxidation of nitrogen in air when welding is carried out in poorly ventilated areas, and from the combustion of nitrogen-​containing substances such as nitrocellulose. A wide range of other chemical agents can cause acute pneumon- itis. Household waterproofing and dirt repellent sprays often con- tain fluorocarbon polymers. When used in confined spaces they can cause acute chemical pneumonitis (Fig. 18.14.11.1) that on oc- casions has been fatal. Exposure to cadmium fumes from welding metal alloys can also cause acute and potentially fatal chemical pneumonitis. Mercury vapour and less commonly antimony, man- ganese, beryllium, vanadium, cobalt, tributyl tin, and halide salts have all been reported to cause similar problems. Acid anhydrides Table 18.14.11.1  The effects of gases and vapours on the airways and lungs Highly soluble gases and vapours with upper airway effects Hydrogen chloride Ammonia Formaldehyde Acrolein Sulphur dioxide Intermediate solubility gases causing upper airway effects and pneumonitis Chlorine Hydrogen sulphide Low solubility gases causing pneumonitis Nitrogen oxides Ozone Phosgene Fig. 18.14.11.1  Acute lung injury following the use of a waterproofing spray in an enclosed area. Lung biopsy showed a desquamative interstitial pneumonia pattern. From Nakazawa A, et al. (2014). Surgically proven desquamative interstitial pneumonia induced by waterproofing spray. Intern Med, 53, 2107–​10.

18.14.11  Toxic gases and aerosols 4269 used as cross-​linking agents in the production of epoxy resins cause pneumonitis with prominent alveolar haemorrhage and haemo- lytic anaemia. Smoking crack cocaine can also cause diffuse alveolar damage with alveolar haemorrhage that presents up to 48 hours after exposure. Nonpulmonary effects Asphyxiants Gases other than oxygen can act as asphyxiants by displacing oxygen from inhaled air. The most commonly encountered are CO2 and methane produced by decomposing vegetable material. The accumulation of oxygen-​deficient air from soil in wells during periods of low barometric pressure has led to asphyxiation of those climbing into them. Blackdamp in coal mines arises from the slow combustion of coal. Occasionally deoxygenated air can escape from disused mines and enter cellars of overlying houses posing a risk to unsuspecting residents. Chemical asphyxiants such as carbon monoxide and hydrogen cyanide act by blocking oxygen uptake by haemoglobin or by inhibiting intracellular oxygen utilization. They are important considerations in the case of smoke inhalation as they may be associated with tissue hypoxaemia despite apparently normal ar- terial oxygen saturation and pO2 measurements. On rare occasions they may require specific treatment such as hyperbaric oxygen for carbon monoxide intoxication or dicobalt edetate for cyanide poisoning. Metal and polymer fume fevers Metal fume fever and polymer fume fever are acute self-​limiting conditions characterized by influenza-​like symptoms with fever, myalgia, headache, malaise, cough, and mild breathlessness, begin- ning within 6 hours of exposure and resolving fully within 24 hours. They are distinguished from inhalation injuries by the greater prom- inence of systemic features and by the absence of chest radiograph abnormalities or hypoxaemia. Metal fume fever is most commonly caused by exposure to zinc from welding galvanized (i.e. zinc-​coated) steel, but can also be caused by copper, magnesium, and other metal fumes. Polymer fume fever is caused by exposure to heated fluoropolymers. Over­ heated frying pans, and fluoropolymer particles from sealant tape transferred from plumbers’ hands onto cigarettes are recognized causes. Tachyphylaxis leads to progressively milder responses with repeated exposures, similar to the ‘Monday fever’ described in cotton workers. Assessment and management Supportive care The initial treatment of acute inhalation injuries is essentially sup- portive. The affected individual should be moved to a safe area and potentially contaminated clothing removed to avoid secondary ex- posure. Carers should wear appropriate protective clothing to en- sure that they themselves do not become contaminated. Oxygen saturation should be monitored and oxygen admin- istered if the patient is hypoxaemic or if there has been possible exposure to carbon monoxide or cyanide (e.g. from fires). Carboxyhaemoglobin, methaemoglobin, and lactate levels should be measured following smoke inhalation. Nebulized bronchodilators should be administered if there is bronchospasm, and oral cortico- steroids considered. Early intubation may be necessary if there is evidence of laryngeal oedema. Bronchoscopy is occasionally neces- sary to remove excessive airway secretions. Other issues A detailed history of the circumstances of the exposure will provide important information to guide further management, such as the likelihood of exposure to a poorly soluble gas and the risk of de- layed pulmonary oedema or systemic toxicity. Unconscious victims are likely to have received particularly heavy exposures. The circum- stances of the exposure may have been psychologically traumatic and panic with psychogenic hyperventilation may need to be iden- tified and managed. A chest radiograph is essential, but an initially normal film does not rule out the later development of pneumonitis and pulmonary oedema. Patients with significant inhalation injury should be moni- tored for at least 24 hours. Even if they are well, they should be ad- vised of the risk of delayed pulmonary oedema developing over the next few days, particularly if there has been exposure to low solu- bility gases such as nitrogen oxides. Recurrent episodes of pulmonary oedema 1–​3 weeks after the initial exposure have been reported following exposure to nitrogen oxides, although the underlying mechanism is obscure. Severe pulmonary oedema should be managed as for the acute respiratory distress syndrome. There is no established role for corticosteroids, but they may help prevent the development of late pulmonary oe- dema after nitrogen dioxide exposure. Subacute toxic injury to the respiratory tract Acute inhalation injuries can give rise to persisting lung damage. Tracheal stenosis, bronchiectasis, asthma, and pulmonary fibrosis have all been reported, but more recently it has become clear that constrictive bronchiolitis is the commonest outcome. Fibrous tissue proliferation with narrowing and obliteration of the small periph- eral airways develops as a consequence of respiratory epithelial and basement membrane damage caused by the toxic exposure. Chronic diseases such as chronic obstructive pulmonary disease (COPD) and pneumoconiosis may arise through other ‘toxic’ or ‘irritant’ mechanisms (see Chapters 18.8 and 18.13). Clinical features Constrictive bronchiolitis following acute inhalation injury Chronic respiratory symptoms were common in World War I veterans who were exposed to chemical warfare agents, but the underling pathophysiology was poorly characterized. A  10-​year follow-​up study of those exposed to sulphur mustard in the Iran–​ Iraq war revealed persisting abnormalities of lung function in al- most 50% of subjects. Features of constrictive bronchiolitis were found in two-​thirds of a small group of patients who underwent lung biopsy. The Bhopal disaster of 1984 involved the release of 40 tonnes of methyl isocyanate gas, with at least 3800 immediate deaths. A high proportion of survivors reported ongoing respiratory symptoms and had impaired lung function, probably caused by bronchiolitis.

section 18  Respiratory disorders 4270 Persisting constrictive bronchiolitis is also described following acute exposure to other irritant gases including nitrogen oxides, sul- phur dioxide, bromine compounds, ammonia, fly ash, and smoke inhalation. The 2001 destruction of the New York World Trade Centre gave rise to a dense dust cloud of very alkaline pH that caused acute airway and eye irritation and inflammation. 14 000 firefighters were involved, all of whom had pre-​exposure lung function meas- urements. They had a mean fall of FEV1 of 440 ml within the first year of exposure, with little recovery over the subsequent 6 years. The pathological process has been poorly characterized, but biopsy studies have suggested that bronchiolitis is an important mech- anism. A  range of other outcomes has been reported, including asthma, bronchitis, and sarcoidosis, but a causal relationship with the exposure has not always been clear. Constrictive bronchiolitis without an antecedent acute injury Early studies of silo fillers exposed to nitrogen dioxide suggested that some individuals developed insidious-​onset constrictive bron- chiolitis. A cluster of cases of constrictive bronchiolitis was reported in US military personnel who served in Iraq and Afghanistan and developed persisting breathlessness and exercise limitation. The diagnosis was confirmed by lung biopsy in 38 cases. The commonest association was with proximity to a mine fire that produced high ambient air levels of sulphur dioxide, but one-​third of those affected reported no unusual exposures. Severe constrictive bronchiolitis was identified in eight former workers of a popcorn factory in 2000. Four required lung transplant- ation. All had handled the butter-​flavouring agent 2,3-​butanedione (diacetyl), and none had reported work-​related symptoms to raise the suspicion of an occupational cause. A subsequent survey of 20 flavouring manufacturing companies identified abnormal lung function in 23% of workers, suggesting a high prevalence of ‘pop- corn workers lung’ (Fig. 18.14.11.2). The disease generally presents insidiously with cough, breathlessness and (in some cases) eye, nose, and throat, and skin irritation. Similar conditions have been re- ported in other industries with flavouring exposures such as cookie manufacture and coffee processing. Severe constrictive bronchiolitis has also been described in workers exposed to glass fibre, resins, accelerating agents, and other chemicals when making fibreglass-​reinforced boats. Other subacute lung disease arising from toxic exposures Outbreaks of respiratory disease have been caused by the inhalation of nylon fragments in the nylon flock industry. Affected workers developed a restrictive ventilatory abnormality with reduced gas diffusion, and interstitial shadowing on chest radiographs or CT scans. Biopsies generally showed a distinctive lymphocytic bron- chiolitis and peribronchiolitis with lymphoid hyperplasia and aggregates. The Ardystil syndrome resulted from an apparently minor change in the formulation of sprayed printing dyes in textile factories. Approximately 10% of exposed workers developed lung disease and 5 of the original case series of 14 patients died. Affected individ- uals reported breathlessness, cough, and prominent epistaxis. The radiological and pathological appearances were those of organizing pneumonia. Respiratory problems have been identified in up to 20% of workers exposed to indium in the manufacture of electronic display screens. Radiological abnormalities have often mimicked those of pulmonary alveolar proteinosis, with ground-​glass shadowing and superimposed ‘crazy paving’ interlobular septal thickening. Biopsies showed granular eosinophilic and intra-​alveolar exudates typical of pulmonary alveolar proteinosis together with diffuse lung fibrosis. Diagnosis and management The recognition of chronic respiratory disease caused by an acute inhalational injury is generally straightforward, but there may be difficulties distinguishing persisting effects of exposure from antecedent lung disease such as asthma or COPD. Disease arising without an acute episode is much more difficult to attribute to the causative exposure. Often effects have been recognized only when a cluster of cases has presented to the same hospital clinic or though detailed epidemiological investigation. Constrictive bronchiolitis is a particularly difficult diagnosis to es- tablish and is easily mistaken for asthma or COPD. Lung function tests typically show airflow obstruction, but there may be an equal re- duction in forced expiratory volume (FEV) and forced vital capacity (FVC) associated with gas trapping and an elevated residual volume. The transfer factor may be normal or impaired. The plain chest radio- graph is often normal. High-​resolution CT (HRCT) findings may also be subtle, with patchy areas of decreased lung density that are en- hanced on expiratory images. Lung biopsies have identified symptom- atic disease in the presence of normal HRCT scans and lung function. Constrictive bronchiolitis generally stabilizes following the ces- sation of exposure, but there is no clear evidence of benefit from therapy. Those exposed to sulphur mustard have been reported to respond to bronchodilators, inhaled glucocorticoids, oral N-​ acetylcysteine, and interferon-γ. Popcorn worker’s lung does not respond to oral corticosteroids or cyclophosphamide. A high pro- portion of those with occupationally-​induced constrictive bron- chiolitis have required lung transplantation. Importantly, the identification of a sentinel case of possibly work-​ related disease should prompt a survey of fellow workers and a re- view of the occupational exposures (see Chapter 10.2.1). Worker education and appropriate surveillance schemes are also important 3.5 3 FEV1 (ltr) 2.5 2 1.5 1 0.5 0 0 5 10 15 20 25 30 Months since start of work Acute exposure 35 40 Fig. 18.14.11.2  Lung function in a flavouring manufacturer before and after exposure to diacetyl. Acute irreversible reduction of FEV caused by constrictive bronchiolitis. Adapted from Hendrick DJ (2008). ‘Popcorn worker’s lung’ in Britain in a man making potato crisp flavouring. Thorax, 63, 267–​268.

18.14.12 Radiation pneumonitis 4271 S.J. Bourke

18.14.12 Radiation pneumonitis 4271 S.J. Bourke

18.14.12  Radiation pneumonitis 4271 in the early detection of subacute disease such as bronchiolitis and limiting its adverse consequences. FURTHER READING Cowl CT (2019). Assessment and treatment of acute toxic inhalations. Curr Opin Pulm Med, 25, 211–16. de Lange DW, Meulenbelt J (2011). Do corticosteroids have a role in preventing or reducing acute toxic lung injury caused by inhalation of chemical agents? Clinical Toxicology, 49, 61–​71. King MS, et al. (2011). Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan. N Engl J Med, 365, 222–​30. Kreiss K (2013). Occupational causes of constrictive bronchiolitis. Curr Opin Allergy Clin Immunol, 13, 167–​72. Sauler M, Gulati M (2012). Newly recognized occupational and envir- onmental causes of chronic terminal airways and parenchymal lung disease. Clin Chest Med, 33, 667–​80. 18.14.12  Radiation pneumonitis S. J. Bourke ESSENTIALS The lungs can be injured by radiation used in the treatment of cancer, with the rapidly dividing endothelial cells and type II pneumocytes most affected. Immediate injury is followed by an inflammatory re- sponse and at a later stage by fibrosis. Chest radiography detects asymptomatic changes in about 50% of patients after radiotherapy. Acute radiation pneumonitis presents with cough, breathlessness, and fever about 2 months after exposure; corticosteroids are usually effective in relieving symptoms but do not prevent the subsequent development of fibrosis. Fibrosis typically develops about 6 months later, may progress for 6 to 24 months, but has usually stabilized by 2 years. Prevention depends on refining techniques for giving radiotherapy. Introduction The lungs are vulnerable to injury from radiation used in the treat- ment of cancers of the lung, breast, oesophagus, spine, thymus, and lymph glands, and when whole-​body irradiation is given in prep- aration for bone marrow transplantation. Radiation pneumonitis continues to cause significant morbidity and rarely mortality, and remains a limiting factor for the intensity of radiation treatment of patients with inoperable lung cancer. It is an important adverse effect which needs to be considered when assessing new treatment strat- egies using high intensity radiation and concurrent chemotherapy and radiation treatment, particularly in an ageing population with pre-​existing lung disease, reduced lung reserve, and comorbidities. Radiation causes direct injury to cells and DNA within the field of radiotherapy, giving rise to pneumonitis and fibrosis. The induction of reactive oxygen species and the initiation of cytokine-​mediated inflammatory responses result sporadically in more diffuse radiation lung injury involving areas of the lung outwith the radiotherapy field. Acute radiation pneumonitis is characterized by interstitial inflam- mation occurring up to 4 months after radiotherapy and then re- solving over a matter of weeks or months. Radiation fibrosis, which can occur without preceding pneumonitis, develops about 6 months after radiotherapy and may progress over 6–​24 months; it does not resolve, but usually stabilizes by 2 years. Pathogenesis Factors which influence the development of radiation pneumonitis and fibrosis include the volume of lung irradiated, the total radiation dose administered, and the dose rate and fractionation. Concomitant use of chemotherapeutic drugs such as taxanes, erlotinib, bleomycin, doxorubicin, methotrexate, and cyclophosphamide can aggravate radiation lung injury. Furthermore, when chemotherapy is given after radiotherapy, ‘recall pneumonitis’ may develop in the areas of lung previously irradiated. Tamoxifen has been shown to enhance lung injury in patients receiving radiotherapy for breast cancer, which may be due to increased release of transforming growth factor β (TGFβ). Corticosteroid withdrawal may also precipitate radiation pneumonitis, and there is increased risk with pre-​existing lung fi- brosis or current lung infection. Absorption of radiation by lung tissues accelerates electrons, generating ion pairs and reactive oxygen species, which damage DNA and produce chemical and biological effects in cells. Rapidly dividing cells, such as endothelial cells and type II pneumocytes, are most affected. The earliest changes involve injury to small vessels with thrombosis, increased permeability, and exudation of protein-​rich fluid into the alveoli. Epithelial injury results in sloughing of cells, hyaline membrane formation, and prolifer- ation of type II pneumocytes. Inflammatory cells accumulate in the alveolar walls, followed at a later stage by fibroblasts. Increased plasma concentrations of TGFβ and intercellular adhesion mol- ecule (ICAM)-​1 correlate with an increased incidence of radiation pneumonitis. ICAM-​1 stimulates the accumulation of inflamma- tory cells, whereas TGFβ stimulates fibroblast proliferation and in- duces synthesis of collagen, and genetic polymorphisms that result in high production of TGFβ are associated with more severe ra- diation fibrosis. Cellular expression of CD95 and CD95-​ligand are increased after radiotherapy, and these receptors are involved in the induction of apoptosis, inflammatory cytokine responses, and the attraction of inflammatory cells. These immunologically mediated responses are not confined to the radiotherapy field. Clinical features Asymptomatic changes are detectable on a chest radiograph in about 50% of patients after radiotherapy. Characteristically there is an area of opacification that does not show a segmental or lobar distribu- tion: it crosses the normal anatomical structures and is demarcated by a sharp margin corresponding to the limits of the radiotherapy field (Fig. 18.14.12.1). Air bronchograms are often present and there is usually a loss of volume.

18.14.13 Drug- induced lung disease 4272 S.J. Bour

18.14.13 Drug- induced lung disease 4272 S.J. Bourke

section 18  Respiratory disorders 4272 Symptoms occur in about 5–​15% of patients, depending on the treatment regimen used, with the onset of cough, breathlessness, and fever about 2 months after radiotherapy. Pre-​existing lung disease may increase the clinical impact of radiation pneumonitis, but symp- toms often resolve spontaneously. Fibrosis may result in permanent loss of lung function, with a reduction in total lung capacity and carbon monoxide transfer factor associated with chronic breathless- ness. This typically develops about 6 months after radiotherapy and may progress for 6–​24 months, but has usually stabilized by 2 years. CT is more sensitive than the chest radiograph in detecting radiation-​induced changes such as ground-​glass shadowing, septal thickening, and fibrosis, and is useful in differentiating radiation in- jury from tumour recurrence or infection. Severe acute reactions to radiotherapy are rare but can occasion- ally result in respiratory failure and the acute respiratory distress syndrome, particularly in patients with pre-​existing interstitial lung disease. Patterns of injury that involve the lungs more diffusely are well recognized. Bilateral lymphocytic alveolitis is often present after unilateral radiotherapy in patients with breast cancer, while posi- tron emission tomography has shown increased metabolic activity in nonirradiated areas of the lung in patients who have had radio- therapy for lung cancer. Diffuse bronchiolitis obliterans organizing pneumonia and chronic eosinophilic pneumonia have also been re- ported in patients with breast cancer treated by radiotherapy. Other short-​term risks of chest radiotherapy relate to pneumo- thorax, pleural reactions, and rib fractures, and in the long term there is an increased risk of lung cancer. Treatment Most cases of radiation pneumonitis are subclinical or cause only minor symptoms that do not require treatment. In more severe cases corticosteroids are usually effective in relieving symptoms during the acute phase, but they do not prevent the subsequent devel- opment of fibrosis. Typically, prednisolone 40–​60 mg daily is given until there is clinical improvement, at which stage the dose is tapered while watching for signs of recrudescence of the pneumonitis. Prevention of radiation-​induced lung injury is particularly focused on refining techniques which increase the radiation dose delivered to the cancer and reduce exposure of normal lung. Radiotherapy lung injury has been reduced in animal models by the administra- tion of agents such as amifostine, captopril, pentoxifylline, and man- ganese superoxide dismutase, but a clinical role for these agents has not been established. FURTHER READING Castillo R, et al. (2014). Pre-​radiotherapy FDG PET predicts radiation pneumonitis in lung cancer. Radiation Oncology, 9, 74–​89. Cottin V, et al. (2004). Chronic eosinophilic pneumonia after radiation therapy for breast cancer. Eur Respir J, 23, 9–​13. Crestani B, et  al. (1998). Bronchiolitis obliterans organizing pneu- monia syndrome primed by radiation therapy to the breast. Am J Respir Crit Care Med, 158, 1929–​35. Hanania AN, et al. (2019) Radiation-induced lung injury: assessment and management. Chest, 156, 150–62. Heinzelmann F, et al. (2006). Irradiation-​induced pneumonitis me- diated by the CD95/​CD95-​ligand system. J Natl Cancer Inst, 98, 1248–​51. Hesham A, et al. (2005). Positron emission tomography demonstrates radiation-​induced changes to non-​irradiated lungs in lung cancer patients treated with radiation and chemotherapy. Chest, 128, 1448–​52. Martin C (1999). Bilateral lymphocytic alveolitis: a common reaction after unilateral thoracic irradiation. Eur Respir J, 13, 727–​32. Movsas B (1997). Pulmonary radiation injury. Chest, 111, 1061–​75. Neugut AI, et  al. (1994). Increased risk of lung cancer after breast cancer radiation therapy in cigarette smokers. Cancer, 73, 1615–​20. Palma DA, et  al. (2013). Predicting radiation pneumonitis after chemoradiation therapy for lung cancer:  an international indi- vidual patient data meta-​analysis. Int J Radiation Oncol Biol Phys, 85, 444–​50. Rowinsky EK, Abeloff MD, Wharam MD (1985). Spontaneous pneumothorax following thoracic irradiation. Chest, 88, 703–​6. Zhuang H, et  al. (2014). Radiation pneumonitis in patients with
non-​small cell lung cancer treated with erlotinib concurrent with thoracic radiotherapy. J Thorac Oncol, 9, 882–​5. 18.14.13  Drug-​induced lung disease S. J. Bourke ESSENTIALS Drug-​induced lung disease is common and needs to be considered in the differential diagnosis of many respiratory conditions. The na- ture and timing of events often provide an important clue and are Fig. 18.14.12.1  Chest radiograph showing radiation-​induced fibrosis, particularly in the right upper zone. Note the sharply demarcated edge to the fibrosis, which does not conform to any normal anatomical structure.

18.14.13  Drug-induced lung disease 4273 sometimes sufficiently characteristic for drug-​induced lung disease to be diagnosed with confidence, with resolution of symptoms on drug cessation providing further supportive evidence. Well-​ recognized adverse drug effects are listed in formularies and drug data sheets, but it is often helpful to consult a constantly updated website (http://​www.pneumotox.com is highly recommended). Direct drug effects may arise through toxic, pharmacological, al- lergic, or idiosyncratic mechanisms, and there may also be indirect effects (e.g. a predisposition to lung infection from cytotoxic and im- munosuppressive therapies). From a clinical perspective, adverse ef- fects may be classified according to the induced disorder and the site of involvement. Asthma is the most common airway disorder to be induced or exacerbated by drugs. It may be produced by a predictable effect related to the drug’s pharmacological properties (e.g. β-​adrenergic antagonists) or as an idiosyncratic reaction (e.g. aspirin). Cough is a well-​recognized side effect of treatment with angiotensin-​ converting enzyme inhibitors. Alveolar and interstitial reactions comprise three main categories: (1) alveolar capillary leakage (e.g. salicylates); (2) interstitial pneu- monitis and fibrosis (e.g. bleomycin, amiodarone, infliximab); and (3) pulmonary eosinophilia (e.g. sulphonamides). Pulmonary vascular involvement includes venous thrombo- embolism (e.g. oral contraceptive pill), and pulmonary hypertension (e.g. aminorex, now withdrawn), dasatinib, and interferons. Pleural effusions and thickening may result from drugs (e.g. dantrolene, bromocriptine, methysergide, and dasatinib). Introduction Drug-​induced lung disease is common and needs to be considered in the differential diagnosis of many respiratory conditions, and in prescribing drugs for the treatment of diseases in all areas of clin- ical practice. Direct effects may arise through toxic, pharmacological, allergic, or idiosyncratic mechanisms, although often the precise mechanism is unknown. There may also be indirect effects (e.g. a pre- disposition to lung infection from cytotoxic and immunosuppressive therapies, and the development of respiratory failure from sedation). Some causes of drug-​induced lung disease have now been eradi- cated (e.g. aminorex pulmonary hypertension) as the causative drug is no longer prescribed. For others, the risks are now so well estab- lished that the potential for lung toxicity is considered in the risk–​ benefit assessment of prescribing (e.g. methotrexate, amiodarone, bleomycin) and the patient is informed of the risks and monitored for the adverse effects. It is for newly introduced drugs that par- ticular vigilance is required: adverse effects must be identified as speedily as possible (e.g. leflunomide, infliximab), early recognition of problems being critical both for the affected individual, so that drug cessation is prompt and the adverse effect is minimized, and also to prevent others coming to harm. Making the diagnosis of drug-​induced lung disease The first step in diagnosis is to consider the possibility that a clin- ical presentation might be drug-​induced. The nature and timing of events often provides important clues. In some circumstances they are sufficiently characteristic that drug-​induced lung disease can be diagnosed with confidence, with subsequent resolution of symptoms on drug cessation providing further supportive evidence. Reintroduction of the drug is rarely indicated unless it is essential in the management of the underlying disease or there is doubt about the diagnosis of an adverse drug effect. The exclusion of an alternative cause of any clinical events is an important step, with the diagnostic approach adapted to the circum- stances of the clinical problem, the likelihood of an adverse drug effect, the possibility of an alternative diagnosis, and the need for a definitive diagnosis to guide management decisions. For example, a patient may develop breathlessness and show diffuse infiltrates on chest radiography when taking immunosuppressive drugs for a connective tissue disease or chemotherapeutic agents for cancer. The clinical features could be due to an adverse drug effect on the lungs, infection, lung involvement by the underlying disease, or the development of coincidental lung disease. Management in these cir- cumstances depends crucially upon accurate diagnosis, and invasive tests such as bronchoscopy, bronchoalveolar lavage, and sometimes lung biopsy may be indicated. Although well-​recognized adverse drug effects are listed in formularies and drug data sheets, the field of drug-​induced lung disease is continuously evolving, and it is often helpful to con- sult a constantly updated website: http://​www.pneumotox.com is highly recommended. It is also important to report possible ad- verse drug reactions to appropriate local authorities, such as the Committee on Safety of Medicines in the United Kingdom, who may also be able to provide information to aid the management of individual cases. The clinical spectrum of drug-​induced lung disease is diverse and complex, and it is therefore advisable to scrutinize the drug list for potential drug causes when patients present with clinical problems for which no other cause is apparent. Drug-​induced lung disease may be classified according to the induced disorder and the site of involvement as airways, alveoli/​interstitium, pulmonary vascula- ture, and pleura. Airways Asthma Drug-​induced bronchoconstriction may arise by a number of dif- ferent mechanisms and sometimes the precise mechanism is uncer- tain. It most often occurs in patients with pre-​existing asthma. In some cases the asthma may not have been recognized until an epi- sode of bronchoconstriction occurs as an adverse effect of a drug, but in these instances clues to pre-​existing asthma may be apparent when the appropriate history is taken. Drugs that exacerbate symptoms in subjects with pre-​existing asthma may be classified as those that produce an effect which is to some extent predictable from their pharmacological properties, and those which produce bronchoconstriction due to an idiosyncratic effect (Table 18.14.13.1). Less commonly, asthma develops de novo, probably because IgE-​mediated immunological hypersensitivity has developed. Drug hypersensitivity reactions that include asthma among the manifestations are often associated with blood eosino- philia and/​or eosinophilic pneumonia.

section 18  Respiratory disorders 4274 Drug-​induced anaphylaxis The most dramatic presentation of drug-​related bronchoconstriction is as part of an acute anaphylactic reaction; penicillin and intra- venously administered iron–​dextran are particularly noteworthy among the causal agents. An anaphylactic reaction is characterized by swelling of the tongue, laryngeal oedema, upper airway obstruc- tion, and bronchospasm occurring within minutes of exposure to the drug. Immunological hypersensitivity is presumed to underlie most causes of occupational asthma, some of which involve pharma- ceutical agents. Most prominent are certain antibiotics (e.g. cephalo- sporins, isoniazid, penicillins, piperazine, spiramycin, tetracycline,), the H2-​receptor antagonist cimetidine, the laxative psyllium (ispa- ghula), pancreatic enzymes, and certain hormones (adrenocor- ticotropic hormone (ACTH), gonadotropin, pituitary snuff). If an individual sensitized by inhalation in the workplace subsequently uses the relevant drug therapeutically, the potential arises for an asthmatic reaction (Fig. 18.14.13.1). The medical history, when symptoms suggest asthma, should always include details of occu- pation and medication, and if the patient has ever worked in the pharmaceutical industry the possibility of occupationally induced hypersensitivity to a current medication should be considered. Cholinergic drugs Cholinergic drugs, such as carbachol, occasionally produced bronchoconstriction when given systemically, and in very sensitive asthmatic patients exacerbations have occurred after use of pilocar- pine eye drops for the treatment of glaucoma. Bronchoconstriction can also occur from the cholinergic effect of pyridostigmine used in the treatment of myasthenia gravis. An inhaled anticholinergic agent has been shown to be effective in reversing occasional unto- ward effects of cholinesterase inhibitors in asthmatic patients with myasthenia gravis. β-​adrenergic antagonists β-​adrenergic antagonists aggravate bronchoconstriction in patients with asthma. Although drugs, such as sotalol and metoprolol, which target β1-​receptors have less adverse effects on airway function, pa- tients with asthma can still show a reduction in forced expiratory volume in 1 s (FEV1) or peak flow which can be severe. By contrast, patients with smoking-​induced chronic obstructive pulmonary dis- ease often tolerate β-​blockers and derive benefit from their use in treating comorbid conditions such as ischaemic heart disease. Although the adverse effects of oral or systemic β-​blockers are well recognized, those of ophthalmic preparations are sometimes Fig. 18.14.13.1  Results of inhalation and ingestion challenge tests with ampicillin. The inhalation test confirmed that the patient had become sensitized to ampicillin as a consequence of respiratory exposure at work, and the ingestion test showed that asthmatic reactions would be provoked also by oral ingestion at therapeutic dose levels. Data taken from Davies RJ, Hendrick DJ, Pepys J (1974). Asthma due to inhaled chemical agents: ampicillin, benzyl penicillin, 6-​amino-​penicillanic acid and related substances. Clin Allergy, 4, 227–​47. Table 18.14.13.1  Drugs that may cause or exacerbate asthma Pharmacological effects Cholinergic agents (e.g. carbachol, pilocarpine) Cholinesterase inhibitors (e.g. pyridostigmine) Prostaglandin F Histamine-​releasing agents (e.g. curare derivatives, morphine, taxanes) β-​Sympathetic antagonists ACE inhibitors (cough without asthma more common) Sensitizing and idiosyncratic effects Oral   Aspirin and other NSAIDs   Tartrazine-​containing preparations   Taxanes (e.g. paclitaxel, docetaxel)   Carbamazepine   Venlafaxine Parenteral   Penicillin   Iron–​dextran complex   Adenosine   Hydrocortisone sodium succinate   N-​Acetylcysteine Inhaled   Nebulized pentamidine, colistin   Inhaled mannitol, hypertonic saline Eye drops   NSAIDs ACE, angiotensin-​converting enzyme; NSAIDs, nonsteroidal anti-​inflammatory drugs.

18.14.13  Drug-induced lung disease 4275 overlooked. Timolol, which is commonly used in eye drops for the treatment of glaucoma, is a potent nonselective β-​blocker. Its use has frequently been associated with worsening asthma. The ophthalmic formulation of a newer β-​blocker, betaxolol, appears to be less dan- gerous, but should only be used in patients with asthma if no suitable alternative is available. Aspirin and nonsteroidal anti-​inflammatory drugs Aspirin and nonsteroidal anti-​inflammatory drugs cause broncho­ constriction in about 10% of patients with asthma. This is thought to be caused by a shift of arachidonic acid metabolism away from the cyclooxygenase pathway towards the lipoxygenase pathway, resulting in increased production of leukotrienes which cause bronchoconstriction. Asthmatic deaths have been reported with both aspirin and indo- methacin. These patients often have a triad of nasal polyps, asthma, and aspirin-​induced bronchoconstriction. Many patients with analgesic-​induced asthma are also sensitive to the azo dye tartrazine, which was a commonly used colouring agent in medications and foodstuffs, and—​since it is an approved food and drug additive—​its presence is not always declared and hence the extent of the problems it may cause is not clear. In the past tartrazine was present, ironically, in some medications used to treat asthma, but most pharmaceutical companies no longer use it in their formulations. The importance of drug formulation Asthmatic symptoms can be a consequence of the particular formu- lation of a drug or its method of delivery. For example, nebulized solutions of low osmolality can trigger asthmatic reactions if the pa- tient has a high level of airway responsiveness. This appears to have been the main mechanism of bronchoconstriction induced para- doxically by nebulized ipratropium bromide, and since the drug was reformulated in isotonic solution the problem has resolved. A further cause of bronchoconstriction from nebulized drugs has been the presence of certain preservatives or stabilizers (e.g. benzalkonium chloride, edetate disodium) in the excipient so- lution. Inhaled antibiotics, such as pentamidine for Pneumocystis jirovecii infection, or colistin, tobramycin, or aztreonam for treating bronchiectasis and cystic fibrosis, sometimes also pro- voke bronchoconstriction. Inhaled mannitol, used as a mucolytic agent in treating patients with cystic fibrosis, is known to provoke bronchoconstriction in patients with asthma and patients should be monitored at the start of treatment with serial spirometry after a trial dose to ensure that they do not develop bronchoconstriction. Prior use of a bronchodilator such as salbutamol is useful in increasing the tolerability of such inhaled medications. Other drugs that can cause asthma The bronchoconstrictor prostaglandin F2α, used to induce abor- tion, may be hazardous in asthmatic patients. The occurrence of bronchoconstriction after thiopentone, opiates, and muscle relax- ants (tubocurarine, suxamethonium, and pancuronium) is probably due to their capacity to release histamine from basophils. Taxanes, such as paclitaxel or docetaxel, may result in mast cell degranula- tion, and this can provoke bronchoconstriction. Corticosteroids and antihistamines are therefore routinely given prior to taxane treatment to reduce the occurrence of this adverse effect. Iodinated contrast media used in radiological imaging may activate the complement system, with activation of mast cells and basophils via anaphylatoxins C3a and C5a receptors. Adenosine given intraven- ously to treat supraventricular tachycardia is a potent constrictor of asthmatic airways. Its effects on the airways are probably due to ac- tivation of mast cells via an A2 receptor. Drug prescribing for patients with asthma The potential exacerbation of asthma by drugs used to treat it pre- sents a special dilemma, as a drug effect may be difficult to dissociate from spontaneous deterioration. There are well-​documented re- ports of worsening asthma after intravenous hydrocortisone. This is a particular problem in asthmatic patients who also show ad- verse reactions to aspirin and nonsteroidal anti-​inflammatory drugs (NSAIDs). The sensitivity to hydrocortisone of these individuals does not extend to other steroids: it appears to be related to the suc- cinate moiety of the hydrocortisone sodium succinate molecule, as it is not seen with the alternative phosphate salt. Idiosyncrasy probably underlies many asthmatic symptoms re- lated to medication and is the likely explanation for exacerbations following use of intravenous N-​acetylcysteine in paracetamol poi- soning, use of which requires caution in asthmatic patients. Drugs masking asthma There are rare situations where cessation of a drug may reveal pre- viously undetected asthma. For example, lithium has been shown to reduce airway responsiveness and inhibit the contractile re- sponse of airway smooth muscle, and there are rare reports of asthma becoming apparent for the first time when this medication is discontinued. Cough Cough in the absence of asthma is a well-​recognized side effect of treatment with angiotensin-​converting enzyme (ACE) inhibitors. It develops in 10 to 20% of individuals treated with these drugs and is an effect of the class of drug rather than of specific agents. The cough is nonproductive. There appears to be a weak relation to dose, such that dose reduction may result in some improve- ment, but in many individuals the symptom remains sufficiently troublesome to necessitate drug withdrawal. Deterioration of pre-​ existing asthma has also been reported occasionally, but features of asthma are not present in most individuals with cough related to ACE inhibition. The mechanism is unclear; ACE catalyses not only the conversion of angiotensin I to angiotensin II, but also the breakdown of bradykinin and substance P. Since these agents are cough stimulants, their accumulation offers a possible mech- anism for this adverse effect. The cough resolves on withdrawal of the drug. Alveoli and the lung interstitium Drug-​induced alveolar and interstitial lung disease may occur in different clinical settings, with a diverse range of drugs, and en- compasses a broad spectrum of disease from acute noncardiogenic pulmonary oedema to insidiously developing pulmonary fibrosis. These conditions are conveniently considered under three main categories: alveolar capillary leakage, interstitial pneumonitis and fibrosis, and pulmonary eosinophilia (Table 18.14.13.2).

section 18  Respiratory disorders 4276 Alveolar capillary leakage Acute pulmonary oedema is a recognized complication of overdoses of salicylates, opiates, and tricyclic antidepressants. The pulmonary oedema develops as a result of increased permeability of the alveolar capillary membrane, which is thought to arise through various mechanisms, sometimes involving immunoglobulin and comple- ment deposition in the lung, cytokine release from lymphocytes, and activated neutrophils aggregating and adhering to endothelial cells, releasing toxins, oxygen radicals and mediators (arachidonic acid, histamine, kinins). Alveolar capillary leakage has also been described with hydro­ chlorothiazide as an idiosyncratic reaction which does not occur with other thiazide drugs. Acute pulmonary oedema has also been reported with interleukin-​2, used in the treatment of melanoma and renal cell carcinoma, and occasionally after injection of radiocontrast media. Infused β2-​adrenergic agonists (terbutaline, isoxsuprine), used as tacolytics to relax the uterus and to inhibit premature labour, may also give rise to florid pulmonary oedema. In these cases there is a close temporal relationship between drug administration and the onset of pulmonary oedema. In other circumstances the acute respira- tory distress syndrome may result from a reaction to more prolonged use of drugs including amiodarone, anticancer chemotherapy (vin- cristine, mitomycin C, melphalan, paclitaxel, cyclophosphamide) and anti-​inflammatory drugs (infliximab, methotrexate). Interstitial pneumonitis and fibrosis Many drugs may provoke an inflammatory reaction in the lungs with interstitial inflammation, alveolitis, and sometimes fibrosis. Many classic causes are very well-​known, but vigilance is required as new drugs are introduced into practice. Early recognition of drug-​ induced interstitial lung disease allows prompt cessation of the drug. Interstitial pneumonitis and fibrosis are particularly well recog- nized with amiodarone, nitrofurantoin, methotrexate, leflunomide, and certain anticancer drugs. When choosing a drug which is rec- ognized to have the potential for lung toxicity, it is important to ad- vise patients of the risk so that they can be alert for the onset of any symptoms. It is also advisable to establish accurately whether the patient has any pre-​existing lung disease, and to undertake baseline investigations such as a chest radiograph and lung function tests. This is particularly relevant where the disease being treated is itself associated with interstitial lung disease, as in the case of rheumatoid arthritis and connective tissue diseases. Clinical presentation and investigation Patients experiencing a drug-​induced pneumonitis may present acutely with cough, fever, shortness of breath, and occasionally sys- temic upset. Alternatively, there is slowly progressive fibrosis with gradually worsening dyspnoea and widespread shadowing on the chest radiograph. The mechanisms of such reactions are uncertain, but may include toxicity, hypersensitivity, and often idiosyncrasy. Table 18.14.13.2  Alveolar and interstitial drug reactions Alveolar capillary leakage Hydrochlorothiazide Interleukin-​2 Naloxone Opiates Salicylates Radiocontrast Tricyclic antidepressants Tocolytic agents (e.g. isoxsuprine, terbutaline) Interstitial pneumonitis and fibrosis Amiodarone Antiretroviral therapy Infliximab Leflunomide Methotrexate Nitrofurantoin Cytotoxic agents   Azathioprine   Bleomycin   Busulfan   Carmustine (BCNU)   Chlorambucil   Cyclophosphamide   Cytosine arabinoside   Lomustine (CCNU)   Melphalan   6-​Mercaptopurine   Mitomycin C Biological agents TNFα inhibitors (e.g. infliximab, etanercept, adalimumab) Monoclonal antibodies (e.g. rituximab, trastuzumab) Tyrosine kinase inhibitors (e.g. gefitinib, erlotinib) Interferon α Pulmonary eosinophilia Aspirin Carbamazepine Chlorpropamide Dapsone Gold salts a Imipramine Methotrexate a Naproxen Nitrofurantoin a Penicillamine a Penicillins Phenytoin Procarbazine a Sulphasalazine Sulphonamides Tetracycline a Pulmonary eosinophilia is a feature of some reactions to these drugs, but adverse effects can also occur by other mechanisms.

18.14.13  Drug-induced lung disease 4277 With some drugs—​including bleomycin, carmustine, amiodarone, and nitrofurantoin—​there is a relation to dose or duration of treat- ment. Evidence in cases of nitrofurantoin-​ and bleomycin-​induced pneumonitis suggests a role for the production of toxic oxygen radicals in the lungs, perhaps providing a link with the known pul- monary toxicity of oxygen itself and the synergistic adverse effects of high oxygen concentrations and some cytotoxic agents. A single drug (e.g. amiodarone, methotrexate) may produce a diverse range of histopathological changes in the lungs, including alveolitis, fibrosis, nonspecific interstitial pneumonitis, crypto- genic organizing pneumonia, and diffuse alveolar damage. Lung biopsy therefore tends to show the pattern and severity of intersti- tial lung disease rather than showing the precise causation, and it is often difficult to establish from biopsy whether fibrosis is due to the underlying disease (rheumatoid or connective tissue lung disease) or a drug reaction. For this reason lung biopsy is of limited value and is rarely performed. Conversely, drugs must always be considered in the differential diagnosis of patients presenting with interstitial lung disease. Histological patterns of nonspecific interstitial pneumonia, usual interstitial pneumonia, and cryptogenic organizing pneu- monia have all been associated with many different drugs. Particular clinical circumstances Amiodarone Much interest has centred on the cardiac antiarrhythmic drug amiodarone. It has been estimated that about 6% of patients taking 400 mg or more per day for 2 months or more will develop overt pulmonary toxicity, but there have been several well-​documented cases involving smaller doses. The mechanisms may include both immunologically mediated and direct toxic effects. Histologically the lung shows features of chronic inflammation together with inter- stitial and intra-​alveolar fibrosis (Fig. 18.14.13.2). Characteristic ‘foamy’ macrophages are seen, but they are not specific for serious toxic reactions as they are also demonstrable in most patients taking the drug without adverse clinical effects. Occasionally the histo- logical picture is of cryptogenic organizing pneumonia. Symptoms include progressive dyspnoea, a troublesome cough, and (occasionally) pleuritic pain. Radiographic appearances are varied: most frequently there is a diffuse nodular or alveolar filling pattern, sometimes with upper lobe predominance (Fig. 18.14.13.3); sometimes a pleural effusion is present. The differential diagnoses of amiodarone pulmonary toxicity particularly include left ventricular failure and pneumonia. Measure­ ment of serum brain natriuretic peptide (elevated in cardiac failure) and assessment of left ventricular function by echocardiography is helpful. Bronchoalveolar lavage may be necessary to exclude in- fection: in amiodarone pulmonary toxicity this typically shows a lymphocytic pattern, but the finding of ‘foamy’ macrophages is insufficient to confirm the diagnosis. If amiodarone lung toxicity is suspected, cessation of treatment is desirable, but the very long half-​life of drug metabolites (many weeks) means that elimination is very slow. Corticosteroids probably suppress the reaction and are often used. Rheumatoid arthritis Drug-​induced interstitial lung disease is particularly common in the treatment of rheumatoid arthritis and connective tissue diseases. Interstitial disease has been well described in relation to penicillamine, gold salts, and sulphasalazine, but these agents are now much less frequently used than they were in the past. Methotrexate is a particularly well recognized cause of drug-​ induced interstitial lung disease. This is usually a hypersensitivity reaction which is not directly related to the cumulative dose or dur- ation of treatment. Patients typically present subacutely with cough and dyspnoea, sometimes with fever. Chest radiography and CT show diffuse infiltrates. Bronchoalveolar lavage may be helpful in excluding infection and may show a neutrophilic or lymphocytic alveolitis. Lung function tests usually show a reduction in lung vol- umes and impairment of gas diffusion, but serial monitoring of lung function has not been shown to be helpful in detecting pneumon- itis before the onset of symptoms. Where lung biopsies have been performed they have shown a spectrum of interstitial inflamma- tion, fibrosis, type II pneumocyte hyperplasia and (sometimes) Fig. 18.14.13.2  Histological specimen of the lung of a patient who died from amiodarone pulmonary toxicity, showing (a) alveolar wall thickening and organizing intra-​alveolar exudates; and (b) the alveolar exudate with characteristic ‘foamy’ macrophages, seen at higher magnification. From Adams PC, et al. (1986). Amiodarone pulmonary toxicity: clinical and subclinical features. Quarterly Journal of Medicine, 59, 449–​71, by permission of Oxford University Press.

section 18  Respiratory disorders 4278 granulomas. Treatment is by stopping the drug, and corticosteroids are often given. Leflunomide-​induced interstitial pneumonitis is thought to be rare, and the incidence may have been exaggerated by the tendency to use leflunomide rather than methotrexate in patients with pre-​existing rheumatoid interstitial lung disease. Nonetheless, it can cause severe pneumonitis, possibly aggravating pre-​existing rheumatoid lung dis- ease, such that particular care is required in managing such patients. Leflunomide should be discontinued if there is evidence of new or deteriorating interstitial lung disease, when cholestyramine or acti- vated charcoal can be used to aid elimination of the drug. Cytotoxic and immunosuppressive drugs Cytotoxic and immunosuppressive drugs are frequently associated with interstitial pneumonitis. Bleomycin causes problems most fre- quently, followed by busulfan and mitomycin C. Cyclophosphamide and azathioprine are the most widely used drugs in this group, be- cause of their roles in nonmalignant disease, but produce adverse pulmonary reactions only occasionally. In most cases it is not clear whether the effects are due to direct toxicity or to hypersensitivity. Bleomycin toxicity is dose-​related, occurring more commonly at cumulative doses greater than 300 000 units (European pharmaco- poeia units). The recorded frequency of adverse reactions varies with the means by which they are detected, with fibrosis occurring in 5 to 10% of patients treated with busulfan on clinical and functional criteria, but a much higher proportion on the basis of pathological and cytological evidence. Similarly, the increasing use of CT scan- ning shows an appreciably higher prevalence than found in surveys that employ plain chest radiography. The frequency of overt lung involvement may also be related to length of survival, as deter- mined by the primary disease. With busulfan, the interval between starting treatment and the appearance of toxic effects can be as long as 4 years, and in some cases the lung changes appear to progress after the drug has been discontinued. With carmustine (BCNU), pulmonary fibrosis may first be recog- nized several years after treatment has finished. Other factors that may increase the toxicity of a given drug include advanced patient age, and synergism with other drugs, lung radiation, or the subse- quent inhalation of high concentrations of oxygen. Histologically, most cytotoxic drugs produce evidence of diffuse alveolar damage with destruction of lining cells, formation of hyaline membranes, and variable degrees of inflammatory infiltration and fibrosis. Fibrosis is particularly common with busulfan and bleomycin, but rare with methotrexate. With methotrexate and procarbazine (and very occa- sionally with bleomycin) there may be blood and tissue eosinophilia, and correspondingly a good therapeutic response to steroids. Biological agents Biological agents are being increasingly used in the treatment of in- flammatory conditions and tumours. Certain drug-​induced lung conditions have been reported with these agents, and there have also been several reports of interstitial pneumonitis. Tumour necrosis factor α (TNFα) inhibitors (infliximab, etanercept, adalimumab) are used in the treatment of rheumatoid arthritis and inflammatory bowel disease. Increased susceptibility to respiratory infections, and to tuberculosis in particular, is an im- portant adverse effect, but there have also been several reports of interstitial pneumonitis with these agents. Monoclonal antibodies (rituximab, trastuzumab) are used in the treatment of some cancers and may cause interstitial pneumonitis. Interstitial pneumonitis has also been reported with tyrosine kinase inhibitors (gefitinib, erlotinib). Interferon-​α, used to treat hepatitis C, has been associated with the development of a sarcoid-​like granu- lomatous disease. The frequency and severity of interstitial lung disease with these different biological agents is not yet well established, but it is im- portant to be alert to possible adverse effects of treatment in patients developing respiratory symptoms on these medications. Drug-induced sarcoidosis-like reactions A granulomatous lung disease, mimicking sarcoidosis, has been described after instituting highly active antiretroviral therapy with protease inhibitors in patients with HIV infection. This pattern of lung disease seems to be related to immune reconstitution with enhanced lymphoproliferative responses rather than to any in- fective organism. Similar drug-induced sarcoidosis-like reactions have also been associated with immune checkpoint inhibitors (e.g. ipilimumab, nivolumab), interferons and TNFalpha antagonists. Pulmonary eosinophilia Eosinophilic reactions in the lung include conditions that would be classified as Löffler’s syndrome, simple or prolonged pulmonary eosinophilia, and eosinophilic pneumonia (see Chapter  18.14.2). Fig. 18.14.13.3  Chest radiograph of a patient with amiodarone pulmonary toxicity showing confluent alveolar shadowing in both upper lobes. From Adams PC, et al. (1986). Amiodarone pulmonary toxicity: clinical and subclinical features. Quarterly Journal Medicine, 59, 449–​71, by permission of Oxford University Press.

18.14.13  Drug-induced lung disease 4279 Tissue eosinophilia is a more consistent feature than peripheral blood eosinophilia. Historically, sulphonamides have been the drugs most frequently reported to cause pulmonary eosinophilia, and sulphonamide sensitivity may also explain some of the reactions to sulphasalazine, which is chemically related. The pulmonary eo- sinophilia recorded with aspirin appears to be distinct from aspirin-​ induced asthma. Nitrofurantoin may produce an acute pulmonary eosinophilic reaction in addition to more insidious fibrosis. The roles of gold salts and penicillamine in eosinophilic reac- tions have been a matter of some debate, but the evidence suggests that both are involved. It seems unlikely, however, that drugs are responsible for many of the cases of lung fibrosis associated with rheumatoid arthritis. Penicillamine has been incriminated in two other types of adverse pulmonary reaction: (1) pulmonary haem- orrhage (Goodpasture’s syndrome) when used in high doses for the treatment of Wilson’s disease, and (2) obliterative bronchiolitis in patients treated for rheumatoid arthritis. The clinical severity of eosinophilic reactions is very variable, ran- ging from a transient and asymptomatic radiographic opacity to a severe eosinophilic pneumonia with dyspnoea, cough, fever, and hypoxaemia. Concomitant asthma is not uncommon. Chest radiog- raphy and CT show fluffy opacities, frequently with a peripheral or predominantly upper lobe distribution (Fig. 18.14.13.4). The prog- nosis is usually good: the changes often subside spontaneously on withdrawal of the drug, while in more severely ill patients there is usually a dramatic improvement on instituting treatment with cor- ticosteroids. Although repeated exposure to the offending agents continues to produce reactions, the severity of these may progres- sively decrease. Pulmonary vasculature Several drugs and toxins have been shown to be associated with the development of pulmonary arterial hypertension (Box 18.14.13.1). Appetite suppressants In the 1960s there was a major outbreak of pulmonary hyperten- sion in relation to the use of aminorex as an appetite suppressant in Switzerland, Germany and Austria, and the drug was withdrawn. Aminorex resembles adrenaline and ephedrine in its chemical structure. Fenfluramine and dexfenfluramine were associated with pul- monary hypertension in the 1980s and 1990s. These are serotonin uptake inhibitors and were used also as appetite suppressants. They increase circulating levels of serotonin (5-​hydroxy tryptamine, 5HT), which is usually stored in platelets. Serotonin is a direct pul- monary artery vasoconstrictor and promotes growth of smooth muscle. These drugs inhibit the uptake and promote release of sero- tonin from platelets. Genetic factors seem to be important, and patients who developed pulmonary hypertension on fenfluramine were more likely to be carriers of bone morphogenetic protein type 2 (BMPR2) mutations. Benfluorex was used in France until 2009 and was also shown to be associated with pulmonary hypertension. Illicit stimulants Amphetamines, methamphetamines, and cocaine are also con- sidered to be risk factors for pulmonary hypertension based on case reports, epidemiological studies, and pharmacological similarities to fenfluramine. Epidemiological studies showed that patients with idiopathic pulmonary hypertension were 10-​fold more likely to have a history of having used these stimulants. Biological agents Dasatinib is a tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. Several reports of pulmonary hypertension have been published in patients receiving this drug. It is thought to act by inhibiting the Src family kinases which play a critical role in smooth muscle cell proliferation and vasoconstriction. There have also been reports of interferon-α and interferon-​β causing pulmonary hypertension. Fig. 18.14.13.4  Eosinophilic pneumonia due to dapsone. CT shows extensive patchy air space opacification in the upper lobes with subpleural predominance. Bronchoalveolar lavage showed eosinophilia and no infection. Blood eosinophil count was elevated
at 1.43 × 109/​litre (0.04–​0.4). Box 18.14.13.1  Drugs associated with pulmonary arterial hypertension Appetite suppressants • Aminorex • Fenfluramine, dexfenfluramine • Benfluorex Illicit stimulants • Amphetamines • Methamphetamine • Cocaine Biological agents • Dasatinib • Interferon-α, interferon-​β

section 18  Respiratory disorders 4280 Other drug effects on the pulmonary circulation Pulmonary thromboembolism related to use of the contraceptive pill is well established; its frequency correlates with the oestrogen con- tent and has been reduced since the introduction of low-​oestrogen preparations. Pulmonary veno-​occlusive disease has been reported after carmustine (BCNU), mitomycin and bleomycin. NSAIDs and selective serotonin-​reuptake inhibitors are associ- ated with persistent pulmonary hypertension in the newborn. This condition is due to an increased pulmonary vascular resistance that prevents normal pulmonary blood flow and causes a right-​to-​left shunt through a patent foramen ovale and patent ductus arteriosus. Analgesics given during labour have also been implicated in the de- velopment of pulmonary hypertension in the newborn; drugs such as aspirin, indomethacin, and naproxen delay premature labour but, by their inhibitory effects on prostaglandin synthesis, may also cause constriction of the ductus arteriosus leading to pulmonary hyper- tension in utero. This persists into the postpartum period and causes respiratory distress. Pleura Some drugs that have been associated with pleural effusions or fibrous thickening are shown in Table 18.14.13.3. Sometimes this arises as part of a syndrome of drug-​induced systemic lupus erythematosus (SLE): the antiarrhythmic procainamide was most often implicated, but other agents include gold, hydralazine, iso- niazid, penicillamine, captopril, and sulphonamides. When drug-​ induced SLE affects the respiratory system it particularly involves the pleura, but there is often some fibrosis of the underlying lung. Practolol, a now obsolete selective β-​sympathetic antagonist, produced a characteristic ‘oculomucocutaneous’ syndrome. This differed from drug-​induced SLE in that autoantibodies to histones were not usually present, and ocular symptoms (not usually a fea- ture of drug-​induced SLE) were common. Pleural effusions and subsequent pleural thickening occurred in association with char- acteristic corneal ulceration, discoid rash, and fibrinous peritonitis. Affected patients sometimes developed effusions months or years after discontinuing the drug, and in some the chronic changes led to significant respiratory disability. Exudative pleural effusions and pleural thickening have been re- ported with ergot-​like drugs, including bromocriptine, cabergoline, ergotamine, methysergide, and pergolide. The pleural effusion may be an isolated manifestation of drug-​induced disease or may occur with some lung fibrosis. The precise mechanisms involved are un- certain, but may include hypersensitivity reactions, direct toxic effects, or chemical-​induced inflammation. There is a suggestion that previous asbestos exposure may be a promoting factor in some cases. The pleural fluid characteristically contains a high proportion of lymphocytes. The frequency of this reaction is uncertain, but it may be relatively common. Methotrexate has also been associated with pleurisy, independent of its alveolar effects. Dasatinib, a tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia, is frequently associated with exudative pleural effusions, possibly by an immune-​mediated mechanism. Eosinophilic pleural effusions have been reported with drugs such as dantrolene, valproate, fluoxetine, propylthiouracil, and sulpha- salazine. In these eosinophilic effusions there is usually no evidence of any parenchymal abnormality, and although the changes grad- ually resolve on withdrawing the drug some residual pleural fibrosis may remain. Pleuroparenchymal fibroelastosis is a distinctive condition characterized by bilateral apical pleural thickening on chest radi- ography and CT with breathlessness and restriction of lung vol- umes. It is often complicated by pneumothorax. There is usually also dense subpleural fibrosis involving the underlying lung paren- chyma, with abrupt transition to normal architecture deeper in the lung. It is often idiopathic but has been reported as a late compli- cation of chemotherapy with drugs such as cyclophosphamide and carmustine (BCNU). FURTHER READING Adams PC, et al. (1986). Amiodarone pulmonary toxicity: clinical and subclinical features. Quat J Med, 229, 449–​71. Beynat-​Mouterde C, et al. (2014). Pleuroparenchymal fibroelastosis as a late complication of chemotherapy agents. Eur Respir J, 44,
523–​7. British Thoracic Society Standards of Care Committee (2005). BTS re- commendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-​TNF-​α treatment. Thorax, 60, 800–​5. Camus P, Rosenow EC (eds) (2010). Drug-​induced and iatrogenic respiratory disease. Hodder Arnold, London. Chopra A, Nautiyal A, Kalkanis A, Judson MA (2018). Chest, 154, 664–77. Convery RP, et al. (1999). Asthma precipitated by cessation of lithium treatment. Postgrad Med J, 75, 637–​8. Cottin V, Bonniaud P (2009). Drug-​induced infiltrative lung disease. Eur Respir Mon, 46, 287–​318. Davies RJ, Hendrick DJ, Pepys J (1974). Asthma due to inhaled chem- ical agents: ampicillin, benzyl penicillin, 6-​amino-​penicillanic acid and related substances. Clin Allergy, 4, 227–​47. De Vuyst P, Pfitzenmeyer P, Camus P (1997). Asbestos, ergot drugs and the pleura. Eur Respir J, 10, 2695–​8. Dhokarh R, et  al. (2012). Drug-​associated acute lung injury:  a population-​based cohort study. Chest, 142, 845–​50. Foucher P, et al. (1997). Drugs that may injure the respiratory system. Eur Respir J, 10, 265–​79. Montani D, et al. (2013). Drug-​induced pulmonary arterial hyperten- sion: a recent outbreak. Eur Respir Rev, 22, 244–​50. Table 18.14.13.3  Drugs associated with pleural effusions and thickening Clinical presentation Drug Drug-​induced lupus Procainamide, etanercept, gold, hydralazine, isoniazid, penicillamine, sulphonamides Oculomucocutaneous syndrome Practolol Isolated pleural effusion Methysergide, bromocriptine, methotrexate, dantrolene, acebutolol, dasatinib Pleuroparenchymal fibroelastosis Cyclophosphamide, carmustine (BCNU)

18.14.13  Drug-induced lung disease 4281 Pneumotox. Drug-​induced lung diseases. http://​www.pneumotox. com Quinta-​Cardama A, et al. (2007). Pleural effusions in patients with chronic myelogenous leukaemia treated with dasatinib after imatinib failure. J Clin Oncol, 25, 3908–​14. Salpeter SR, Ormiston TM (2001). Cardioselective beta-​blockers in patients with reversible airways disease. Cochrane Database, 2, CD002992. Sczeklik A, Picado C (2003). Aspirin-​induced asthma. Eur Respir Monogr, 23, 239–​48. Simonneau G, et al. (1998). Primary pulmonary hypertension associ- ated with use of fenfluamine derivatives. Chest, 114, 195–​9s. Takeishi M, et al. (2005). Leflunomide induced acute interstitial pneu- monia. J Rheumatol, 32, 1160–​3. Vahid B, Marik PE (2008). Pulmonary complications of novel antineoplastic agents for solid tumours. Chest, 133, 528–​38.

18.14.2 Eosinophilic pneumonia 4238 S.J. Bourke an

18.14.2 Eosinophilic pneumonia 4238 S.J. Bourke and G.P. Spickett

section 18  Respiratory disorders 4238 FURTHER READING Casian A, Jayne D (2011). Plasma exchange in the treatment of Wegener’s granulomatosis, microscopic polyangiitis, Churg–​ Strauss syndrome and renal limited vasculitis. Curr Opinion Rheumatol, 23, 12–​17. De Groot K, et  al. (2009). Pulse versus daily oral cyclophospha- mide for induction of remission in antineutrophil cytoplasmic antibody-​associated vasculitis: a randomized trial. Ann Int Med, 150, 670–​80. De Prost N, et al. (2012). Diffuse alveolar haemorrhage in immuno- competent patients: aetiologies and prognosis revisited. Resp Med, 106, 1021–​32. Ioachimescu OC, Sieber S, Kotch A (2004). Idiopathic pulmonary haemosiderosis revisited. Eur Respir J, 24, 162–​70. Keogh KA, et  al. (2006). Rituximab for refractory Wegener’s granulomatosis. Am J Respir Crit Care Med, 173, 180–​7. Kim D, et al. (2017). Clinical characteristics and outcomes of diffuse alveolar hemorrhage in patients with systemic lupus erythematosus. Semin Arthritis Rheum, 46, 782–7. Lazor R (2011). Alveolar haemorrhage syndromes. Eur Respir Mon, 54, 15–​31. Pedchenko V, et  al. (2010). Molecular architecture of the Goodpasture autoantigen in anti-​GBM nephritis. N Engl J Med, 363, 343–​54. Puchecco A, et  al. (1991). Long-​term clinical follow-​up of adult idiopathic pulmonary hemosiderosis and celiac disease. Chest, 99, 1525–​6. Saeed MM, et al. (1999). Prognosis in pediatric idiopathic pulmonary hemosiderosis. Chest, 116, 721–​5. 18.14.2  Eosinophilic pneumonia S. J. Bourke and G.P. Spickett ESSENTIALS Eosinophilic pneumonia is characterized by eosinophilic inflam- mation of the alveoli, usually with an accompanying eosinophilia of peripheral blood. The diagnosis should be considered when in- filtrates on a chest radiograph are associated with blood eosino- philia, and is confirmed by demonstrating an excess of eosinophils in bronchoalveolar lavage fluid. Aetiology—​before concluding that the cause is ‘idiopathic’, the fol- lowing must be considered: (1) parasitic infestation with blood-​borne parasites such as (in tropical eosinophilia) filarial worms; (2) adverse drug reaction; (3)  asthma; (4)  allergic bronchopulmonary mycosis; (5)  vasculitis, notably eosinophilic granulomatosis with polyangiitis (previously known as Churg–​Strauss syndrome); (6) hypereosinophilic syndrome, a rare haematological disorder; and (7)  other disorders known to be associated with eosinophilic pneumonia. Management—​causal factors need to be treated, but eosino- philic pneumonia otherwise often responds well to corticosteroid medication. Introduction Eosinophilic pneumonia is characterized by eosinophilic inflam- mation of the lung, usually in association with peripheral blood eo- sinophilia (>0.45 × 109/​litre) such that the presentation is often as pulmonary infiltrates on the chest radiograph with blood eosino- philia (PIE syndrome). Several descriptive terms are used to classify the diverse range of clinical syndromes, but there are often overlapping features (Table 18.14.2.1). The initial focus is on identifying any provoking factors and excluding other diseases. Particular attention should be paid as to whether the patient been in areas where parasitic dis- eases are endemic, has pre-​existing asthma or atopy, has recently started medications, has contact with pets, or has features of sys- temic disease or vasculitis. Important aspects of eosinophilic pneu- monia to consider are: • It may arise acutely and resolve quickly over a matter of days—​ acute eosinophilic pneumonia, Löffler’s syndrome, simple pul- monary eosinophilia. • It may arise gradually and persist for many months, leading some- times to pulmonary fibrosis or fixed airway obstruction—​chronic eosinophilic pneumonia. • It may be a consequence of allergy, particularly to blood-​borne parasites (tropical eosinophilia), inhaled moulds (allergic bronchopulmonary mycosis), or other common environmental allergens. • It is often due to drugs, including prescribed medications, over-​ the-​counter medications, and illicit substances. • It is often associated with asthma—​asthmatic eosinophilia. • It may be associated with pulmonary vasculitis—​ eosinophilic granulomatosis with polyangiitis. • It may be a component of the hypereosinophilic syndrome. • It may seem to be idiopathic. Since there is often overlap, there is limited benefit from using any classification system; the important issue is to identify potentially remediable causes, and to exclude infection or other causes before starting treatment with corticosteroids. Diagnosis In practice the finding of blood eosinophilia in association with pulmonary infiltrates on a chest radiograph provides a valuable Table 18.14.2.1  The spectrum of eosinophilic pneumonia Simple pulmonary eosinophilia Chronic eosinophilic pneumonia Acute eosinophilic pneumonia (Löffler’s syndrome) Drug-​induced pulmonary eosinophilia Tropical/​parasite-​induced eosinophilic pneumonia Allergic bronchopulmonary aspergillosis Eosinophilic granulomatosis with polyangiitis Hypereosinophilic syndrome Eosinophilic pneumonia encompasses a spectrum of conditions characterized by eosinophilic inflammation of the lung, often with blood eosinophilia. There are diverse provoking factors resulting in a confusing range of overlapping conditions.

18.14.2  Eosinophilic pneumonia 4239 clue that pneumonia of infectious origin may not be the diag- nosis. Once suspected, eosinophilic pneumonia is most conveni- ently confirmed by demonstrating an excess of eosinophils in bronchoalveolar lavage fluid in the absence of pathogenic micro- organisms. Sometimes sputum alone is sufficient, whether ex- pectorated spontaneously or induced. Alternatively, an excess of alveolar eosinophils is revealed in lung biopsy tissue. Not surpris- ingly, the use of CT scanning in subjects with confirmed eosino- philic pneumonia has shown that episodes of recurrent pulmonary infiltration occur more frequently than can be detected from plain chest radiographs. As different segments of lung become involved the infiltrates may characteristically ‘migrate’ from one to another. Once eosinophilic pneumonia is confirmed, a variety of possible causes should be considered before it is assumed to be idiopathic in origin and before empirical treatment with corticosteroids is admin- istered. Look for evidence of: • parasitic infestation • administration of drugs • inhaled tobacco smoke, cocaine, marijuana • asthma • allergic bronchopulmonary mycosis (particularly aspergillosis) • other manifestations of vasculitis • other manifestations of the hypereosinophilic syndrome • other disorders known to be associated with eosinophilic pneumonia Treatment Eosinophilic pneumonia is a very distinct type of interstitial lung disease in that the lung architecture is usually preserved such that there is often a complete response to treatment with corticoster- oids without any permanent lung damage. Treatment may need to be prolonged (6 months or more) in the chronic forms of the dis- order. The importance of identifying whether it is associated with the aforementioned causal factors listed lies with the additional need to treat these also, otherwise eosinophilic pneumonia may not re- spond adequately to steroid therapy and the associated diseases may produce other manifestations. Particular forms of eosinophilic pneumonia Acute eosinophilic pneumonia (Löffler’s syndrome, simple pulmonary eosinophilia) The essential features are transitory migratory pulmonary shadows associated with modest peripheral eosinophilia in patients with a mild self-​limiting illness. Some cases are asymptomatic and dis- covered incidentally. Most patients present with cough, sometimes with oddly yellowish sputum containing an abundance of eosino- phils, and a few have general malaise and a mild fever. The pul- monary shadows reflect fan-​shaped areas of consolidation, often peripheral and sometimes rather nodular, which last a few days only and appear haphazardly in various lobes, seldom following a truly segmental pattern. In some cases they are single and in others they are multiple. The peripheral eosinophilia is obvious but rarely gross; a differential of more than 20% in a modestly raised total white cell count is unusual and more often the absolute eosinophil count ranges between 1 × 109 and 2 × 109/​litre (normal <0.45 × 109/​litre). Patients are often atopic and may have other manifestations of an atopic diathesis, such as asthma, urticaria, and angio-​oedema. Allergic reactions to parasites or drugs are the best recognized forms, but sometimes no provoking factor is identified. Eosinophilic pneumonia may be an allergic reaction to blood-​borne parasites migrating through the lung, particularly larvae of Ascaris lumbri- coides and (occasionally) A.  suum. Ancylostoma, strongyloides, taenia, trichinella, and trichuris may also cause eosinophilic pneu- monia. Drugs form the second major aetiological group. Löffler’s syndrome is described after administration of aspirin, amiodarone, angiotensin converting enzyme inhibitors, β-​blockers, metho- trexate, nitrofurantoin, imipramine, penicillin, p-​aminosalicylic acid, sulphonamides, toxic smoke, and lymphangiography contrast medium. Successful management requires the eradication of any parasites or the cessation of relevant medication, as well as the administration (if necessary) of oral corticosteroids. Tropical eosinophilia Eosinophilic pneumonia in tropical climates is often a consequence of migrating larvae of the filarial worms Wuchereria bancrofti and Brugia malayi. The effects are fundamentally similar to those of Löffler’s syndrome, but tend to be more persistent and more ser- ious, are more often associated with asthma, and may be associated with systemic symptoms of weight loss, persistent fever, and lymph- adenopathy. The peripheral eosinophil count tends to be greater than in Löffler’s syndrome (>3 × 109/​litre), and the total serum IgE level is markedly elevated. With chronicity, pulmonary fibrosis may develop. A cure is to be expected with antifilariasis medication (e.g. diethylcarbamazine). Chronic eosinophilic pneumonia (prolonged pulmonary eosinophilia) Eosinophilic pneumonia persisting for more than a month is distin- guished from the more transitory Löffler’s syndrome, although its clinical characteristics are fundamentally similar. As with eosino- philic pneumonia associated with tropical filariasis, it tends to be more persistent and more serious than Löffler’s syndrome, and may be associated with systemic symptoms, such as fever, malaise, and fatigue. It can sometimes progress to pulmonary fibrosis. It may last for several months and be associated additionally with eosinophilic pleural effusion, focal skin lesions, atopic manifestations such as rhinitis, sinusitis, and angio-​oedema, hepatosplenomegaly, and even hepatic necrosis. The pulmonary disease is often extensive, and may cause hypoxaemia as well as dyspnoea. A curious peripheral radio- graphic distribution of infiltrates, dubbed a ‘negative photographic image of pulmonary oedema’, is particularly suggestive of chronic eosinophilic pneumonia but occurs in only a few cases. The radio- logical abnormalities tend to recur and last for weeks or months, and like the shadows of Löffler’s syndrome may vary in site during the course of the illness. Chronic eosinophilic pneumonia is more commonly idiopathic than Löffler’s syndrome, but may also be a consequence of para- site infestation (e.g. tropical filariasis) or drug hypersensitivity. Case reports have identified aminoglutethimide, BCG vaccin- ation, bicalutamide, captopril, chlorpropamide, clarithromycin, clomipramine, dapsone, ethambutol, ibuprofen, meloxicam, mesalazine, minocycline, nitrofurantoin, perindopril, progesterone, sertraline, sotalol, sulphonamides, trimethoprim, and venlafaxine as

section 18  Respiratory disorders 4240 possible causes. Peripheral blood eosinophilia is less consistent with chronic compared with acute forms of eosinophilic pneumonia, although is often of greater level (>1 × 109/​litre). When a definitive cause is identified, appropriate specific man- agement should follow, but often no cause is evident and oral cor- ticosteroid therapy should be given. Responses are often dramatic, but recurrences are common if treatment is discontinued within 6 to 12 months. There may be a persistent mixed obstructive and re- strictive loss of ventilatory function, and radiographic evidence of persistent pulmonary fibrosis. Eosinophilic pneumonia with asthma Eosinophilic pneumonia is commonly associated with asthma, even in the absence of parasite infestation or drug hypersensitivity. In a study of 53 cases, asthma preceded eosinophilic pneumonia in about half, and then worsened; in the remainder it arose by similar pro- portion either contemporaneously or within about 2 years. Two par- ticular associations with asthma are noteworthy. Allergic bronchopulmonary mycosis When fungal hypersensitivity develops in atopic subjects with asthma, additional manifestations may occur in the lung:  these include eosinophilic pneumonia, mucoid impaction, bronchiec- tasis, and pulmonary fibrosis. The ensuing syndrome of allergic bronchopulmonary mycosis occurs most commonly with Aspergillus fumigatus, though has been reported with other aspergillus, can- dida, curvularia, and helminthosporium species. It accounts for most cases of eosinophilic pneumonia with asthma in the United Kingdom and is best considered a complication of atopic asthma, appearing to result from airway colonization by the relevant mould. The mechanism, however, is clearly one of hypersensitivity, not in- fection or invasion, and both IgE and IgG antibodies are necessary to support its diagnosis. Allergic bronchopulmonary aspergillosis is also common in patients with cystic fibrosis lung disease. In acute phases there is patchy obstruction of bronchi with inspis- sated mucus that, if expectorated, appears as brown rubbery lumps in the sputum (plugs). Fungal hyphae may be recovered from them, indicating that fungal growth has occurred within the airway. This impaction of mucus in one or more bronchi leads to atelectasis of segments or lobes of the lung, and is often associated with eosino- philic pneumonia. The radiographic appearances are of fleeting pul- monary infiltrates (Fig. 18.14.2.1). The condition usually responds well to corticosteroids, a useful diagnostic feature being the expectoration of plugs during this period of resolution. In the medium term the involved bronchi (generally proximal) may become bronchiectatic, leading in turn to the char- acteristic features of bronchiectasis (productive cough, intermittent haemoptysis). In the longer term, pulmonary fibrosis may ensue, particularly in the upper lobes and apices, so that the radiographic appearances resemble tuberculosis. If mucoid impaction and/​or eo- sinophilic pneumonia become superimposed, the radiographic ap- pearances may simulate active tuberculosis very closely. Suspicion of tuberculosis in an individual with atopic asthma should always prompt consideration of allergic bronchopulmonary mycosis. Antifungal agents (itraconazole, voriconazole) decrease the antigen burden and the associated immune response, but need to be used in conjunction with corticosteroids. They are particularly useful in allowing a reduction in the dose of corticosteroids. Eosinophilic granulomatosis with polyangiitis A much rarer association of eosinophilic pneumonia with asthma is that involving eosinophilic granulomatosis with polyangiitis. This is a vasculitic and granulomatous disorder that commonly involves lungs, gut, peripheral nerves, skin, and kidneys, and occasionally heart. It is characterized typically by asthma, eo- sinophilic pneumonia, and very high numbers of circulating eo- sinophils (>5 × 109/​litre), but the pulmonary manifestations may additionally include haemorrhage and haemoptysis. Serological investigation may also demonstrate raised serum levels of IgE and eosinophil cationic protein, P-​ANCA (perinuclear antineutrophil cytoplasmic antibodies) with myeloperoxidase activity (in most cases), and C-​ANCA with proteinase-​3 specificity (in a few cases). Autoantibodies against eosinophil granule enzymes have also been described. Pathologically there is vasculitis of small arteries and veins with necrotizing extravascular granulomas. Biopsy of af- fected tissue may be needed to confirm the diagnosis, and may be diagnostic even in the prevasculitic phase if there is characteristic eosinophilic infiltration of involved tissue. See Chapter 19.11.7 for further discussion. Fig. 18.14.2.1  Allergic bronchopulmonary aspergillosis: two radiographs taken 6 months apart from a woman with asthma, peripheral eosinophilia, and high titres of IgE and precipitating IgG antibodies to Aspergillus fumigatus.

18.14.3 Lymphocytic infiltrations of the lung 4241

18.14.3 Lymphocytic infiltrations of the lung 4241 S.J. Bourke

18.14.3  Lymphocytic infiltrations of the lung 4241 Hypereosinophilic syndrome Hypereosinophilic syndrome is a rare haematological disorder with sustained overproduction of eosinophils in the bone marrow. It is characterized by blood eosinophilia exceeding 1.5 × 109/​litre for at least 6 months, no identifiable cause after extensive investigation, and end organ damage associated with eosinophil infiltration. The heart, skin, and nervous system are the most common targets: the lungs are not commonly involved and hence hypereosinophilic syn- drome is a particularly rare cause of eosinophilic pneumonia. Hypereosinophilic syndrome is heterogenous, sometimes due to a myeloproliferative disorder or a clonal expansion of specific T cells, but often no cause is apparent. A bone marrow biopsy is usually an important investigation. In some cases an underlying mechanism has been identified, involving either tyrosine kinase activity or inter- leukin 5. An interstitial deletion on chromosome 4 can produce a ‘fusion’ gene by the fusion of the PDGFRA and FIP1L1 genes, the new gene encoding a protein with tyrosine kinase activity that af- fects early myeloid differentiation. These findings are closely asso- ciated with eosinophilic leukaemia, and treatment with imatinib, interferon-α or hydroxycarbamide is effective in treatment. In lymphocytic hypereosinophilic syndrome, there is an abnormal clone of T cells which releases ‘eosinophilic’ cytokines, principally interleukin 5 (IL-​5), that stimulate bone marrow generation and inhibit peripheral destruction. This condition is less likely to cause end organ dysfunction and is often readily controlled with cortico- steroids. An anti-​IL-​5 monoclonal antibody (mepolizumab) may be effective in treating this form of hypereosinophilic syndrome. FURTHER READING Allen JN (2010). Eosinophilic pneumonia induced by drugs. In: Camus P, Rosenow EC (eds) Drug-​induced and iatrogenic respi- ratory disorders. Hodder Arnold, London. Camuset J, et al. (2007). Treatment of chronic pulmonary aspergillosis by voriconazole in nonimmunocompromised patients. Chest, 131, 1435–​41. Cogan E, Roufosse F (2012). Clinical management of the hypereo­ sinophilic syndromes. Expert Rev Hematol, 5, 275–​90. Cools J, et al. (2003). A tyrosine kinase created by fusion of PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med, 348, 1201–​14. Cottin V et al. (2016). Respiratory manifestations of eosinophilic granulo­ matosis with polyangiitis (Churg-Strauss). Eur Respir J, 48, 1429–41. De Giacomi F, et al. (2018). Acute eosinophilic pneumonia. Causes, diagnosis and management. Am J Respir Crit Care Med, 197, 728–36. DuMouchel W, et  al. (2004). Association of asthma therapy and Churg-​Strauss syndrome: an analysis of postmarketing surveillance data. Clin Therapeut, 26, 1092–​1104. Guillevin L, Dunogue B, Pagnoux C (2011). Churg-​Strauss syndrome. Eur Resp Mon, 54, 140–​51. Kunst H, et al. (2011). Parasitic infections of the lung: a guide for the respiratory physician. Thorax, 66, 528–​36. Marchand E, Cordier JF (2006). Idiopathic chronic eosinophilic pneu- monia. Semin Respir Crit Care Med, 27, 134–​41. Patterson K, Strek ME (2010). Allergic bronchopulmonary aspergil- losis. Proc Am Thorac Soc, 7, 237–​44. Simon HU, Plotz G, Dummer R, Blaser K (1999). Abnormal clones of T cells producing interleukin-​5 in idiopathic eosinophilia. N Engl J Med, 341, 1112–​20. Tefferi A, Gotlib J, Pardanani A (2010). Hypereosinophilic syndrome and clonal eosinophilia:  point-​of-​care diagnostic algorithm and treatment update. Mayo Clinic Proceedings, 85, 158–​64. 18.14.3  Lymphocytic infiltrations of the lung S. J. Bourke ESSENTIALS Lymphocytic infiltrations of the lung arise from the proliferation of bronchus-​associated lymphoid tissue, resulting in a spectrum of rare conditions ranging from benign polyclonal lymphoid inter- stitial pneumonia to monoclonal primary malignant lymphomas of the lung. Lymphoid interstitial pneumonia is most commonly seen in Sjögren’s syndrome or other connective tissue diseases, and in as- sociation with HIV infection, and is characterized by reticulonodular shadowing on CT imaging and (usually) a good response to corticosteroids. Primary pulmonary lymphomas fall into three categories: lymphomatoid granulomatosis, low-​grade B-​cell lymphoma, and high-​grade B-​cell lymphoma. The latter require treatment with cyto- toxic drugs and have a poor prognosis. Introduction Lymphoid tissue is usually inconspicuous or absent in normal lung tissue. Bronchus-​associated lymphoid tissue develops as a reaction to exogenous stimuli such as smoking, infection, and antigen in- halation, or endogenous circulating antigens in autoimmune and connective tissue diseases. Reactive hyperplasia of this bronchus-​ associated lymphoid tissue occurs in conditions such as chronic infections, immune deficiency syndromes, obstructive pneumo- nias, and collagen vascular diseases. Both benign lymphoid infil- trations of the lung, such as lymphoid interstitial pneumonia (LIP), and neoplastic infiltrations in primary pulmonary lymphomas, are related to lymphoid hyperplasia of bronchus-​associated lymphoid tissue (Box 18.14.3.1). Lymphoid interstitial pneumonia Lymphoid (lymphocytic) interstitial pneumonia (LIP) is a rare disease in which pulmonary lymphoid hyperplasia progresses to a diffuse polyclonal lymphoid cell infiltration, surrounding the air- ways as follicular bronchiolitis, and expanding the interstitium of the lung. In some cases it is idiopathic with no identifiable cause, but it is most commonly associated with collagen vascular dis- eases such as Sjögren’s syndrome, systemic lupus erythematosus,

section 18  Respiratory disorders 4242 rheumatoid disease, autoimmune diseases such as primary bil- iary cirrhosis, myasthenia gravis and Hashimoto’s thyroiditis, and immune deficiency states such as common variable immunodefi- ciency and HIV infection. It has also been described in relation to drugs such as phenytoin and captopril. Epstein–​Barr virus has been isolated in some cases. It most commonly presents in middle age and is more common in women. Symptoms usually include breathlessness, dry cough, and sometimes systemic symptoms of weight loss and malaise. Crackles may be audible. Features of an underlying autoimmune or systemic disease may be present, and should be sought. In HIV infection LIP is most common in children and is rare in adults. It may occur relatively early in the course of HIV infection, when the CD4+ T lymphocytes count is still within the normal range. The chest radiograph shows nonspecific reticulonodular opacities, usually most apparent at the lung bases. CT imaging shows ground-​glass attenuation with centrilobular nodules and thickened bronchovascular bundles and interlobular septa, some- times with cysts. Lung function tests typically show restriction of lung volumes and impaired gas diffusion. Bronchoalveolar lavage shows lymphocytosis. Surgical biopsy is often required to confirm the diagnosis. The histology shows that the alveolar septa are extensively infiltrated by lymphocytes, plasma cells, and histiocytes with associated type II cell hyperplasia. The dif- ferential diagnosis includes nonspecific interstitial pneumonia, hypersensitivity pneumonitis, usual interstitial pneumonia, and pulmonary lymphoma. Careful immunohistochemistry and mo- lecular analysis are required to differentiate LIP from lymphoma. When a histological diagnosis of LIP has been established, investigations for associated diseases should be undertaken including HIV testing and auto-​antibodies tests for connective tissue diseases. There is often polyclonal elevation of IgG and IgM but sometimes hypogammaglobulinaemia and monoclonal gammopathies. The clinical course of LIP is very variable and reflects also the course of the underlying disease. In many cases the disease is indolent, with little progression over many years, but about one-​third of cases progress to pulmonary fibrosis. LIP is usually treated by corticosteroids, often with a good response. In HIV-​ associated LIP, antiretroviral treatment results in improvement. Lung transplant has been performed in very rare cases which have failed to respond to corticosteroids and progressed to end-​ stage fibrosis. Lymphoma The lung parenchyma may be involved in disseminated nodal lymphomas of all types but the clinical presentation of these sec- ondary lymphomas is usually dominated by disease at other sites (Chapter  22.4.3). Primary pulmonary lymphoma arises from bronchus-​associated lymphoid tissue rather than lymph nodes, and is very rare, accounting for less than 0.5% of all primary lung neoplasms. Classification of primary pulmonary lymphomas is complex and different from nodal lymphomas, but generally falls into the categories of lymphomatoid granulomatosis (angiocentric lymphoma), low-​grade B-​cell lymphoma, and high-​grade B-​cell lymphoma. It seems that prolonged stimulation of bronchus-​ associated lymphoid tissue with a high turnover of B-​cells in con- ditions such as Sjögren’s syndrome, autoimmune disease, and Epstein–​Barr virus infection, may contribute to the development of lymphoma. Immunosuppression may also be an important factor, particularly in patients who have undergone organ transplantation, or in those with HIV infection. Additional neoplastic change seems to occur in prolonged lymphoid hyperplasia, with chromosomal translocations leading to constitutive activation of signalling path- ways progressing to lymphoproliferative change and lymphomatous transformation. Post-​transplant lymphoproliferative disease may result from a decreased T-​cell immune response to the Epstein–​Barr virus induced by immunosuppression, and includes a spectrum of disease from lymphoid hyperplasia to high-​grade lymphoma. The Epstein–​Barr virus latent membrane protein has been shown to have oncogenic properties and may be a key factor in the development of some pulmonary lymphomas. Lymphomatoid granulomatosis (angiocentric lymphoma) Lymphomatoid granulomatosis is considered separately as a unique type of lymphoproliferative disorder with a propensity for blood vessel destruction, which particularly affects the lungs. It is now classified as an angiocentric, Epstein–​Barr virus-​associated B-​cell lymphoma rather than a vasculitis. The lungs are the most com- monly involved site, but it is a multisystem disease which can also involve the skin, kidney, liver, and central and peripheral nervous systems. Although it is a lymphoproliferative disorder it is rare for it to involve the lymph nodes, spleen, or bone marrow. The disease is very uncommon in childhood but occurs through­ out adult life, particularly in middle age, with a slight predilection for males. Patients often present with prominent systemic symp- toms of fever, weight loss and general malaise, in addition to chest symptoms such as cough, haemoptysis, and chest pain. About a quarter have neurological symptoms and half develop skin lesions. Lymphadenopathy is not usually present. The chest radiograph and CT imaging typically show multiple rounded masses, sometimes with cavitation, such that the disease mimics metastatic carcinoma, infection, or vasculitis (Fig. 18.14.3.1). Surgical biopsy of a lung lesion is usually necessary to establish the diagnosis. Histologically the disease is characterized by atypical B-​cells infiltrating around the bronchovascular and perivascular Box 18.14.3.1  Lymphocytic infiltrations of the lung Reactive polyclonal lymphoid infiltration • Lymphoid interstitial pneumonia • Follicular bronchiolitis • Lymphoid hyperplasia Pulmonary lymphomas Secondary lymphoma involving the lung • Non-​Hodgkin’s lymphoma • Hodgkin’s lymphoma Primary pulmonary lymphomas • Lymphomatoid granulomatosis (angiocentric lymphoma) • Bronchus-​associated lymphoma (high/​low grade) • HIV-​related lymphoma • Post-​transplantation lymphoproliferative disorder

18.14.3  Lymphocytic infiltrations of the lung 4243 regions, with associated T-​cells, plasma cells, and histiocytes. Immunocytochemistry and molecular analysis show that the B-​cells are clonal and malignant, and evidence of Epstein–​Barr virus infection may be present. Vascular infiltration is a prominent feature and patients may have haemoptysis and lung haemorrhage. Patients have sometimes been given corticosteroids because of a suspicion of a vasculitic or inflammatory disease, and temporary improvement in symptoms sometimes occurs from treatment with corticosteroids alone, but this is an aggressive malignant lymphoma with a high mortality and requires cytotoxic therapy. Chemotherapy usually involves drugs such as cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab, but regimens are not well established because of the rarity of the disease. The prognosis is gen- erally poor with a 5-​year mortality of 50–​70%. Low-​grade B-​cell lymphoma Low-​grade B-​cell non-​Hodgkin’s lymphomas account for about 80–​90% of primary lymphomas affecting the lung parenchyma. They generally arise in middle aged or elderly adults from mucosa-​ associated lymphoid tissue of the bronchi, and may occur after a prolonged period of antigenic stimulation and high B-​cell turn- over associated with Sjögren’s syndrome, dysgammaglobulinaemia, amyloid deposition, collagen vascular disease, and HIV infection. Presentation is commonly as an incidental finding on a chest radio- graph, before symptoms have developed. When symptoms do occur, they include cough, haemoptysis, chest pain and (occasionally) breathlessness, and there may be systemic symptoms such as fever, malaise, and weight loss. The chest radiograph and CT imaging usu- ally shows multiple parenchymal nodules with diameters ranging up to a few centimetres. Sometimes spread outside the bronchi and pul- monary vessels, but within the bronchovascular bundles, may leave the airway patent and so produce air bronchograms within the tu- morous opacities. In a few cases there is a diffuse nodular infiltration. The clinical presentation and radiological features often cause confusion, hence biopsy is required to establish a diagnosis and to demonstrate a B-​cell clone and the grade of activity of the lymphoma. These low-​grade lymphomas can behave indolently and initial observation may be appropriate, before considering cytotoxic chemotherapy. The prognosis is generally good with an estimated 5-​ and 10-​year survival rate of 90% and 72%, respectively. High-​grade B-​cell lymphoma High-​grade B-​cell non-​Hodgkin’s lymphomas account for 10–​20% of primary lymphomas affecting the lung parenchyma. They par- ticularly occur in immunosuppressed patients in the context of HIV infection or after organ transplantation. The more aggressive nature of high-​grade disease is reflected by the greater likelihood of respiratory and systemic symptoms. Multifocal involvement may cause cough, dyspnoea, haemoptysis, and chest pain, often with systemic symptoms of weight loss, fever, and malaise. Local infiltration by lymphomatous masses may pro- duce atelectasis of a segment or lobe of lung, sometimes with pleural effusions. The prognosis of high-​grade pulmonary lymphoma is much less favourable than that of low-​grade disease. In post-​transplant lymphoma associated with Epstein–​Barr virus, a reduction in im- munosuppression and antiviral treatment, such as ganciclovir or valganciclovir, may be appropriate. Chemotherapeutic regimens for the treatment of pulmonary lymphoma are similar to those used in other lymphomas, including drugs such as rituximab, chlorambucil, cyclophosphamide, fludarabine, doxorubicin, and vincristine, ad- ministered under specialist oncology supervision. FURTHER READING Bae YA, et al. (2008). Marginal zone B-​cell lymphoma of bronchus-​ associated lymphoid tissue: imaging findings in 21 patients. Chest, 133, 433–​40. Borie R, et al. (2009). Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur Respir J, 34, 1408–​16. Borie R, et al. (2017). Lymphoproliferative disorders of the lung. Respiration, 94, 157–75. Cha SI, et al. (2006). Lymphoid interstitial pneumonia: clinical fea- tures, associations and prognosis. Eur Respir J, 28, 364–​9. Das S, Miller RF (2003). Lymphocytic interstitial pneumonitis in HIV infected adults. Sex Transm Infect, 79, 88–​93. (a) (b) Fig. 18.14.3.1  CT of a patient with lymphomatoid granulomatosis showing (a) a cavitating mass in the left lower lobe (arrow) and (b) a further mass in the right lower lobe (arrow).

18.14.4 Hypersensitivity pneumonitis 4244 S.J. Bou

18.14.4 Hypersensitivity pneumonitis 4244 S.J. Bourke and G.P. Spickett

section 18  Respiratory disorders 4244 Hare SS, et  al. (2012). The radiological spectrum of pulmonary lymphoproliferative disease. Br J Radiol, 85, 848–​64. Jaffre S, et al. (2006). Fatal haemoptysis in a case of lymphomatoid granulomatosis treated with rituximab. Eur Respir J, 27, 644–​6. Katzenstein AL, Doxtader E, Narendra S (2010). Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol, 34, e35–​e48. Kido T, et al. (2012). Detection of MALT1 gene rearrangements in BAL fluid cells for the diagnosis of pulmonary mucosa-​associated lymphoid tissue lymphoma. Chest, 141, 176–​82. Makol A, et al. (2009). Lymphomatoid granulomatosis masquerading as interstitial pneumonia in a 66-​year-​old man: a case report and re- view of literature. J Hematol Oncol, 2, 39–​45. Tian X, et al. (2012). Lymphocytic interstitial pneumonia and other benign lymphoid disorders. Semin Respir Crit Care Med, 33, 450–​61. Verschuuren EAM (2009). Post-​transplant lymphoproliferative dis- ease and other malignancies. Eur Respir Mon, 45, 226–​37. 18.14.4  Hypersensitivity pneumonitis S. J. Bourke and G.P. Spickett ESSENTIALS Hypersensitivity pneumonitis is an immune-​mediated lung disease in which the repeated inhalation of certain antigens provokes a hypersensitivity response, with granulomatous inflammation in the distal bronchioles and alveoli of susceptible people. A diverse range of antigens including bacteria (Thermophilic actinomycetes), fungi (Trichosporon cutaneum), animal proteins (bird antigens), mycobac- teria, and chemicals may cause the disease. The commonest forms are bird fancier’s lung, farmer’s lung, humidifier lung, and metal-​ working fluid pneumonitis. In some cases no antigen is identified. Acute disease is characterized by recurrent episodes of breath- lessness, cough, fevers, malaise, and flu-​like symptoms occurring
4–​8 hours after antigen exposure. Fever and basal crackles are the main physical signs. This form of hypersensitivity pneumonitis is most commonly seen where there is intermittent high-​level antigen exposure, as in the case of pigeon fancier’s lung or farmer’s lung. Most patients recover fully from each acute exacerbation within a day or so, and if the cause is recognized and further exposure avoided there is little risk of persisting pulmonary dysfunction. Chronic disease is characterized by the insidious development of dyspnoea and persistent pneumonitis, sometimes progressing to lung fibrosis. This form of the disease is typically seen following long-​ standing low-​level antigenic exposure, such as occurs in a person who keeps a single budgie (parakeet) in the home. Clinical features are similar to those of other varieties of pulmonary fibrosis, but clubbing is uncommon. Permanent fibrotic lung damage can eventually lead to hypoxaemia, pulmonary hypertension, right heart failure, and death. Investigation—​the chest radiograph may be normal or show a ground-​glass appearance; in subacute disease small reticular opacities may be seen; in chronic disease there is fibrosis. CT char- acteristically shows centrilobular nodules, mosaic air trapping, and ground-​glass shadowing. Lung function studies typically show a re- strictive pattern with impaired gas diffusion. IgG antibody against the provoking antigen indicates sufficient exposure for the disease to de- velop, but such antibodies are frequently found in subjects who are similarly exposed but clinically unaffected. Bronchoalveolar lavage typically shows a lymphocytic alveolitis, and lung biopsy shows peri-​bronchocentric lymphocytic inflammation with poorly formed granulomas and sometimes fibrosis. Management—​complete cessation of contact with the provoking antigen is the safest advice for patients with hypersensitivity pneu- monitis. This usually leads to resolution of the acute form of the dis- ease. Corticosteroids hasten the rate of recovery, but do not alter the long-​term outcome. Some patients with chronic hypersensitivity pneumonitis progress to severe fibrotic lung disease resembling idio- pathic pulmonary fibrosis. If these patients fail to respond to cortico- steroids and other immunosuppressive agents, lung transplantation is sometimes appropriate. Introduction Hypersensitivity pneumonitis (HP), previously known as extrinsic allergic alveolitis, is an immune-​mediated lung disease in which the repeated inhalation of certain antigens provokes a hypersensitivity reaction with granulomatous inflammation in the distal bronchioles and alveoli of susceptible people. The essence of the disease is an interaction between specific inhaled antigens and the patient’s im- mune system. It is therefore an allergic lung disease and it should be distinguished from several nonallergic inflammatory reactions such as inhalation fevers, toxic alveolitis, and organic dust toxic syn- drome, which occur after a single exposure to an unusually high level of organic dust by toxic rather than immune mechanisms. By con- trast, individual susceptibility is a characteristic feature of immune-​ mediate disease such as HP, and only a small percentage of those repeatedly exposed to the antigen develop the disease. Aetiology HP can be caused by a diverse range of antigens including bac- teria (Thermophilic actinomycetes), fungi (Trichosporon cutaneum, Aspergillus fumigatus), animal proteins (bird antigens), mycobacteria (Mycobacterium immunogenum), and chemicals (di-​isocyanates). Geographical, social, and occupational factors determine the particular types of HP found in different parts of the world (Table 18.14.4.1). Because of the great diversity and distribu- tion of these antigens, many individuals are exposed to potential causes of HP as part of their occupational, home, or recreational environments. Farmer’s lung is regarded as the prototype of HP since the classic description by Campbell et al. in 1932. Occupations in which there is contact with mouldy vegetation are particularly associated with the disease, and specific syndromes have therefore been described, for example, in respect of farmers, mushroom workers, and sugar cane workers (bagassosis). Those exposed to raw wood products have been

18.14.4  Hypersensitivity pneumonitis 4245 Table 18.14.4.1  Agents reported to cause hypersensitivity pneumonitis Agent Source Appellation (if any) Microorganisms Acinetobacter woffii Metal-​working fluid Machine worker’s lung Alternaria Paper-​mill wood pulp Wood pulp worker’s lung Aspergillus sp. Farm produce, maize (corn) Farmer’s lung Aspergillus clavatus Whisky maltings Malt worker’s lung Aspergillus fumigatus Vegetable compost, cork Farmer’s lung, suberosis Aspergillus versicolor Dog bedding (straw) Dog house disease Aureobasidium pullulans Redwood/​domestic cellar Sequoiosis Bacillus subtilis Wood/​cleaning preparations Candida albicans Heated swimming pool; saxophonist lung Saxophonist lung Cephalosporium Sewage Sewage worker’s lung Cryptococcus albidus Asian homes in humid summers Summer-​type hypersensitivity pneumonitis Cryptostroma corticale Maple Maple bark stripper’s lung Debaryomyces hansenii Home ultrasonic nebulizer Eurotium sp. Metal-​working fluid Machine worker’s lung Fusarium sp. Metal-​working fluid/​home Machine worker’s lung Graphium Redwood Sequoiosis Grifola fondosa Maitake mushrooms Mushroom worker’s lung Humicola fuscoatra Domestic home Hypsizigus marmoreus Mushrooms Mushroom worker’s lung Lentinus edodes Mushrooms Mushroom worker’s lung Lycoperdon Puffballs Lycoperdonosis Lyophyllum aggregatum Mushrooms Mushroom worker’s lung Merulius lacrymans Domestic wood Mucor stolonifer Paprika Paprika splitter’s lung Mycobacterium sp. Metal-​working fluid Machine worker’s lung Paecilomyces sp. (nivea/​variotii) Hardwood, oil heater Penicillium camemberti Salami production P. casei Cheese Cheese washer’s lung P. chrysogenum/​cyclopium Domestic wood P. citrinum Enoki mushroom cultivation P. frequentens Cork Suberosis P. nalgiovense Pork sausage mould P. verrucosum Gorgonzola cheese Peziza domiciliana Flooded basement El Niño lung Pleurotus ostreatus/​eryngii Mushrooms Mushroom worker’s lung Pseudomonas fluorescens Metal-​working fluid Machine worker’s lung Rhodotorula sp. Ultrasonic humidifier Saccharomonspora viridis Logging plant Sphingbacterium spiritvorum Domestic steam iron Sporobolomyces Horse barn straw Streptomyces albus Soil/​peat Thermophilic actinomycetes (Saccharopolyspora rectivirgula, Thermoactinomyces vulgaris) Hay/​straw/​grain/​mushroom compost/​bagasse/​heated water/​domestic cellar/​esparto grass Farmer’s lung Mushroom worker’s lung Bagassosis Esparto plasterer’s lung Trichosporon cutaneum/​ovoides Asian homes in humid summers Summer-​type hypersensitivity pneumonitis (continued)

section 18  Respiratory disorders 4246 affected as maple bark stripper’s lung, sequoiosis, and suberosis (cork worker’s lung). Office and factory workers may be exposed to aetio- logical agents via humidifier or ventilation systems that have become contaminated with a variety of agents including bacteria, mycobac- teria, fungi, protozoa (amoebae), and metazoa (nematode debris). Workers exposed to some reactive chemicals, such as di-​isocyanates, may also develop HP, and here the chemical acts as a hapten com- bining with body proteins to produce larger antigenic molecules. As practices change, some classic causes of HP have faded, but new syndromes are constantly being identified. Metal-​working fluid pneumonitis has recently come to prominence because of outbreaks of HP in workers in car manufacturing, due to contamination of coolant and lubricant fluid. The home environment may also be a rich source of the antigens of HP. Budgie fancier’s lung may be the commonest form of the dis- ease in the United Kingdom due to pet birds kept in homes. Mould contaminating houses may also provoke HP: summer-​type HP is common in Japan and due to contamination of the home environ- ment by fungi such as Trichosporon cutaneum or Cryptococcus albi- dus. Mould contamination of domestic environments (e.g. cellars, Agent Source Appellation (if any) Miscellaneous bacteria/​mycobacteria/​fungi/​ amoebae/​nematode debris Air conditioners/​humidifiers/​tap water/​showers/​heated pools, saunas, tubs/​metal fluids Humidifier lung Ventilation pneumonitis Sauna taker’s lung Unknown Roof thatch New Guinea lung Animals Arthropods (Sitophilus granarius) Grain dust Wheat weevil disease Birds Feather bloom/​droppings Bird fancier’s lung Fish Fish meal Fish meal worker’s lung Mammal pituitary (cattle, pig) Pituitary extracts Pituitary snuff taker’s lung Mammal hair Fur Furrier’s lung Mollusc shell Nacre-​button manufacture Urine (rodents) Urinary protein Rodent handler’s lung Vegetation Cabreuva Wood dust Coffee Coffee bean dust Coffee worker’s lung Esparto grass Plaster Esparto plasterer’s lung Amorphophalus konjac Konjac flour Konnyaku maker’s lung Peat moss Peat moss packaging plant Shimeji Shimeji cultivators Tiger nut Tiger nut dust Wood (Gonystylus bacanus) Wood dust Wood worker’s lung Chemicals Bordeaux mixture (fungicide) Vineyards Vineyard sprayer’s lung Cobalt dissolved in solvents Tungsten carbide grinding Diphenyl methane diisocyanate Plastics industry Hexamethylene diisocyanate Plastics industry Methyl methacrylate Dentistry Pauli’s reagent Laboratory Phthalic (or trimellitic) anhydride Epoxy polyester powder paint Pyrethrum Insecticide spray Tetrachloroethylene Dry cleaning Toluene diisocyanate Plastics industry Triglycidyl isocyanate Plastics industry Trimellitic anhydride Plastics industry Vanadium catalyst Maleic anhydride manufacture Miscellaneous Hijikia fusiforme (algae) Konjac flour Konnyaku maker’s lung Pet fish food Table 18.14.4.1  Continued

18.14.4  Hypersensitivity pneumonitis 4247 ultrasonic nebulizers, steam irons, oil heaters, air conditioners) is a less common cause of HP worldwide, but there are many con- vincing case reports of domestic causes. Composter’s lung has been described in relation to inhaling Aspergillus fumigatus from a compost heap. Recreational exposure to antigens occurs in the case of pigeon fancier’s lung, where pigeons are kept for the sport of pigeon racing. The widespread nature of provoking antigens is illustrated by ex- amples of the syndrome being attributed to contamination of water by a pullularia fungus in sauna taker’s disease (hot tub lung), and the mouthpiece of wind instruments by Candida albicans in saxopho- nist lung and trombone lung. Farmer’s lung Farmer’s lung results from the repeated inhalation of thermophilic actinomycetes from mouldy organic dust such as hay, straw, or crops. When hay is harvested during a wet summer it has a high mois- ture content of 30–​60%, such that it undergoes moulding during storage with proliferation of thermophilic actinomycetes such as Saccharopolyspora rectivirgula (formerly Micropolyspora faeni) or Thermoactinomyces vulgaris. When that hay is then used for feeding cattle or animal bedding during the winter, spores are inhaled, pro- voking HP. It has been estimated that up to 1.6 × 109 spores may be present in the air after disturbing mouldy hay, and that a farmer working in a confined space, such as a poorly ventilated barn, might inhale 750 000 spores per minute. The prevalence of farmer’s lung varies in different regions from approximately 0.5–​5%, and this relates to differences in climate and farming practices in the harvesting, drying, and storage of hay and crops. Farmer’s lung as a HP must be distinguished from other dis- eases such as inhalation fever, silo-​filler’s lung, and organic dust toxic syndrome, which can arise from the inhalation of endotoxins and other substances on farms. It can be difficult for patients diagnosed as having farmer’s lung to leave their work, and many continue to work on the farm using precautionary measures such as respiratory protection devices and avoidance of situations with high antigen exposures. In areas of heavy rainfall, the prevalence of farmer’s lung can be reduced by improved farming techniques, involving the artificial drying of crops and hay using a blower, better barn ventilation, and the addition of propionic acid to hay to reduce moulding. There have been many changes in the practice of farming over the years, and less than 2% of the population in the United Kingdom now works in agriculture, such that farmer’s lung is much less common than previously. Bird fancier’s lung Bird fancier’s lung remains one of the most common forms of HP throughout the world. Although it has been described in people ex- posed to avian antigens in many different circumstances, it is more common in those exposed to flying birds such as budgies or pigeons, whose feathers are covered by a fine powdery substance called bloom, than in those working with nonflying poultry, such as ducks or turkeys, whose feathers are not well developed and lack bloom. In bird breeder’s HP, multiple antigens have been extracted from bird droppings, feathers, serum, egg yolk, egg white, and gut wall. Many of these antigens are dispersed in the air from bloom or droppings and easily inhaled. In the United Kingdom, pigeons are mainly bred for the sport of pigeon racing, and fanciers typically keep 100–​200 pigeons in a loft. The resultant high-​intensity intermittent antigen exposure seems to favour the development of acute HP and particularly affects men. By contrast, small numbers of pigeons, typically 1–​10, are kept in homes in Mexico as pets, and this chronic low-​level antigen ex- posure is associated with chronic HP progressing to severe lung fi- brosis, particularly in women. In some unusual circumstances, where there is particularly close contact, bird fancier’s lung can occur in relation to wild pigeons. Occasionally bird antigens give rise to HP from a hidden source, such as feathered duvets or pillows. A variety of different lung diseases are associated with bird keeping, including inhalation fevers, asthma, psittacosis (infection with Chlamydia psittaci) and HP. Although it is often relatively easy to remove exposure to a pet bird, pigeon fanciers are frequently very committed to their sport and reluctant to stop contact with their pigeons. Many continue to keep pigeons despite a diagnosis of HP, using antigen avoidance and respiratory protection to reduce their level of contact. Metal-​working fluid HP Metal-​working fluids (MWF) are a mixture of water-​oil emulsion containing biocides and lubricants which are sprayed onto metal and machines to act as a lubricant and coolant in industries such as car manufacture. The MWF is usually collected and recirculated from a sump or reservoir, and can become contaminated with a var- iety of bacteria, fungi, and environmental mycobacteria. Several respiratory diseases may result from the inhalation of the mist of MWF, including lipoid pneumonia, inhalation fevers, asthma, and HP. Several outbreaks of MWF-​HP have been re- ported in metal workers in the United Kingdom, United States, and Europe. Some cases have been attributed to a specific antigen, such as Mycobacterium immunogenum, but in other cases workers have demonstrated high IgG levels to a range of bacteria and fungi, hence the precise causative antigen is uncertain and likely to differ between outbreaks depending on the exact circumstances. The diagnosis of a case of MWF-​HP should prompt an inspection of the workplace to review risk management and exposure control, and a survey of other workers who might also be affected. Prevention can be achieved by exhaust-​ventilation to reduce the escape of the MWF mist into the air, by monitoring and reducing microbial con- tamination of the fluid, and sometimes by use of respiratory protec- tion masks by the workers. Idiopathic HP (no antigen identified) It is common for CT imaging or lung biopsies to show features sug- gesting HP in patients attending specialist hospital clinics with inter- stitial lung disease who have no apparent contact with an antigen or environment known to cause HP. The CT features suggesting HP in- clude centrilobular nodules, mosaic air trapping, and ground-​glass shadowing with an upper lobe distribution. Biopsy features sug- gesting HP include bronchiolocentric distribution of inflammation and fibrosis with poorly formed granulomas. Up to 30% of patients with CT and biopsy features suggesting HP have no identifiable antigen exposure. Clearly when the potential diagnosis of HP is suggested, a detailed history should be taken from the patient, looking for any potential antigens or environments.

section 18  Respiratory disorders 4248 A visit to the patient’s home and work environment may identify potential sources of antigens such as mould, humidifiers, or aero- sols. It is also common for pigeon fanciers to be reluctant to inform doctors that they keep pigeons, because of a perception that doctors disapprove of the sport. It may be useful to measure antibody responses to avian antigens, Aspergillus, and thermophilic actinomycetes to detect evidence of unrecognized exposure to these antigens. Some cases of idiopathic HP have subsequently been attributed to previously undetected contact with avian antigens from feathers in duvets or pillows. Measurement of auto-​antibodies may provide clues to alternative diagnoses such as interstitial lung disease associated with connective tissue disease. The lack of an identifiable antigen casts doubt on the provoking factors and mechanisms of disease in cases of idiopathic HP, and it is important to realize that HP is not fundamentally a histopatho- logical or radiological diagnosis, but rather a clinical syndrome. The histopathology describes the pattern of disease rather than the pre- cise causation. Patients with idiopathic HP (no antigen identified) appear to have a worse prognosis than patients with HP and an identifiable antigen. It is possible that failing to identify an antigen perpetuates exposure that drives disease progression. It is also possible that pa- tients classified as having idiopathic HP may have a disease process driven by other mechanisms, and there is sometimes difficulty in differentiating HP from other diseases such as nonspecific intersti- tial pneumonia, idiopathic pulmonary fibrosis, airways centred fi- brosis, and connective tissue disease. In practice, patients classified as having idiopathic HP (no antigen identified) are usually given trials of treatment with corticosteroids and other immunosuppres- sive agents, but there is some evidence that their response to treat- ment is poorer than those in whom an antigen has been identified. Epidemiology The epidemiology of HP is difficult to define because of the diverse circumstances in which the disease occurs, the complex dynamic nature of the clinical syndromes, and the different forms of the dis- ease. Very different patterns of disease are seen when studies are undertaken at community level in patients at home, in workplace-​ based outbreaks, in primary care, or in specialist hospital settings (Fig. 18.14.4.1). Prevalence rates vary widely between countries and are influenced by factors such as climate, local customs, smoking habits, and dif- ferent work practices and processes. The most common types of HP in several series are bird fancier’s lung from a pet bird in the home or the sport of pigeon racing, farmer’s lung due to fungi in mouldy hay or straw, and various types of humidifier lung due to fungi or bacteria in water aerosols in the home or workplace. A study by the international HP research group showed that 61% of cases were due to birds, 21% to farming, and 12% to various fungi encountered in the home or workplace. In the United Kingdom it is estimated that 1 million homes have a pet bird, 2% of the population work in agriculture, and there are approximately 43 000 registered pigeon fanciers. Only a small per- centage of those of those exposed to an antigen of HP develop the disease. It is estimated that 3.4% of budgie fanciers, 10–​15% of pigeon fanciers and up to 5% of farmers develop HP. A study of pri- mary care data in the United Kingdom estimated that there were about 600 new cases of HP in the United Kingdom each year, giving an incidence of HP of 1 per 100 000 person-​years with a mean age of diagnosis of 51 years. HP accounts for only about 6% of occupational lung disease re- ported to the United Kingdom surveillance scheme, of which almost 50% of reported cases involved farmers or farm workers, followed by 15% affecting workers in material, metal, or electrical processing trades. However, in recent years there has been a change, with metal-​ working fluid HP becoming the most commonly reported cause of occupational HP. In reported outbreaks of humidifier lung in offices and factories in North America the prevalence rates among workers have varied from 15 to 70%. The risk of developing HP from metal-​ working fluids varies substantially according to the degree and na- ture of microbial contamination, and the ease with which aerosols of the fluids are released into the working environment. Up to one-​ third of workers have been affected in some outbreaks. Smaller numbers of people are employed making whisky from germinating barley (maltings), raising mushrooms on a variety of antigenic composts, or handling bagasse (the fibrous stem that re- mains when sugar is extracted from sugar cane), but within some of these populations HP was a common problem until excessive ex- posure levels were controlled. In Japan, the seasonal summer growth of T. cutaneum in the home is a common cause of HP. Pathogenesis Antigens of HP The antigens which provoke HP have important characteristics that distinguish them from the antigens that provoke asthma. Hypersensitivity pneumonitis Population studied Form of HP Death Specialist
Chronic Fibrosis Recurrent alveolitis Hospital Subacute Acute severe alveolitis Acute Community Acute mild stable symptoms Normal Asymptomatic antigen sensitization Fig. 18.14.4.1  Hypersensitivity pneumonitis is a heterogeneous dynamic clinic syndrome which varies in its initial presentation and clinical course. Traditionally the disease is classified into acute, subacute, and chronic forms. The clinical features depend on the population studied. Community-​based studies often identify subjects with mild intermittent acute symptoms, and subjects who have an immune response to the antigen but who have not developed disease. In hospital practice, patients may present acutely with severe alveolitis. Studies from specialist interstitial lung disease services tend to have selected populations of patients who have developed chronic disease with progressive fibrosis.

18.14.4  Hypersensitivity pneumonitis 4249 These characteristics include their size, solubility, particulate na- ture, and their capacity to provoke a nonspecific inflammatory response and a specific immune reaction. They are usually small, with a particle size less than 3 µm in diameter, such that they can be inhaled into the distal bronchial tree and alveoli, where they are cleared via local lymphatics to the hilar nodes, which seems to be important in producing IgG antibody responses. By contrast, antigens more typically associated with asthma are larger at about 30 µm in diameter, and are preferentially deposited in the proximal airways, where they tend to provoke an IgE antibody response in atopic subjects. The antigens of HP have powerful adjuvant prop- erties, with a capacity to activate complement by the alternative pathway, to stimulate macrophages, and to enhance delayed cel- lular responses, with the release of interleukin (IL)-​1 and tumour necrosis factor (TNF)α. Susceptibility and environmental factors Individual susceptibility is important in determining the immune response: less than 10% of subjects repeatedly exposed to antigens of HP develop the disease. Host risk factors are poorly under- stood. Several studies have suggested links between HLA types and HP, with an increased occurrence of HLA DR7 in pigeon fancier’s lung in a Mexican population, HLA B8 in farmer’s lung and pigeon fancier’s lung in Caucasians, and HLA-​DQw3 in Japanese summer-​ type HP, but other studies have found no association. Genetic factors are known to influence immune response. Gene polymorphisms resulting in high-​responders for TNFα result in a greater risk for developing HP. Similarly, animal models of HP suggest that multigenic factors are important in determining the susceptibility of certain strains of mice to the development of granulomatous inflammation. Environmental factors, including antigen concentration, dur- ation, and frequency of exposure, particulate size, antigen solubility, and variability in work practices may influence the prevalence, se- verity, and course of HP. It has been repeatedly shown that HP is less common in current smokers, and smoking reduces the IgG response to inhaled antigens, influences cytokine production and impairs macrophage function. Smoking may also reduce the risk for other T-​cell-​mediated immunological disorders such as sarcoidosis, ul- cerative colitis, and some types of occupational asthma. The key cell in a complex series of interactions is probably the alveolar macro- phage, which is critical in presenting antigen to CD4+ T lympho- cytes and so to activating cellular immune mechanisms. Although smoking increases macrophage numbers and their metabolic ac- tivity, the activated cells show impairment of both the expression of surface major histocompatibility (MHC) class 2 antigens and the production or release of IL-​1 and inflammatory mediators derived from arachidonic acid metabolism (leukotriene B4, prostaglandin E2, thromboxane B2). It is also argued that the increased macrophage numbers down-​regulate pulmonary immune responses in a purely nonspecific fashion by impairing antigen access to more effective blood monocytes. There is some evidence that the onset of HP may be precipitated by additional nonspecific lung inflammation. Respiratory viruses, such as influenza A, are commonly detectable by the polymerase chain reaction in the lower airways of patients presenting with acute HP, and in a mouse model of HP it has been shown that Sendai virus infection enhances the lung response to antigenic challenge with Saccharopolyspora rectivirgula. Other animal models of HP require the induction of nonspecific lung inflammation by adjuvants such as Bacille Calmette–​Guérin (BCG) or carrageenan, before HP can be provoked by antigen challenge. Immunopathogenesis The immunopathogenesis of HP is complex and incompletely understood. Patients have high levels of antigen exposure and dem- onstrate complex immune responses involving antibody and cellular immune mechanisms. An outline of the possible immunopathology of HP is illustrated in Figs. 18.14.4.2 and 18.14.4.3, and it is likely that different mechanisms are important at different stages of the process, depending on whether the patient is presenting with acute HP, chronic HP, or progressive pulmonary fibrosis. Initially it was thought that HP was an immune complex-​mediated disease, but greater emphasis has subsequently been placed on the role of cellular immune responses. The evidence for deposition of immune complexes is not convincing, and neither IgG nor IgM anti- bodies are uniformly demonstrated in the sera of affected subjects unless sensitive detection techniques such as the enzyme-​linked im- munosorbent assay (ELISA) or radioimmunoassays are used. More importantly, these antibodies are frequently found in subjects who are similarly exposed but clinically unaffected. A closer association of disease with the IgG4 antibody subclass has been suggested, but the significance of this is not yet apparent. It is clear, however, that vasculitis—​a cardinal feature of the experimental Arthus reaction—​ is not a characteristic feature. The inflammatory reaction is dominantly lymphocytic or mono- nuclear rather than polymorphonuclear, although a transitory poly- morphonuclear leucocyte response is typical immediately following exposure. In experimental animal models of HP, the disease cannot be induced by the passive transfer of hyperimmune serum, but transfer of specifically sensitized lymph node cells intraperitoneally followed by antigen challenge produces lesions closely resem- bling those seen in HP. Immediately after antigen challenge there is an influx of neutrophils into the alveoli. This may be stimulated by the formation of immune complexes and direct activation of Smooth muscle constriction Air space Spores +C3bi Activated macrophage T lymphocyte IL-2 Activated endothelium Bloodstream Neutrophil Alternate pathway complement C3bi (opsonin) C3a + C5a (chemotactic factors; bronchoconstriction) Cell recruitment and activation Cytokines IL-1/TNF Systemic effects of cytokines (fever, malaise) Antigen presentation Mediator release (leukotrienes, prostaglandins) Fig. 18.14.4.2  Possible immunopathogenesis: acute phase.

section 18  Respiratory disorders 4250 complement by the alternative pathway. This neutrophilic alveolitis is transient and is followed by the influx of activated T-​cells with a preponderance of CD8 T-​cells. As time passes from antigen ex- posure, the number of CD8 cells decreases and there is an increase in CD4 T-​cells. Alveolar macrophages are activated and an array of pro-​inflammatory cytokines such as tumour necrosis factor (TNF)-​α, interleukin (IL)-​6, IL-​17 and interferon (IFN)-​γ is pro- duced. Regulatory cytokines such as IL-​10 are also secreted and may play a role in damping down the inflammatory response. Toll-​ like receptors (TLR) may also be involved. These recognize par- ticular bacterial and fungal lipoproteins. TLR2 and TLR9 appear to be important in the initial response. The factors governing granulomatous inflammation are uncer- tain, but animal models of schistosome-​induced granulomatous inflammation show that certain factors, such as T-​suppressor ef- fector factor and cyclo-​oxygenase products, inhibit macrophage expression and granuloma formation, whereas other factors such as lipoxygenase products enhance granuloma formation. There are therefore certain modulating factors which may enhance or sup- press the disease process at various stages. Bronchoalveolar lavage in subjects exposed to HP antigens has shown excess numbers of T lymphocytes, whether they were clinically affected or not, although the proportions of T-​cell subpopulations have varied according to disease activity and the circumstances of exposure. It is known that different antigenic de- terminants from a given inducing microbial source may lead to dif- ferent immunological responses, and it seems likely that cytotoxic activity and released cytokines (e.g. IL-​6 and TNFα) play some role, possibly by activating the vascular endothelium and thereby recruiting and activating further macrophages and inflammatory cells. In experimental models IFN-​γ has been shown to play a major role (an excess of IFN-​γ-​producing T-​cells is present in the lungs), and IL-​10 ameliorates the disease. Other studies implicate IL-​6, IL-​8, IL-​12, IL-​17, IL-​18, and IL-​22, monocyte chemotactic protein-​1 (MCP-​1), intercellular adhesion molecule 1 (ICAM-​1), mast cells, and NK cells. Cytokines, possibly together with anaphylatoxins from the deg- radation of complement components (C4, C3, C5), are likely to be responsible for the systemic influenza-​like symptoms that are so characteristic of the acute form of HP. These symptoms are indistin- guishable from those of grain fever in grain workers, ‘Monday fever’ in cotton workers, humidifier fever in subjects exposed to contamin- ated humidifiers, and metal fume fever in welders. In these situations the febrile disorder is not characteristically associated with clinical alveolitis, raising the possibility that its occurrence with the acute form of HP is an independent phenomenon, rather than an integral part of the disease progression. In favour of this hypothesis has been the finding of high levels of endotoxin from Gram-​negative bacteria (which are known to provoke these symptoms) in grain dust, cotton dust, contaminated humidifiers, and many of the ‘mouldy’ vegetable dusts that cause HP. Pulmonary fibrosis may represent a common pathway for many interstitial lung diseases. The precise links between inflammation and fibrosis in interstitial lung disease are also poorly understood, but may relate to the extent of injury to epithelial cells and base- ment membrane, and factors governing fibroblast activation, col- lagen deposition, and collagen degradation. The onset of fibrosis is associated with a poor response to treatment and increased mor- tality. The mechanisms for profibrotic and antifibrotic regulation by various cytokines and cell surface markers are uncertain. In ad- vanced fibrotic disease it is often difficult to differentiate HP from idiopathic pulmonary fibrosis. However, there are different gene expression signatures in these diseases. In HP, the gene expres- sion signature on oligonucleotide arrays are is of those function- ally associated with inflammation, T-​cell activation, and immune responses, whereas idiopathic pulmonary fibrosis is character- ized by the expression of tissue remodelling, and epithelial and myofibroblast genes. In summary, the immune mechanisms underlying HP are com- plex and may differ at different stages of the disease. This diversity is reflected in a dynamic heterogeneous clinical syndrome which varies greatly in its initial presentation and subsequent clinical course. Air space Spores CD4+ lymphocytes Cytokines Bloodstream Activated endothelium CD8+ lymphocyte Efferent lymph Regional lymphoid tissue Precipitating antibodies [IgG] Multinucleate giant cell Activated CD4+ lymphocytes Antigen transported to lymph node in afferent lymph Follicles [B cells] Fig. 18.14.4.3  Possible immunopathogenesis: subacute/​chronic phase.

18.14.4  Hypersensitivity pneumonitis 4251 Clinical features The clinical features of the disease depend greatly on the population studied, the clinical circumstances of antigen exposure, and the pat- tern of the disease in an individual patient. The clinical spectrum varies from mild recurrent symptoms, often managed by patients themselves at community level, to acute severe pneumonitis pre- senting to hospital, and to progressive fibrotic lung disease in pa- tients seen in specialist interstitial lung disease clinics. Traditionally HP is classified into acute, subacute, and chronic forms, although patients do not always fit neatly into this classifica- tion, and different patterns emerge over time. Acute hypersensitivity pneumonitis Acute HP is characterized by recurrent episodes of breathlessness, cough, fevers, malaise, and flu-​like symptoms, occurring 4–​8 hours after antigen exposure. Lung function tests, chest radiographs, and CT images may be abnormal after exposure but usually return to normal between episodes. Characteristically there is a latency period, which may vary from weeks to years, during which there are no symptoms, as sensitization to the antigen develops before the onset of disease. The severity and duration of symptoms depend critically on ex- posure dose and individual susceptibility. With low levels of acute exposure, symptoms are mild and persist for a few hours only. When occupation is responsible, the affected worker may feel unwell only at home during the following evening or night, and be fully recovered by the next morning, such that the relevance of the workplace envir- onment may not be initially obvious. In hospital practice, patients may present acutely with severe HP with fever, breathlessness, hypoxia, and diffuse shadowing on a chest radiograph or CT. Initially these patients may be suspected to have developed infective pneumonia and may receive antibiotics. The symptoms may resolve as admission to hospital removes them from further antigenic contact, but they may present again with recurrent episodes. It is crucial to ask about potential antigenic exposure to identify the correct diagnosis in such cases. Chronic hypersensitivity pneumonitis Chronic HP is characterized by the insidious development of breathlessness and persistent pneumonitis. It is typically seen in a person who keeps a single budgie in the home. The level of antigenic exposure to avian dust is comparatively small compared with that of the farm worker forking bales of heavily contaminated hay in a poorly ventilated barn, but it is encountered almost continuously, particularly if the affected individual is housebound. Subacute hypersensitivity pneumonitis In subacute HP patients may demonstrate chronic pneumonitis with episodes of acute symptoms after antigen exposure. Diagnostic criteria and investigation No single clinical feature or laboratory test is diagnostic of HP, and the diagnosis is made from a combination of characteristic clinical features, radiographic abnormalities, lung function tests, immunological tests and (in some cases) lung biopsy, and the exclu- sion of alternative disease processes. The diagnostic approach should be adapted to the circumstances of the clinical problem, and very few patients will demonstrate all features of the disease at any one point in time. In many cases the diagnosis can be established from clinical features supported by chest radiography, CT, serology, and lung function tests. In those with lung fibrosis the difficulty is in differentiating chronic HP from idiopathic pulmonary fibrosis, and invasive tests such as bronchoalveolar lavage, lung biopsy, and antigen challenge tests may be appropriate. Suspicion of an association between symptoms and contact with a provoking antigen is a key step in the diagnostic process. In the acute form of HP this association may be readily apparent. In the chronic form symptoms often do not show a temporal relationship to antigen exposure, and sometimes no antigenic source is apparent. An important step is the demonstration of either an antibody or cellular immune response to the provoking antigen. However, this merely confirms that that the patient has had a sufficient level of ex- posure to the antigen to develop sensitization, and this is not suf- ficient to establish a diagnosis of HP, since many asymptomatic subjects show similar antibody or cellular responses. Serological tests for antibodies to avian antigens, thermophilic actinomycetes, and Aspergillus may be useful in identifying exposure to a relevant antigen. Radiological imaging With the acute form of the disease the chest radiograph commonly shows no abnormality between episodes. When the radiograph is abnormal, there is a widespread ground-​glass appearance or an al- veolar filling pattern, particularly in the lower and mid-​zones. This may resolve within 24–​48 h once exposure has ceased. In more sub- acute forms small reticular opacities may persist for several weeks despite cessation of exposure. Occasionally a more nodular pattern occurs. In practice, the radiographic appearances vary considerably from patient to patient and correlate poorly with the clinical severity of the disease. High-​resolution CT is more sensitive than chest radiography in demonstrating parenchymal changes. The typical features are diffuse bilateral ground-​glass attenuation with small centrilobular nodules with a mid and lower zone distribution. A characteristic finding is of a mosaic pattern due to focal areas of air trapping, often with a clear lobular distribution, within diffuse areas of ground-​glass attenu- ation. The extent of air-​trapping on expiratory CT correlates with an increase in residual volume on pulmonary function tests. In more advanced chronic HP, the CT findings are of pulmonary fibrosis with linear opacities, architectural distortion, and honeycombing, often indistinguishable from other causes of pulmonary fibrosis. Features which suggest HP rather than idiopathic pulmonary fi- brosis include a relative sparing of the lung bases, lack of peripheral subpleural distribution of fibrosis and the presence of centrilobular nodules (Fig. 18.14.4.4). Lymph node enlargement and/​or pleural involvement are not characteristic. Lung function studies The results of lung function studies vary according to severity of the disease and the interval to last antigen exposure. When lung function is impaired, the pattern suggests parenchymal and interstitial disease,

section 18  Respiratory disorders 4252 but is otherwise nonspecific. There is a restrictive defect with reduced lung volumes and impaired carbon monoxide gas transfer (dimin- ished TLco and Kco), decreased compliance, and in more severe cases arterial hypoxaemia. Although total lung capacity is reduced, residual volume is often increased, suggesting air trapping as a result of bronchiolar involvement. Occasionally there is also evidence of obstruction of the large and peripheral airways. Serial measurements of lung function may be particularly useful in demonstrating that im- pairment is closely related to the relevant exposure. Bronchoalveolar lavage Bronchoalveolar lavage characteristically shows a lymphocytic alve- olitis with a predominance of CD8 T-​cells, but the cell profile is de- pendent upon the interval from last antigen exposure. A neutrophilic alveolitis is seen immediately after antigen challenge and the number of CD8 T-​cells falls after cessation of antigen contact. A lymphocytic alveolitis is seen in asymptomatic subjects exposed to an antigen and in patients with organic dust toxic syndrome. Sarcoidosis is also characterized by lymphocytosis in bronchoalveolar lavage fluid, but B-​lymphocyte numbers are decreased and the excess T lymphocytes are typically CD4 + helper cells, with the CD4 + to CD8 + ratio nor- mally exceeding 1. By contrast, the ratio is typically reversed in HP, CD8 + cells outnumbering CD4 + cells, and B-​lymphocyte numbers are not decreased. Lymphocyte markers may therefore help distin- guish sarcoidosis from HP. Lung biopsy Lung biopsy typically shows lymphocytic infiltration, foamy macro- phages, poorly formed granulomas, and bronchiolitis, but this depends on the stage of the disease and in more advanced disease the predominant feature may be pulmonary fibrosis resembling usual interstitial pneumonia of idiopathic pulmonary fibrosis. Close correlation with all the clinical details is required to differentiate the granulomatous inflammation of HP from other disease processes such as sarcoidosis. There has been little opportunity to characterize the pathology of the acute form of HP histologically because biopsies are very rarely taken within 24–​48 h of a provoking exposure. Initially there is a nonspecific diffuse pneumonitis with inflammatory cellular infiltra- tion of the bronchioles, alveoli, and interstitium, accompanied by oedema and luminal exudation. With ongoing exposure, whether continuous or intermittent, the more familiar appearances of the subacute forms of HP evolve. The typical histological appearance of subacute HP is illustrated in Fig. 18.14.4.5. The most characteristic feature is the formation of epithelioid noncaseating granulomas. These are generally less well formed than in sarcoidosis, less profuse, and often evanescent. They can be recognized within 3 weeks of the initiating exposure, and generally resolve within 6–​12 months. In parallel, fibrosis evolves alongside cellular infiltration of the interstitium with histiocytes, lymphocytes, and plasma cells. Macrophages with foamy cytoplasm may be prominent in the alveolar spaces, and organization of the in- flammatory exudate may lead to intra-​alveolar fibrosis. Obstruction or obliteration of bronchioles is common. Foreign-​body giant cells may reflect the dependence of HP on antigens derived from inhaled foreign material, as does a peribronchial predominance of the in- flammatory response. Vasculitis is notable by its absence. Immunological tests The demonstration of a serum IgG antibody response to the inducing organic dust is the most widely used method of confirming an im- mune response to an inhaled antigen. Although affected subjects tend to have higher antibody levels than those who are exposed but unaffected, the antibody response tends to correlate more closely with exposure than with disease. If the more sensitive ELISA is used, rather than the traditional Ouchterlony double-​gel diffusion test, even higher rates of false-​positive results are obtained. Fig. 18.14.4.5  Histological appearance: subacute disease. There is bronchocentric interstitial fibrosis and chronic inflammation, with poorly formed interstitial granulomas including giant cells. (Haematoxylin and eosin stain at medium magnification.) Courtesy of Dr T. Ashcroft. Fig. 18.14.4.4  (a) CT scan of a woman aged 44 years who had never smoked whose lung biopsy showed the typical appearances of subacute HP. She kept two budgies in her home and had serum precipitins to avian antigens. The scan shows marked ground-​glass attenuation of the lung parenchyma, which is nodular in some areas due to characteristic peribronchiolar (and centrilobular) foci. In other areas there is increased translucency because of bronchiolar obstruction and air trapping. Both the ground-​glass attenuation and the increases in translucency are exaggerated in the expiratory film (b), giving a ‘mosaic’ pattern. She recovered fully after the birds left her home.

18.14.4  Hypersensitivity pneumonitis 4253 In practice, the absence of an IgG precipitin response is un- common in subjects eventually proven to have HP. This is of con- siderable value in that a negative test generally makes the diagnosis unlikely. The proliferative response of peripheral blood lymphocytes to specific antigens has been used in some research studies as a measure of a cellular immune response in establishing a diagnosis of HP in patients with interstitial lung disease, but these tests are not widely available and their sensitivity and specificity for diagnosing HP are not established. Challenge tests When the diagnosis remains in doubt, some form of inhalation challenge test may be necessary. The simplest method involves com- parison of experimental periods spent away from the suspected causative environment with similar periods of continuing exposure. This can be done in workplace-​based settings or in the setting of a pigeon loft, for example, where subjects undertake their usually activities, with monitoring of symptoms, clinical signs, and lung function. The acute form of the disease is likely to be recognized in this way. When a definitive diagnosis is particularly important, laboratory-​ based inhalation challenge tests can be used. These employ a variety of techniques, ranging from nebulizing soluble extracts to recre- ating natural environmental exposures in an exposure chamber. However, the use of such inhalational challenge studies in the diagnosis of HP has been hampered by the lack of standardized antigens, the diversity of the clinical manifestations of the disease, and the difficulties in defining objective criteria that characterize a positive test. The influenza-​like component of positive reactions is often uncomfortable, and if excessive doses are administered these tests can be hazardous. Furthermore, objective evidence for posi- tive reactions may be difficult to obtain from conventional lung function tests. Table 18.14.4.2 outlines the sensitivity and specificity of certain parameters from a study of 144 inhalation challenge tests. Together they provide high specificity and high sensitivity. Auscultation, chest radiography, measurements of gas transfer, and arterial blood gas analyses are often too insensitive to provide useful diagnostic information. Differential diagnosis The differential diagnoses to be considered depend on the popula- tion studied and the circumstances of the disease. The acute form of HP needs to be distinguished from organic dust toxic syndrome and mere sensitization to the antigen. The chronic fibrotic form may mimic idiopathic pulmonary fibrosis or nonspecific interstitial pneumonia. Organic dust toxic syndrome Systemic influenza-​like symptoms and respiratory distress may also follow an unusually heavy exposure to contaminated vegetable pro- duce. In 1986 an international symposium considered a further dis- order that occurs within hours of heavy respiratory exposure to dusts containing fungal toxins, especially those released on decapping silos. The condition typically occurs after a single exposure to an un- usually high level of organic dust, and may arise in subjects who have not had previous exposure. All subjects that have a similar degree of exposure develop a similar clinical illness. It is the result of direct toxicity rather than hypersensitivity, and the term ‘organic dust toxic syndrome’ was recommended to describe it. Its effects are usually mild and self-​limiting, but severe respira- tory embarrassment can occur. Not only does organic dust toxic syndrome occur in circumstances which favour the occurrence of HP (particularly silos and swine/​poultry confinement buildings), but its clinical features have much in common with HP, and to a lesser extent with nitrogen dioxide toxicity, which may also affect silo workers (Table 18.14.4.3). Most organic dusts contain an array of bacteria, fungi, and en- dotoxins, which can give rise to this direct toxic lung inflamma- tion. These are sometimes associated with systemic febrile reactions without impairment of lung function, as in the case of farmer’s fever, grain fever, swine fever, and humidifier fever. These patients do not usually have antibodies to relevant antigens. Nitrogen dioxide toxicity In the agricultural silo, decomposing grain or silage releases ni- trogen dioxide into the confined space immediately above the level of the stored produce. Since this is denser than air it disperses slowly and may reach sufficiently high concentrations to cause asphyxia. Silo-​fillers lung is a toxic pneumonitis resulting from inhalation of nitrogen dioxide. It can produce severe pneumonitis with pul- monary oedema and death. Treatment and prognosis Antigen avoidance Removal of exposure to the provoking antigen is the key treatment for patients with HP, and complete cessation of contact is the safest advice for these patients. In patients with the acute form of HP ces- sation of antigenic exposure usually results in rapid resolution of the disease. In patients admitted to hospital with more severe acute pneumonitis there is often an apparent beneficial response to cor- ticosteroids, although it is difficult to distinguish between the effects of treatment and the effects of antigen avoidance brought about by the admission to hospital. Table 18.14.4.2  Diagnostic features of positive inhalation challenge tests Diagnostic changes within 36 h of challenge exposure Sensitivity (%) Increase in body temperature to >37.2°C 78 Increase in circulating neutrophils by ≥2.5 × 109/​litre 68 Decrease in circulating lymphocytes by ≥0.5 × 109/​litre,
with lymphopenia (<1.5 × 109/​litre) 52 Decrease in forced vital capacity by ≥15% 48 Increase in exercise minute volume by ≥15% 85 Increase in exercise respiratory frequency by ≥25% 64 The data were taken from a series of 144 antigen and control challenge tests in 31 subjects. Diagnostic endpoints were chosen to produce specificities of approximately 95% after mean changes associated with positive challenge tests were shown to be highly significant. When each monitoring parameter was given a score of 1 for a significant result, a total score of 2/​6 or more was associated with a specificity of 100% and a sensitivity of 78% for the 144 challenge tests.

section 18  Respiratory disorders 4254 Some patients have had mild stable symptoms for several years, but have not consulted doctors because they fear that their liveli- hood is at stake in the case of farmers, or that their commitment to their sport will not be appreciated in the case of pigeon fanciers. Sometimes it is unrealistic for the affected individual to change the relevant working, domestic, or recreational environment com- pletely, and many such patients continue some exposure, and sur- prisingly this does not inevitably result in progressive disease. Many patients will have adopted strategies to reduce antigen exposure, and further advice can be given in that regard. For ex- ample, pigeon fanciers can be encouraged to spend less time in the loft, to avoid activities where there is a high level of antigen, such as ‘scraping out’, and to wear a loft coat and hat that are removed on leaving the loft so as to avoid continuing contact with antigen car- ried on clothing or in hair. In particular, pigeon fanciers should be specifically advised not to transport pigeons on the back seat of their car, as this can result in intense exposure in a confined space. Farmers can use silage rather than hay for feeding animals, and can adopt modern practices with drying systems which reduce the moisture and mould content of hay. An alternative is some form of ‘pickling’, so that the produce is preserved chemically. With silage, for example, newly cut grass is kept under impervious covering in relatively sealed conditions. Initial enzymatic and moulding pro- cesses use up available oxygen, and produce aldehydes and other preservative chemicals. These create nearly anaerobic conditions and protect the produce until it is used. Similarly, hay may be sealed in plastic bags, or grain or bagasse may be treated with propionic acid. Occupational aspects Where outbreaks of HP occur in workplaces, it is important that an industrial hygienist and occupational physician work with the management and employees to identify the process involved and to reduce or remove the risk to the affected individual and fellow workers. If workers suffer disability or have to stop work because of occupational HP, they are entitled to compensation either through governmental compensation schemes or through pursuit of a legal claim via the civil courts. Sometimes, as in the case of contamin- ated metal-​working fluid or a humidifier system, the source of the antigen can be identified and removed. Assessment and surveillance of other workers is important as often they may have been affected but not diagnosed correctly. The affected individuals who continue to work in the occupation respon- sible for their disease can often reduce their exposure substantially by changing the pattern of their particular duties, or working in Table 18.14.4.3  Characteristics of nitrogen dioxide toxicity (silo-​filler’s disease), organic dust toxic syndrome, and acute farmer’s lung Nitrogen dioxide toxicity Organic dust toxic syndrome Acute farmer’s lung Susceptibility in smokers Unknown Unknown Decreased Relation to time of harvest Days Months to years Months to years Microbial decomposition of harvest product Little Marked Variable Confined exposure space +++ + + Previous episodes –​ + ++ Symptoms   Dry cough ++ ++ ++   Breathlessness ++ ++ ++   Wheeze –​ –​ –​   Systemic upset + + ++ Signs   Basal crackles + + +   Fever + + + Time of onset after beginning exposure 1–​10 h 1–​10 h 1–​10 h Duration Hours to days Hours to days Hours to days Investigations Leucocytosis + + + Radiograph–​small irregular opacities, alveolar shadows + ± + Restricted ventilation + ± + Reduced gas transfer + ± + Hypoxaemia + ± + Fungi from secretions/​biopsy –​ ++ + Methaemoglobinaemia + –​ –​ Serum precipitins –​ –​

–​ ++ Life-​threatening Not uncommonly Rarely Rarely

18.14.4  Hypersensitivity pneumonitis 4255 different areas of the factory. Modifications can always be made to the environment to lessen the level of exposure, but their extent will be limited by expense and should be justified by need. When ventila- tion and humidification systems are themselves responsible for HP, major mechanical alterations may be necessary, and the methods of humidification and temperature control may need to be changed. The crucial need is to reduce the ease with which normal airborne microbial contaminants are able to proliferate in stagnant, reservoir, collections of water. For this there may be a role for ‘biocide’ steril- izing agents, but these are also likely to become airborne and respir- able and so must have low intrinsic toxicity and sensitizing potency. Respiratory protection masks have been shown to improve symp- toms and prevent a reaction to an antigen challenge, but these have to be of sufficient quality to filter out small particles of respirable dust, and they have to be worn regularly and have a close fit to the face to prevent antigens being inhaled. Continued exposure Where a patient with HP decides to continue exposure to the antigen, there is a risk of recurrent episodes of acute HP and some- times progression of the disease to lung fibrosis. Complete cessation of antigen exposure remains the safest advice, but where this is not possible methods to reduce the level of antigen exposure should be recommended, and measuring the level of circulating antibody to the antigen may be a useful guide to the effectiveness of avoidance measures. Ongoing medical supervision of symptoms, lung func- tion, and chest radiographs is advisable. Surprisingly, acute HP does not usually progress to chronic fi- brotic disease, even when there is continued antigen exposure. A long-​term follow-​up study of 92 farm workers presenting with acute farmer’s lung showed that while most continued to live on farms, only some developed radiographic evidence of pulmonary fi- brosis (39%) or impairment of carbon monoxide gas transfer (30%), but 28% gave histories of chronic productive cough and 25% had airway obstruction. A similar 10-​year outcome has been reported in pigeon fanciers with acute HP; again, most elected to continue their antigenic exposures despite medical advice to the contrary, but symptoms tended to improve and only a few had residual abnormal- ities on chest radiographs or lung function tests. Some patients seem to remain in a state of equilibrium with the antigen over long periods of time without developing progressive disease. This intriguing phe- nomenon has also been reported in animal models of the disease, where repeated antigen challenges result in a waning of the immune response rather than progression of the disease. The interaction of the antigen and the host response in HP is complex, and it is clear that there are several factors which modulate the response. This also suggests that the underlying pathogenic mechanisms differ between acute HP and chronic fibrotic disease. Acute severe alveolitis Patients presenting to hospital with acute severe alveolitis are usually treated with corticosteroids. A randomized, double-​blind, placebo-​ controlled study of corticosteroids in patients with acute farmer’s lung showed more rapid improvement in lung function, with a sig- nificantly higher transfer factor for carbon monoxide (TLco) and transfer coefficient (Kco) at one month compared to the control group, but there was no difference in the long-​term outcome be- tween the two groups. Chronic fibrotic hypersensitivity pneumonitis Patients with chronic fibrotic HP have severe disease which is often progressive, and it is essential for these patients to avoid further con- tact with the provoking antigen. Sometimes this fibrotic form of HP progresses even after cessation of antigen exposure, suggesting that the disease mechanisms giving rise to fibrosis may be progres- sive and not dependent on ongoing antigenic stimulation. Many of these patients improve on corticosteroids, particularly where a lung biopsy shows a nonspecific pneumonia or cryptogenic organizing pneumonia pattern of disease rather than a usual interstitial pneu- monia pattern. Evidence of lung fibrosis on biopsy or CT imaging is an adverse feature and is associated with a high likelihood of pro- gressive disease and death from respiratory failure. Some of these patients show a similar pattern of disease progression as is seen in idiopathic pulmonary fibrosis. Acute exacerbations of chronic HP may also occur, and are charac- terized by an acute deterioration in breathlessness, oxygenation, and lung function. As is the case with acute exacerbations of idiopathic pulmonary fibrosis, these patents are usually treated by corticoster- oids during exacerbations. Where patients fail to respond to cor- ticosteroids other immunosuppressive drugs, such as azathioprine, cyclophosphamide, or mycophenolate, are often tried, but evidence of benefit is based on case reports rather than formal clinical trials. Rituximab, a B-​cell depleting anti-​CD20 antibody, has also been re- ported to have a beneficial effect, suggesting an immunopathogenic role for B cells in some patients with severe HP. Lung transplantation may be necessary in patients with progres- sive HP who have failed to respond to antigen avoidance and im- munosuppressive treatments. Although patients with HP have an exaggerated immune response to certain inhaled antigens, they have lower rates of acute rejection of transplanted lungs and a better prog- nosis than patients with idiopathic pulmonary fibrosis. There have been reports of recurrence of the disease in the transplanted lungs if there is re-​exposure to the antigen. FURTHER READING Anderson K, et al. (1989). The long-​term effect of a positive pressure respirator on the specific antibody response in pigeon breeders. Clin Expt Allergy, 19, 45–​9. Bourke S, Boyd G (1997). Pigeon fancier’s lung. Brit Med J, 315, 70–​1. Bourke SJ, et al. (1989). Longitudinal course of extrinsic allergic alve- olitis in pigeon breeders. Thorax, 44, 415–​18. Bourke SJ, et al. (2001). Hypersensitivity pneumonitis: current con- cepts. Eur Respir J, 32 (Suppl), 81–​92. Braun SR, et al. (1979). Farmer’s lung disease: long-​term clinical and physiologic outcome. Am Rev Respir Dis, 119, 185–​91. Camarena A, et al. (2001). Major histocompatibility complex and tu- mour necrosis factor-​alpha polymorphisms in pigeon breeder’s dis- ease. Am J Respir Crit Care Med, 163, 1528–​33. Cormier Y, et al. (1994). Long-​term viral enhancement of lung re- sponse to Saccharopolyspora rectivirgula. Am J Respir Crit Care Med, 149, 490–​4.

18.14.5 Pulmonary Langerhans’ cell histiocytosis 4

18.14.5 Pulmonary Langerhans’ cell histiocytosis 4256 S.J. Bourke

section 18  Respiratory disorders 4256 Cullinan P, et al. (2014). Extrinsic allergic alveolitis and metal working fluids. Thorax, 69, 1059–​60. Dakhama A, et al. (1999). Common respiratory viruses in lower air- ways of patients with acute hypersensitivity pneumonitis. Am J Respir Crit Care Med, 159, 1316–​22. Du Marchie Sarvaas GJ, et al. (2000). A family with extrinsic allergic alveolitis caused by wild city pigeons. Pediatrics, 105, e62–​70. Girard M, et  al. (2011). Impaired function of regulatory T-​cells in hypersensitivity pneumonitis. Eur Respir J, 37, 632–​9. Hendrick DJ, Faux JA, Marshall R (1978). Budgerigar fancier’s lung: the commonest variety of allergic alveolitis in Britain. Br Med J, ii, 81–​4. Hendrick DJ, et al. (1980). Positive ‘alveolar’ responses to antigen in- halation provocation tests: their validity and recognition. Thorax, 35, 415–​27. Ishizuka M, et al. (2015). Validation of inhalation provocation test in chronic bird-​related hypersensitivity pneumonitis and a new predic- tion score. Ann Am Thorac Soc, 12, 167–​73. Kern RM, et al. (2015). Lung transplantation for hypersensitivity pneu- monitis. Chest, 147, 1558–​65. Kokkarinen JI, et al. (1992). Effect of corticosteroid treatment on the recovery of pulmonary function in farmer’s lung. Am Rev Respir Dis, 145, 3–​5. Lacasse Y, et al. (2012). Recent advances in hypersensitivity pneumon- itis. Chest, 142, 208–​17. Lota HK, et al. (2013). Novel use of rituximab in hypersensitivity pneumonitis refractory to conventional treatment. Thorax, 68, 780–​1. May JJ, et al. (1986). Organic dust toxicity associated with silo un- loading. Thorax, 41, 919–​23. McSharry C, et al. (2000). A review of antigen diversity causing lung disease among pigeon breeders. Clin Expt Allergy, 30, 1221–​9. McSharry C, et al. (2002). Takes your breath away—​the immunology of allergic alveolitis. Clin Expt Immunol, 128, 3–​9. Miyazaki Y, et al. (2008). Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest, 134, 1265–​70. Morell F, et al. (2013). Chronic hypersensitivity pneumonitis in pa- tients diagnosed with idiopathic pulmonary fibrosis: a prospective case-​cohort study. Lancet Respir Med, 9, 685–​94. Ohtani Y, et al. (2005). Chronic bird fancier’s lung: histopathological and clinical correlation. Thorax, 60, 665–​71. Okamoto T, et  al. (2013). Nationwide epidemiological survey of chronic hypersensitivity pneumonitis in Japan. Respir Investig, 51, 191–​9. Perez E, et al. (2013). Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneu- monitis. Chest, 144, 1644–​51. Schuyler MR, et al. (1983). Pulmonary responses to repeated exposure to Microployspora faeni. Am Rev Respir Dis, 128, 1071–​6. Selman M, et  al. (2006). Gene expression profiles distinguish idio- pathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med, 173, 188–​98. Selman M, et al. (2010). Hypersensitivity pneumonitis caused by fungi. Proc Am Thorac Soc, 7, 229–​36. Solaymani-​Dodaran M, et  al. (2007). Extrinsic allergic alveol- itis: incidence and mortality in the general population. Q J Med, 100, 233–​7. Vasakova M, et al. (2017). Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am J Respir Crit Care Med, 196, 680–9. 18.14.5  Pulmonary Langerhans’ cell histiocytosis S. J. Bourke ESSENTIALS Pulmonary Langerhans’ cell histiocytosis is characterized by a re- active monoclonal proliferation of activated histiocytes in the distal bronchioles. It presents with cough, breathlessness and (some- times) systemic symptoms. Chest radiography and CT typically show nodules which then cavitate and may rupture, causing pneumo- thorax. Corticosteroids and/​or cytotoxic drugs are of some benefit, and lung transplantation is an option for progressive disease. Introduction Pulmonary Langerhans’ cell histiocytosis (LCH) is a rare disease characterized by a reactive monoclonal proliferation of activated his- tiocytes in the distal bronchioles, resulting in inflammatory nodules, cyst formation, and fibrosis. Langerhans’ cells are a particular type of histiocyte derived from dendritic cells in the bone marrow. They normally migrate in the blood to the squamous epithelium of the skin, lungs, gastrointestinal, and female genital tract, where they are involved in antigen presentation to T cells. Abnormal proliferation of histiocytes is also the pathological basis for acute disseminated LCH (Letterer–​Siwe disease) and multifocal LCH (Hand–​Schüller–​ Christian disease)—​disorders which produce a spectrum of distinct clinical feature (see Chapter 22.3.9). Epidemiology and aetiology LCH affects about one in 560 000 adults, with an equal male to fe- male ratio and a peak age of onset between 20 and 40 years. There is a strong association with smoking, with more than 90% of patients having smoked tobacco. Patients with pulmonary LCH have ab- normal T-​cell proliferative responses to tobacco glycoproteins and an increased secretion of bombesin-​like peptides from neuroendo- crine cells in the lung. Recently mutations in the mitogen-activated protein kinase pathway (such as the BRAF V600 mutation) have been identified in about half of tissue samples of LCH. Clinical features Cough and breathlessness are the most common symptoms, and about one-​third of patients have systemic symptoms such as fever or weight loss. Pneumothorax occurs in about 25% of patients and may be re- current and sometimes bilateral. About 25% of patients have no symp- toms and the diagnosis is made incidentally from a chest radiograph. In adult pulmonary LCH the clinical manifestations are usually confined to the lungs, but in 10–​15% of cases lesions are also present in bone, skin, lymph nodes, and the posterior pituitary (sometimes causing diabetes insipidus).

18.14.6 Lymphangioleiomyomatosis 4257 S.J. Bourke

18.14.6 Lymphangioleiomyomatosis 4257 S.J. Bourke

18.14.6  Lymphangioleiomyomatosis 4257 Investigation and diagnosis The chest radiograph typically shows nodules, reticulation, and cysts in the mid and upper zones symmetrically, with sparing of the costophrenic angles; the lung volumes are often normal or increased, in contrast with many other fibrotic lung diseases. High-​resolution CT (Fig. 18.14.5.1) characteristically shows multiple centrilobular nodules with cavitation, progressing to cyst formation and fibrosis in later stage disease. Pulmonary function tests often show a mixture of airways ob- struction, air trapping with elevated residual volume, and impaired diffusing capacity for carbon monoxide. Typical clinical and CT features may be sufficient for diagnosis, but video-​assisted thoracoscopic lung biopsy is sometimes required. The characteristic histopathological features are mitotically active Langerhans’ cells forming nodules and granulomas with a sur- rounding inflammatory cell infiltrate of lymphocytes, macrophages, and eosinophils (hence the previous diagnostic labels of eosinophilic granuloma and Langerhans’ cell granulomatosis). Langerhans’ cells are identified by immunostaining of the CD1a membrane antigens or the S100 intracellular protein, and by electron microscopy showing Birbeck granules—​rods of tennis racket-​shaped structures unfolding from the cell membrane. In advanced disease, fibrosis and honeycombing predominate. Biopsies often show features of other smoking-​related diseases such as desquamative interstitial pneu- monia, obstructive bronchiolitis, and emphysema. Langerhans’ cells can also be identified in bronchoalveolar lavage fluid, but this is nei- ther sensitive nor specific in diagnosing the disease. Management Because pulmonary LCH varies greatly in its clinical course, man- agement has to be individualized for the particular patient. Smoking cessation is crucial. About 25% of cases resolve, 50% stabilize, and 25% progress with loss of lung function. Corticosteroid therapy is usually given for progressive disease, but the benefits are unclear. Cytotoxic drugs such as vinblastine, cyclophosphamide, and cladri­ bine show benefit in some reported cases. Treatment with inhibitors of mutated BRAF has resulted in stabilization or improvement in some patients. Pleurodesis or pleurectomy may be needed for recurrent pneumothoraces and, in view of the risk of bilateral pneumothorax, is best considered sooner rather than later. Lung transplantation is the main option for patients with advanced disease, although recurrence in the transplanted lungs has been described. FURTHER READING Caminati A, Harari S (2006). Smoking-​related interstitial pneumonias and pulmonary Langerhans’ cell histiocytosis. Proc Am Thorac Soc, 3, 299–​306. Gaelle D, et al. (2006). Lung transplantation for pulmonary Langerhans’ cell histiocytosis: a multicentre analysis. Transplantation, 81, 746–​50. Hyman D, et al. (2015). Vemurafenib in multiple nonmelanoma can- cers with BRAF V600 mutations. N Engl J Med, 373, 726–36. Lorillon G, et  al. (2012). Cladribine is effective against cystic pul- monary Langerhans’ cell histiocytosis. Am J Respir Crit Care Med, 186, 930–​2. Tazi A, et al. (2012). Serial computed tomography and lung function testing in pulmonary Langerhans’ cell histiocytosis. Eur Respir J, 40, 905–​12. Vassallo R, Harari S, Tazi A (2017). Current understanding and manage- ment of pulmonary Langerhans cell histiocytosis. Thorax, 72, 937–45. Websites Histiocytosis Association of America. http://​www.histio.org Histiocytosis Research Trust (UK). http://​www.hrtrust.org/​web/​guest/​ about 18.14.6  Lymphangioleiomyomatosis S. J. Bourke ESSENTIALS Lymphangioleiomyomatosis is characterized by cystic destruc- tion of the lungs due to abnormal proliferation of smooth muscle cells. It is caused by mutations of the genes encoding hamartin and tuberin, sometimes in association with tuberous sclerosis. CT imaging shows characteristic multiple thin-​walled cysts. There is usually progressive airways obstruction and impaired gas diffusion, and two-​thirds of patients suffer pneumothoraces. Sirolimus can stabilize lung function and improve symptoms. Lung transplant- ation is the main option for advanced disease. Introduction Lymphangioleiomyomatosis (LAM) is a rare disease in which lymphatics (‘lymph’), blood vessels (‘angio’), and airways are infil- trated by proliferating abnormal smooth muscle cells (‘leiomyo’), Fig. 18.14.5.1  High-​resolution CT of a 45-​year-​old smoking man with biopsy-​proven Langerhans’ cell histiocytosis, showing centrilobular nodules, cysts, and reticulation.

section 18  Respiratory disorders 4258 resulting in cystic destruction of the lungs, pneumothoraces, chylous effusions, and haemorrhage. LAM cells have low-​grade neoplastic properties with enhanced proliferation and invasiveness. LAM can occur as a sporadic disorder or in association with tu- berous sclerosis. Pathogenesis Both sporadic and tuberous sclerosis-​associated LAM result from mutations of the tumour suppressor genes TSC1 and TSC2, which encode hamartin and tuberin that form a cytoplasmic com- plex that inhibits the protein mTOR. Loss of suppressor function upregulates mTOR, resulting in proliferation of LAM cells. Sporadic LAM occurs exclusively in women, predominantly between the menarche and the menopause. Exceptionally rare cases of LAM have been reported in men with tuberous scler- osis, but the disease is almost confined to women. The origin of LAM cells is unknown but they might arise from the uterus, and oestrogen and progesterone receptors have been found in some LAM cells. Sporadic LAM is due to somatic (noninherited) mutations in the TSC1 and TSC2 genes and occurs in about 2 in a million women. Tuberous sclerosis results from a germ-​line mutation of the TSC1 and TSC2 genes and is an autosomal dominant inherited dis- order (OMIM 191 100) whose manifestations include epilepsy, learning difficulties, skin lesions (angiofibromas, shagreen patches), and hamartomas in the brain, kidneys, and other organs (see Chapter 24.17). Most women with tuberous sclerosis ultimately de- velop evidence of LAM on CT as they get older, with 63% developing symptoms and 12.5% dying of LAM. Clinical features and diagnosis Pneumothorax occurs in about two-​thirds of patients with LAM and is a common mode of presentation. Other manifestations include breathlessness from progressive parenchymal involvement, cough, haemoptysis, and chest pain. Involvement of the thoracic duct may result in chylous pleural effusions and ascites. Other ab- dominal features include renal angiomyolipomas, cystic lymphatic masses, and lymphadenopathy. Renal angiomyolipomas are present in about 50% of patients: they rarely cause symptoms, but bleeding may require treatment by embolization or surgical resection. The chest radiograph typically shows diffuse small cysts with re- ticular shadowing, but normal or increased lung volumes. Lung function tests usually show progressive airways obstruction and reduced gas transfer. The CT features are sufficiently character- istic to establish the diagnosis in many cases, with well-​defined cystic airspaces with thin walls distributed throughout both lungs (Fig. 18.14.6.1), and more widespread use of CT imaging is detecting milder cases in an extended spectrum of patients including some postmenopausal women. Lung biopsy may be needed where there is doubt about the diag- nosis: this shows abnormal infiltration by smooth muscle cells, which can be identified by immunohistochemical staining for the HMB45 (human melanoma black) antigen. Aspirated pleural fluid may show diagnostic clusters of immature muscle cells. The serum levels of vascular endothelial growth factor, VEGF-​D, are elevated, and this may be a useful biomarker of the disease. Management and prognosis Sirolimus inhibits the protein mTOR and has been shown to sta- bilize lung function, reduce symptoms, and improve quality of life and functional performance, such that it is now the recommended treatment for patients with progressive disease. Treatment has to be continued indefinitely, with the risk of adverse effects, and there is some evidence that low-​dose therapy may sufficient. Patients should avoid exogenous oestrogens, including oestrogen contraceptives or hormonal replacement therapy. Pregnancy may be associated with an increased risk of pneumothorax and loss of lung function. Hormonal therapy with progesterone or tamoxifen appears to be ineffective; other antioestrogen therapies, such as letrozole, are being studied. Recent research shows that human LAM lungs express the immune checkpoint ligand PD-L1 and that treatment of a mouse LAM model with anti-PD-1 antibody improved survival. Pneumothorax is common and likely to recur such that med- ical or surgical pleurodesis is advisable. Lung transplantation is the main option for patients with advanced LAM, but recurrence of the disease due to migration of LAM cells to the donor lung has been reported. The clinical course of LAM is variable, but by 10 years after diag- nosis, 55% of patients are breathless on daily activities, 20% require supplemental oxygen, and 10% have died. Fig. 18.14.6.1  CT scan of a 37-​year-​old woman with pulmonary lymphangioleiomyomatosis and tuberous sclerosis. She had experienced sequential spontaneous pneumothoraces affecting each side. The scan shows multiple thin-​walled cysts throughout the lung.

18.14.7 Pulmonary alveolar proteinosis 4259 S.J. B

18.14.7 Pulmonary alveolar proteinosis 4259 S.J. Bourke

18.14.7  Pulmonary alveolar proteinosis 4259 FURTHER READING Cottin V (2014). Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases. Eur Respir J, 43, 966–​9. Cudzilo CJ, et  al. (2013). Lymphangioleiomyomatosis screening in women with tuberous sclerosis. Chest, 144, 578–​85. Gupta N, et al. (2015). Diffuse cystic lung disease. Am J Respir Crit Care Med, 191, 1354–​66. Gupta N, et al. (2019). The NHLBI LAM Registry. Prognostic, physio- logic and radiologic biomarkers emerge from a 15-year prospective longitudinal analysis. Chest, 155, 288–96. Johnson SR, et al. (2010). European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J, 35, 14–​26. Karbowniczek M, et  al. (2003). Recurrent lymphangiomyomatosis after transplantation. Am J Respir Crit Care Med, 167, 976–​82. Maisel K, et al. (2018). Immune checkpoint ligand PD-L1 is upregulated in pulmonary lymphangioleiomyomatosis. Am J Respir Cell Mol Biol, 59, 723–32. McCormack FX, et  al. (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med, 364, 1595–​606. Taveira-​DaSilva A, et al. (2015). Severity and outcome of cystic lung dis- ease in women with tuberous sclerosis complex. Eur Resp J, 45, 171–​80. Yao J, et al. (2014). Sustained effects of sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis. Am J Respir Crit Care Med, 190, 1273–​82. 18.14.7  Pulmonary alveolar proteinosis S. J. Bourke ESSENTIALS In 90% of cases pulmonary alveolar proteinosis is caused by auto- immune antibodies to GM-​CSF which impair the function of al- veolar macrophages in clearing surfactant from the alveoli, giving rise to impaired gas exchange, breathlessness, and respiratory failure. Chest radiography shows extensive alveolar shadowing simulating pulmonary oedema, and CT scanning shows a characteristic ‘crazy paving’ pattern. The presence of GM-​CSF antibodies in the serum is useful in diagnosis. Bronchoalveolar lavage or lung biopsy demon- strates alveolar secretions that are strongly PAS-​positive. Treatment is by physical removal of the lipoproteinaceous material from the alveoli by whole-​lung lavage. Massive inhalation of dust and fumes may overwhelm macrophage function, giving rise to secondary pulmonary alveolar proteinosis. Introduction Pulmonary alveolar proteinosis was first described by Rosen et al.
in 1958. It is a rare disease, characterized by the accumulation of surfactant lipids and proteins in the alveoli, giving rise to impaired gas exchange, breathlessness, and respiratory failure. Detailed registry studies in Japan showed an incidence of 0.5 per million and a preva- lence of 6.2 per million, with a median age of onset of 51 years and a male:female ratio of 2:1, but the disease seems to be less common in other countries. Whole-​lung lavage is effective in removing the lipoproteinaceous material from the alveoli. Aetiology and pathogenesis Surfactant is secreted by type 2 pneumocytes in the alveolar wall. It is a lipoproteinaceous material consisting of the phospholipid dipalmitoyl phosphatidylcholine which has an important role in reducing the surface tension of the alveoli, maintaining patency and preventing collapse. In pulmonary alveolar proteinosis there is defective clearance of surfactant, and this may arise by different mechanisms such that the disease is classified into three distinct forms: autoimmune, secondary, and hereditary. Autoimmune Autoimmune pulmonary alveolar proteinosis is the commonest form of the disease, accounting for 90% of cases. It is due to the development of systemic neutralizing antibodies to granulocyte macrophage-​colony stimulating factor (GM-​CSF). The mechan- isms giving rise to GM-​CSF autoantibodies are unclear, and these patients do not usually have any other autoimmune diseases. The alveolar macrophage has an essential role in clearing surfactant, and in the presence of GM-​CSF antibodies their function is impaired, clearance of surfactant is reduced, and the alveoli become filled with this lipoproteinaceous material. Inflammation and/​or fibrosis are not usually found, and alveolar architecture is well preserved. Secondary infection can, however, give rise to additional problems. Secondary Secondary pulmonary alveolar proteinosis accounts for about 9% of cases and arises as a complication of other diseases. Acute inhal- ation of dust and fumes may cause the condition, presumably by overwhelming macrophage function, much as silica is known to impair macrophage handling of tubercle bacilli. This has been best described in acute silicosis (silicoproteinosis), which arises within months of massive exposure to respirable crystalline silica. It has also occurred after inhalation of aluminium, titanium, insecticides, or petrol fumes. Secondary pulmonary alveolar proteinosis may also occur as a complication of haematological disorders such as myelodysplasia, leukaemia, or lymphoma, and may also occur in association with im- munodeficiency states and chronic infections such as histoplasmosis, Pneumocystis jirovecii, and mycobacterial infections. The mechanisms underlying pulmonary alveolar proteinosis in these disorders are un- clear, but are thought to involve a reduction in the number or function of alveolar macrophages. These patients do not have GM-​CSF antibodies. Hereditary Hereditary pulmonary alveolar proteinosis is a very rare form of the disease caused by mutations of the genes involved in GM-​CSF signalling, particularly mutations in the CSF2RA and CSF2RB genes encoding for the GM-​CSF receptor α- and β-chains. It presents as pro- gressive breathlessness in young children. These patients do not have GM-​CSF autoantibodies, but have increased serum GM-​CSF levels which can be a useful pointer in identifying the diagnosis.

section 18  Respiratory disorders 4260 Clinical features and diagnosis The clinical features depend on the stage and context of the disease. Typically the patient presents with progressive shortness of breath. Cough is common but is usually nonproductive. Some patients are seen at a time when they have developed a superadded infection, when they may then present with acute symptoms of fever, cough, and breathlessness, but they may well have had more prolonged insidious symptoms. Some patients are found to have extensive shadowing on an incidental chest radiograph before they have no- ticed symptoms. Physical examination is often normal despite extensive alveolar shadowing on the radiograph, but crackles may be present and some patients have clubbing. In advanced disease patients develop severe breathlessness, cyanosis, and respiratory failure. Investigation The predominant abnormality in pulmonary function tests is a re- strictive ventilatory defect with a reduction in lung volumes and gas diffusion. As the disease progresses the patients become hypoxic, initially on exercise and then even at rest. The chest radiograph typically shows an extensive bilateral alveolar filling pattern, which often initially suggests pulmonary oedema or pneumonia. CT scanning shows a very characteristic pattern of widespread air space consolidation with thickened interlobular septa, producing a so-​called ‘crazy paving’ pattern (Fig. 18.14.7.1). Some other conditions can give a similar appearance, including lipoid pneumonia, diffuse lepidic adenocarcinoma (bronchoalveolar cell carcinoma) and pneumocystis pneumonia. Bronchoalveolar lavage characteristically yields ‘milky fluid’ which consists of lipoproteinaceous material that stains a deep pink with periodic acid Schiff (PAS) stains. The material is negative on alcan blue stain, which differentiates it from mucins. There is a not- able absence of inflammatory cells, but the macrophages are en- larged and contain abundant phospholipoprotein inclusions giving the appearance of ‘foamy macrophages’. Lung biopsy is not often necessary, but pathological findings confirm a similar appearance to bronchoalveolar lavage fluid (Fig. 18.14.7.2). The alveolar architecture is usually well preserved, although there is septal thickening from oedema. Electron micros- copy shows lamellar bodies within the alveolar lumen representing phospholipids. In autoimmune pulmonary alveolar proteinosis the demonstra- tion of serum GM-​CSF autoantibodies is both sensitive and specific in the diagnosis. These are not found in patients with secondary causes of pulmonary alveolar proteinosis, and it is important to obtain a detailed occupational and environmental history to assess for any inhalation of dust or fumes, and to identify any associated haematological conditions. In the very rare form of hereditary pul- monary alveolar proteinosis in children, GM-​CSF antibodies are also absent, but these children often have high serum GM-​CSF levels which may be a useful pointer to the diagnosis. Bronchoalveolar lavage is also useful in identifying any infections which may complicate pulmonary alveolar proteinosis. Because of impaired macrophage function these patients are vulnerable to opportunistic infections with nocardia, cryptococcus, cytomegalo- virus, histoplasmosis, and mycobacteria. Management and prognosis Whole-​lung lavage The standard treatment of pulmonary alveolar proteinosis is whole-​lung lavage, which is effective in physically removing the lipoproteinaceous material from the alveoli, thereby restoring gas Fig. 18.14.7.1  Computed tomography of a patient with pulmonary alveolar proteinosis, showing diffuse alveolar filling with septal thickening from oedema, giving a ‘crazy pavement’ pattern. Fig. 18.14.7.2  Pulmonary alveolar proteinosis arising acutely following massive exposure to silica. Some alveoli are filled with a noninflammatory proteinaceous exudate, characteristic of pulmonary alveolar proteinosis. The lung interstitium shows fibrosis and inflammation, which can be attributed to acute silicosis (haematoxylin and eosin, medium magnification). Courtesy of Dr D. E. Banks.

18.14.8  Pulmonary amyloidosis 4261 exchange, improving macrophage function and reducing the occur- rence of secondary infections. This is a complex procedure, best per- formed in specialist centres with experience in the technique. Under general anaesthesia patients are intubated with a double-​lumen endotracheal tube. The appropriate placement of the tube with iso- lation of each lung is crucial. Ventilation is then given to one lung while the other lung is lavaged with warmed normal (0.9%) saline, in aliquots of 250–​500 ml, with total volumes of up to 60 litres. Effective removal of the lipoproteinaceous material may be enhanced by pos- itional changes, assisted clearance and percussion physiotherapy during the procedure. The fluid removed is initially milky but clears as the procedure progresses. The procedure is then reversed so that the other lung is treated. Most patients show substantial clinical improvement after whole-​ lung lavage, with immediate improvement in oxygenation. Lung function tests show that the vital capacity improves within one week and continues to improve over the subsequent year. The transfer factor for carbon monoxide tends to improve more slowly, with no increase at one week but substantial improvement over the next six months. The longer-​term outcome after whole-​lung lavage is vari- able: about 50% of patients go into prolonged remission after one lavage, but some need repeat lavage as the lipoproteinaceous ma- terial reaccumulates. GM-​CSF Autoimmune pulmonary alveolar proteinosis may also be treated by GM-​CSF, which can be administered subcutaneously or by aerosol. A meta-​analysis of GM-​CSF treatment showed a response rate of about 60%, varying between 40 and 90% in different studies, with a relapse rate of about 30%. GM-​CSF therapy is associated with minor systemic complications such as fever, and local complications at the site of injection. The optimal indication, dose and duration of therapy, and the sfactors predicting response and relapse, all need further clarification, but this treatment may be particularly useful in those with a poor response to whole-​lung lavage or in those requiring repeated lavages. Other treatments Plasmapheresis has been used to reduce levels of GM-​CSF autoanti- bodies, but this did not result in clinical improvement in the severity of the lung disease. Rituximab, a monoclonal antibody directed against the B-​lymphocyte antigen CD20, has also been used, and resulted in a reduction in GM-​CSF antibody levels and improve- ment in some patients, but whole-​lung lavage remains the standard treatment. Recurrence of alveolar proteinosis has been reported in a patient who underwent lung transplantation for this condition. Secondary infections can occur and need to be promptly identified and treated. The occurrence of infection is reduced by effective whole-​lung lavage, which restores macrophage function. Prognosis Seymour and Presneill reviewed 343 published cases and found survival rates of 79% (2 years), 75% (5 years), and 68% (10 years). Of the 69 deaths, 60 were attributed to pulmonary alveolar proteinosis—​47 (72%) from respiratory failure, 12 (18%) from complicating infection, and one (2%) from cardiac arrest during lavage. The actuarial 5-​year disease-​specific survival was 88%. Of those dying within 5 years, more than 80% did so during the first year after diagnosis: thereafter there was a significantly reduced risk of mortality. FURTHER READING Bonella F, Theegarten D, Guzman J, Costabel U (2011). Alveolar lipoproteinosis syndromes. Eur Respir Mon, 54, 171–​86. Borie R, et al. (2011). Pulmonary alveolar proteinosis. Eur Respir Rev, 20, 98–​107. Inoue Y et al. (2008). Characteristics of a large cohort of patients with autoimmune pulmonary alveolar proteinosis in Japan. Am J Respir Crit Care Med, 177, 752–​62. Ishii H, et  al. (2011). Clinical features of secondary pulmonary
alveolar proteinosis: pre-​mortem cases in Japan. Eur Respir J, 37,
465–​8. Kavuru MS, et al. (2011). An open-​label trial of rituximab therapy in pulmonary alveolar proteinosis. Eur Respir J, 38, 1361–​7. Khan A, Agarwal R, Aggarwal AN (2012). Effectiveness of granulocyte-​ macrophage colony stimulating factor therapy in autoimmune pul- monary alveolar proteinosis. Chest, 141, 1273–​83. Kumar A, Abdelmalal B, Inoue Y, Culver DA (2018). Lancet Respir Med, 6, 554–65. Luisetti M, et al. (2009). Plasmapheresis for treatment of pulmonary alveolar proteinosis. Eur Respir J, 33, 1220–​2. Rosen SH, et al. (1958). Pulmonary alveolar proteinosis. N Engl J Med, 258, 1123–​42. Suzuki T, et al. (2010). Hereditary pulmonary alveolar proteinosis. Am J Respir Crit Care Med, 182, 1292–​304. Tazawa R, et  al. (2014). Duration of benefit in patients with auto- immune pulmonary alveolar proteinosis after inhaled GM-​CSF therapy. Chest, 145, 729–​37. Trapnell BC, et al. (2019). Pulmonary alveolar proteinosis. Nat Rev Dis Primers, 5(1), 16. doi: 10.1038/s41572-019-0066-3. 18.14.8  Pulmonary amyloidosis S. J. Bourke ESSENTIALS Pulmonary amyloidosis is characterized by the deposition of mono- clonal immunoglobulin light chain amyloid protein locally or dif- fusely in lung tissue. Local amyloid deposits in the airways, produced by B-​cell clones within local tissues, may cause stridor, wheeze, cough, and haemoptysis. Diffuse alveolar deposition can occur as a complication of systemic amyloidosis when the AL protein is de- rived from immunoglobulins produced from bone marrow B cells in diseases such as multiple myeloma, lymphoma, and monoclonal gammopathy.

section 18  Respiratory disorders 4262 Introduction Amyloidosis is a diverse disease characterized by the deposition of amyloid proteins in extracellular tissues (see Chapter 12.12.3). The aetiology and manifestations vary depending on the different pre- cursor amyloid protein and whether deposition is local or systemic. Several different amyloid proteins have been described, but the two main types relevant to lung disease are reactive systemic (AA) amyloidosis, in which the amyloid protein is derived from the acute phase protein serum amyloid A, and monoclonal immunoglobulin light chain (AL) amyloidosis, in which the amyloid protein is derived from monoclonal immunoglobulin light chains. In amyloidosis these proteins are deposited in extracellular tissue in an abnormal fibrillar form as aggregates of misfolded protein with an abnormal β-​sheet conformation that is insoluble and resistant to proteolysis. Amyloid deposits are demonstrated in biopsies of affected tissues by Congo red dye producing green birefringence when viewed in po- larized light. The protein type can be identified by immunostaining or proteomic analysis. Amyloid deposits also contain some normal nonfibrillar plasma glycoprotein, serum amyloid P (SAP), and radiolabelled SAP scintigraphic imaging is available in some spe- cialist centres and is useful in defining the extent and burden of dis- ease in patients. AA systemic amyloidosis This form of amyloidosis does not cause pulmonary disease al- though amyloid may be present in the pulmonary vessels at post-​ mortem examination. In a large series of 374 patients with systemic AA amyloidosis, Lachmann et al. found that bronchiectasis was the underlying cause in 5%, and tuberculosis in 1% of patients, but in no case did AA amyloidosis cause clinically significant lung disease. Treatment is aimed at controlling the underlying inflammatory dis- ease to reduce the overproduction of serum amyloid proteins. AL amyloidosis In systemic AL amyloidosis the lungs show evidence of amyloid deposition in about 50% of patients, but only rarely does this give rise to symptoms. However, diffuse alveolar–​interstitial deposition causes progressive impairment of gas diffusion in some cases. In local AL amyloidosis, isolated nodules of amyloid are deposited in the larynx, trachea, bronchial tree, or lung parenchyma. These nodules arise from B-​cell clonal expansion in the tissues close to the amyloid deposits, such that the disease is localized without systemic involvement. The factors provoking local B-​cell clonal expansion and local amyloid nodules are not understood. Clinical features The clinical features of pulmonary amyloidosis are diverse and de- pend on the location and pattern of amyloid deposits. Localized laryngotracheobronchial disease Amyloid deposits may produce nodules or more extensive plaques in the walls of the airways or the peribronchial tissues. In laryngeal amyloidosis the key features are hoarseness, stridor, and cough. In the bronchial tree symptoms depend on the anatomical location, but amyloid deposits may cause cough, obstruction, and haemoptysis. Obstruction of airways may lead to atelectasis of a lobe or segment with distal infection. Central lesions may pose particular difficulty for intubation and the administration of anaesthesia. When a single lesion is involved it may simulate the effects of a bronchial adenoma, appearing as a polypoid mass on endoscopic inspection. CT scans and bronchoscopy give anatomical definition of the disease, but bi- opsy is necessary to demonstrate amyloid. Localized parenchymal nodules Discrete nodules or masses, which may be single or multiple, are seen within the lung parenchyma on the chest radiograph and CT. They rarely cause symptoms or disrupt lung function and may eventually calcify, cavitate, or even ossify. They are likely to simu- late bronchial neoplasms if single and hence biopsy and surgical resection are often performed. Caution in conducting a biopsy on lesions is required because amyloid deposits may disrupt blood ves- sels, preventing vasoconstriction and contributing to an increased risk of bleeding. Diffuse alveolar–​interstitial disease Amyloid deposited diffusely throughout the alveolar walls and interstitium of the lung is a rare manifestation of AL amyloidosis (Figs. 18.14.8.1 and 18.14.8.2). Here the lung disease is part of more widespread systemic amyloidosis and these patients often also have cardiac and renal amyloidosis. There have been a few reports of AA amyloid affecting the lungs, but the fibril type may have been misidentified and all studies in which the fibril protein has been sequenced show AL type amyloid. Systemic symptoms of tiredness, malaise, and weight loss are common. There is progressive breathlessness and a dry cough, with prominent crackles on examination. Lung function testing shows impairment of gas diffusion and restriction of lung volumes. The prognosis is poor, with progressive hypoxia and respiratory failure, although death more commonly results from cardiac or renal involvement. Fig. 18.14.8.1  Alveolar–​interstitial-​type amyloidosis of the lung. Staining with haematoxylin and eosin (medium magnification) reveals interstitial deposits of hyaline eosinophilic material with a foreign body type giant cell response in adjacent tissue. This is an almost unique feature of amyloidosis affecting the lung. By courtesy of Dr T. Ashcroft.

18.14.8 Pulmonary amyloidosis 4261 S.J. Bourke

18.14.8 Pulmonary amyloidosis 4261 S.J. Bourke

Contents xxvi 18.11 Diffuse parenchymal lung diseases  4166

18.11.1 Diffuse parenchymal lung disease: An introduction  4166 F. Teo and A.U. Wells

18.11.2 Idiopathic pulmonary fibrosis  4177 P.L. Molyneaux, A.G. Nicholson, N. Hirani, and A.U. Wells

18.11.3 Bronchiolitis obliterans and cryptogenic
organizing pneumonia  4185 Vasilis Kouranos and A.U. Wells

18.11.4 The lung in autoimmune rheumatic disorders  4191 M.A. Kokosi and A.U. Wells

18.11.5 The lung in vasculitis  4200 G.A. Margaritopoulos and A.U. Wells 18.12 Sarcoidosis  4208 Robert P. Baughman and Elyse E. Lower 18.13 Pneumoconioses  4219 P.T. Reid 18.14 Miscellaneous conditions  4235

18.14.1 Diffuse alveolar haemorrhage  4235 S.J. Bourke and G.P. Spickett

18.14.2 Eosinophilic pneumonia  4238 S.J. Bourke and G.P. Spickett

18.14.3 Lymphocytic infiltrations of the
lung  4241 S.J. Bourke

18.14.4 Hypersensitivity pneumonitis  4244 S.J. Bourke and G.P. Spickett

18.14.5 Pulmonary Langerhans’ cell
histiocytosis  4256 S.J. Bourke

18.14.6 Lymphangioleiomyomatosis  4257 S.J. Bourke

18.14.7 Pulmonary alveolar proteinosis  4259 S.J. Bourke

18.14.8 Pulmonary amyloidosis  4261 S.J. Bourke

18.14.9 Lipoid (lipid) pneumonia  4263 S.J. Bourke

18.14.10 Pulmonary alveolar microlithiasis  4265 S.J. Bourke

18.14.11 Toxic gases and aerosols  4267 Chris Stenton

18.14.12 Radiation pneumonitis  4271 S.J. Bourke

18.14.13 Drug-​induced lung disease  4272 S.J. Bourke 18.15 Chronic respiratory failure  4282 Michael I. Polkey and P.M.A. Calverley 18.16 Lung transplantation  4292 P. Hopkins and A.J. Fisher 18.17 Pleural diseases  4305 D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell 18.18 Disorders of the thoracic cage and diaphragm  4328 John M. Shneerson and Michael I. Polkey 18.19 Malignant diseases  4338

18.19.1 Lung cancer  4338 S.G. Spiro and N. Navani

18.19.2 Pulmonary metastases  4360 S.G. Spiro

18.19.3 Pleural tumours  4361 Y.C. Gary Lee

18.19.4 Mediastinal tumours and cysts  4368 Y.C. Gary Lee and Helen E. Davies SECTION 19 Rheumatological disorders Section editor: Richard A. Watts 19.1 Joints and connective tissue—​structure and function  4379 Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann, and Jessica Bertrand 19.2 Clinical presentation and diagnosis of rheumatological disorders  4386 Christopher Deighton and Fiona Pearce 19.3 Clinical investigation  4395 Michael Doherty and Peter C. Lanyon 19.4 Back pain and regional disorders  4406 Carlo Ammendolia and Danielle Southerst 19.5 Rheumatoid arthritis  4415 Kenneth F. Baker and John D. Isaacs 19.6 Spondyloarthritis and related conditions  4441 Jürgen Braun and Joachim Sieper 19.7 Infection and arthritis  4457 Graham Raftery and Muddassir Shaikh 19.8 Reactive arthritis  4464 Carmel B. Stober and Hill Gaston 19.9 Osteoarthritis  4470 Andrew J. Barr and Philip G. Conaghan

Contents xxvii 19.10 Crystal-​related arthropathies  4482 Edward Roddy and Michael Doherty 19.11 Autoimmune rheumatic disorders and vasculitides  4495

19.11.1 Introduction  4495 David A. Isenberg and Ian Giles

19.11.2 Systemic lupus erythematosus and related disorders  4499 Anisur Rahman and David A. Isenberg

19.11.3 Systemic sclerosis (scleroderma)  4513 Christopher P. Denton and Carol M. Black

19.11.4 Sjögren’s syndrome  4532 Wan-​Fai Ng

19.11.5 Inflammatory myopathies  4537 Ingrid E. Lundberg, Hector Chinoy, and
Robert Cooper

19.11.6 Large vessel vasculitis  4546 Raashid Luqmani and Cristina Ponte

19.11.7 ANCA-​associated vasculitis  4556 David Jayne

19.11.8 Polyarteritis nodosa  4569 Loïc Guillevin

19.11.9 Small vessel vasculitis  4573 Richard A. Watts

19.11.10 Behçet’s syndrome  4579 Sebahattin Yurdakul, Izzet Fresko, and
Hasan Yazici

19.11.11 Polymyalgia rheumatica  4584 Bhaskar Dasgupta and Eric L. Matteson

19.11.12 Kawasaki disease  4590 Brian W. McCrindle 19.12 Miscellaneous conditions presenting to the rheumatologist  4598 Stuart Carter, Lisa Dunkley, and Ade Adebajo SECTION 20 Disorders of the skeleton Section editor: Cyrus Cooper 20.1 Skeletal disorders—​general approach and clinical conditions  4615 B. Paul Wordsworth and M.K. Javaid 20.2 Inherited defects of connective tissue:
Ehlers–​Danlos syndrome, Marfan’s syndrome, and pseudoxanthoma elasticum  4670 N.P. Burrows 20.3 Osteomyelitis  4688 Martin A. McNally and Anthony R. Berendt 20.4 Osteoporosis  4696 Nicholas C. Harvey, Juliet Compston, and Cyrus Cooper 20.5 Osteonecrosis, osteochondrosis, and osteochondritis dissecans  4703 Gavin Clunie 20.6 Bone cancer  4709 Helen Hatcher SECTION 21 Disorders of the kidney and
urinary tract Section editor: John D. Firth 21.1 Structure and function of the kidney  4717 Steve Harper and Robert Unwin 21.2 Electrolyte disorders  4729

21.2.1 Disorders of water and sodium homeostasis  4729 Michael L. Moritz and Juan Carlos Ayus

21.2.2 Disorders of potassium homeostasis  4748 John D. Firth 21.3 Clinical presentation of renal disease  4764 Richard E. Fielding and Ken Farrington 21.4 Clinical investigation of renal disease  4781 Andrew Davenport 21.5 Acute kidney injury  4807 John D. Firth 21.6 Chronic kidney disease  4830 Alastair Hutchison 21.7 Renal replacement therapy  4861

21.7.1 Haemodialysis  4861 Robert Mactier

21.7.2 Peritoneal dialysis  4874 Simon Davies

21.7.3 Renal transplantation  4879 Nicholas Torpey and John D. Firth 21.8 Glomerular diseases  4909

21.8.1 Immunoglobulin A nephropathy and IgA
vasculitis (HSP)  4909 Jonathan Barratt and John Feehally

21.8.2 Thin membrane nephropathy  4918 Peter Topham and John Feehally

Contents xxviii

21.8.3 Minimal-​change nephropathy and focal segmental glomerulosclerosis  4919 Moin Saleem and Lisa Willcocks

21.8.4 Membranous nephropathy  4928 An S. De Vriese and Fernando C. Fervenza

21.8.5 Proliferative glomerulonephritis  4933 Alan D. Salama and Mark A. Little

21.8.6 Membranoproliferative glomerulonephritis  4937 Tabitha Turner-​Stokes and Mark A. Little

21.8.7 Antiglomerular basement membrane
disease  4943 Mårten Segelmark and Thomas Hellmark 21.9 Tubulointerstitial diseases  4951

21.9.1 Acute interstitial nephritis  4951 Simon D. Roger

21.9.2 Chronic tubulointerstitial nephritis  4956 Marc E. De Broe, Channa Yamasumana,
Patrick C. D’Haese, Monique M. Elseviers, and
Benjamin Vervaet 21.10 The kidney in systemic disease  4975

21.10.1 Diabetes mellitus and the kidney  4975 Rudolf Bilous

21.10.2 The kidney in systemic vasculitis  4988 David Jayne

21.10.3 The kidney in rheumatological
disorders  5001 Liz Lightstone and Hannah Beckwith

21.10.4 The kidney in sarcoidosis  5012 Ingeborg Hilderson and Jan Donck

21.10.5 Renal involvement in plasma cell dyscrasias, immunoglobulin-​based amyloidoses, and fibrillary glomerulopathies, lymphomas, and leukaemias  5016 Pierre Ronco, Frank Bridoux, and Arnaud Jaccard

21.10.6 Haemolytic uraemic syndrome  5027 Edwin K.S. Wong and David Kavanagh

21.10.7 Sickle cell disease and the kidney  5032 Claire C. Sharpe

21.10.8 Infection-​associated nephropathies  5034 A. Neil Turner

21.10.9 Malignancy-​associated renal disease  5041 A. Neil Turner

21.10.10 Atherosclerotic renovascular disease  5044 Philip A. Kalra and Diana Vassallo 21.11 Renal diseases in the tropics  5049 Vivekanand Jha 21.12 Renal involvement in genetic disease  5065 D. Joly and J.P. Grünfeld 21.13 Urinary tract infection  5074 Charles Tomson and Neil Sheerin 21.14 Disorders of renal calcium handling, urinary stones, and nephrocalcinosis  5093 Christopher Pugh, Elaine M. Worcester, Andrew P. Evan, and Fredric L. Coe 21.15 The renal tubular acidoses  5104 John A. Sayer and Fiona E. Karet 21.16 Disorders of tubular electrolyte handling  5112 Nine V.A.M. Knoers and Elena N. Levtchenko 21.17 Urinary tract obstruction  5124 Muhammad M. Yaqoob and Kieran McCafferty 21.18 Malignant diseases of the urinary tract  5136 Tim Eisen, Freddie C. Hamdy, and Robert A. Huddart 21.19 Drugs and the kidney  5150 Aine Burns and Caroline Ashley Index Volume 4 List of abbreviations  xxxv List of contributors  xlv SECTION 22 Haematological disorders Section editors: Chris Hatton and Deborah Hay 22.1 Introduction to haematology  5169 Chris Hatton 22.2 Haematopoiesis  5172

22.2.1 Cellular and molecular basis of haematopoiesis  5172 Paresh Vyas and N. Asger Jakobsen

22.2.2 Diagnostic techniques in the assessment of haematological malignancies  5181 Wendy N. Erber

Contents xxix 22.3 Myeloid disease  5189

22.3.1 Granulocytes in health and disease  5189 Joseph Sinning and Nancy Berliner

22.3.2 Myelodysplastic syndromes  5197 Charlotte K. Brierley and David P. Steensma

22.3.3 Acute myeloid leukaemia  5205 Nigel Russell and Alan Burnett

22.3.4 Chronic myeloid leukaemia  5213 Mhairi Copland and Tessa L. Holyoake†

22.3.5 The polycythaemias  5227 Daniel Aruch and Ronald Hoffman

22.3.6 Thrombocytosis and essential thrombocythaemia  5239 Daniel Aruch and Ronald Hoffman

22.3.7 Primary myelofibrosis  5247 Evan M. Braunstein and Jerry L. Spivak

22.3.8 Eosinophilia  5254 Peter F. Weller

22.3.9 Histiocytosis  5259 Chris Hatton 22.4 Lymphoid disease  5263

22.4.1 Introduction to lymphopoiesis  5263 Caron A. Jacobson and Nancy Berliner

22.4.2 Acute lymphoblastic leukaemia  5269 H. Josef Vormoor, Tobias F. Menne, and
Anthony V. Moorman

22.4.3 Hodgkin lymphoma  5280 Vijaya Raj Bhatt and James O. Armitage

22.4.4 Non-​Hodgkin lymphoma  5288 Vijaya Raj Bhatt and James O. Armitage

22.4.5 Chronic lymphocytic leukaemia  5302 Clive S. Zent and Aaron Polliack

22.4.6 Plasma cell myeloma and related monoclonal gammopathies  5310 S. Vincent Rajkumar and Robert A. Kyle 22.5 Bone marrow failure  5325

22.5.1 Inherited bone marrow failure syndromes  5325 Irene Roberts and Inderjeet S. Dokal

22.5.2 Acquired aplastic anaemia and pure red cell aplasia  5336 Judith C.W. Marsh, Shreyans Gandhi,
and Ghulam J. Mufti

22.5.3 Paroxysmal nocturnal haemoglobinuria  5348 Lucio Luzzatto 22.6 Erythroid disorders  5354

22.6.1 Erythropoiesis  5354 Vijay G. Sankaran

22.6.2 Anaemia: pathophysiology, classification, and clinical features  5359 David J. Weatherall† and Chris Hatton

22.6.3 Anaemia as a challenge to world health  5366 David J. Roberts and David J. Weatherall†

22.6.4 Iron metabolism and its disorders  5371 Timothy M. Cox and John B. Porter

22.6.5 Anaemia of inflammation  5402 Sant-​Rayn Pasricha and Hal Drakesmith

22.6.6 Megaloblastic anaemia and miscellaneous deficiency anaemias  5407 A.V. Hoffbrand

22.6.7 Disorders of the synthesis or function of haemoglobin  5426 Deborah Hay and David J. Weatherall†

22.6.8 Anaemias resulting from defective maturation
of red cells  5450 Stephen J. Fuller and James S. Wiley

22.6.9 Disorders of the red cell membrane  5456 Patrick G. Gallagher

22.6.10 Erythrocyte enzymopathies  5463 Alberto Zanella and Paola Bianchi

22.6.11 Glucose-​6-​phosphate dehydrogenase deficiency  5472 Lucio Luzzatto

22.6.12 Acquired haemolytic anaemia  5479 Amy Powers and Leslie Silberstein 22.7 Haemostasis  5490

22.7.1 The biology of haemostasis and
thrombosis  5490 Gilbert C. White, II, Harold R. Roberts,
and Nigel S. Key

22.7.2 Evaluation of the patient with a bleeding tendency  5509 Trevor Baglin

22.7.3 Thrombocytopenia and disorders of platelet function  5520 Nicola Curry and Susie Shapiro

22.7.4 Genetic disorders of coagulation  5532 Eleanor S. Pollak and Katherine A. High

22.7.5 Acquired coagulation disorders  5546 T.E. Warkentin † It is with great regret that we report that Tessa L. Holyoake died on 30 August, 2017. † It is with great regret that we report that David J. Weatherall died on 8 December, 2018.

Contents xxx 22.8 Transfusion and transplantation  5563

22.8.1 Blood transfusion  5563 D.S. Giovanniello and E.L. Snyder

22.8.2 Haemopoietic stem cell transplantation  5579 E.C. Gordon-​Smith and Emma C. Morris SECTION 23 Disorders of the skin Section editor: Roderick J. Hay 23.1 Structure and function of skin  5591 John A. McGrath 23.2 Clinical approach to the diagnosis of skin disease  5596 Vanessa Venning 23.3 Inherited skin disease  5602 Thiviyani Maruthappu and David P. Kelsell 23.4 Autoimmune bullous diseases  5612 Kathy Taghipour and Fenella Wojnarowska 23.5 Papulosquamous disease  5621 Christopher E.M. Griffiths 23.6 Dermatitis/​eczema  5630 Peter S. Friedmann, Michael J. Arden-​Jones, and Roderick J. Hay 23.7 Cutaneous vasculitis, connective tissue diseases, and urticaria  5639 Volha Shpadaruk and Karen E. Harman 23.8 Disorders of pigmentation  5677 Eugene Healy 23.9 Photosensitivity  5688 Hiva Fassihi and Jane McGregor 23.10 Infections of the skin  5695 Roderick J. Hay 23.11 Sebaceous and sweat gland disorders  5699 Alison M. Layton 23.12 Blood and lymphatic vessel disorders  5709 Peter S. Mortimer and Roderick J. Hay 23.13 Hair and nail disorders  5724 David de Berker 23.14 Tumours of the skin  5732 Edel O’Toole 23.15 Skin and systemic diseases  5743 Clive B. Archer and Charles M.G. Archer 23.16 Cutaneous reactions to drugs  5752 Sarah Walsh, Daniel Creamer, and Haur Yueh Lee 23.17 Management of skin disease  5761 Rod Sinclair SECTION 24 Neurological disorders Section editor: Christopher Kennard 24.1 Introduction and approach to the patient with neurological disease  5775 Alastair Compston and Christopher Kennard 24.2 Mind and brain: Building bridges
between neurology, psychiatry, and psychology  5778 Adam Zeman 24.3 Clinical investigation of neurological disease  5781

24.3.1 Lumbar puncture  5781 R. Rhys Davies and Andrew J. Larner

24.3.2 Electrophysiology of the central and peripheral nervous systems  5785 Christian Krarup

24.3.3 Imaging in neurological diseases  5802 Andrew J. Molyneux, Shelley Renowden, and
Marcus Bradley

24.3.4 Investigation of central motor pathways:
Magnetic brain stimulation  5817 K.R. Mills 24.4 Higher cerebral function  5821

24.4.1 Disturbances of higher cerebral function  5821 Peter J. Nestor

24.4.2 Alzheimer’s disease and other dementias  5830 Jonathan M. Schott 24.5 Epilepsy and disorders of consciousness  5860

24.5.1 Epilepsy in later childhood and adulthood  5860 Arjune Sen and M.R. Johnson

24.5.2 Narcolepsy  5882 Matthew C. Walker

24.5.3 Sleep disorders  5886 Paul J. Reading

24.5.4 Syncope  5896 Andrew J. Larner

24.5.5 The unconscious patient  5901 David Bates

Contents xxxi

24.5.6 Brainstem death and prolonged disorders of consciousness  5908 Ari Ercole, Peter J. Hutchinson, and John D. Pickard 24.6 Disorders of the special senses  5913

24.6.1 Visual pathways  5913 Sara Ajina and Christopher Kennard

24.6.2 Eye movements and balance  5922 Michael Strupp and Thomas Brandt

24.6.3 Hearing loss  5931 Linda Luxon 24.7 Disorders of movement  5937

24.7.1 Subcortical structures: The cerebellum, basal ganglia, and thalamus  5937 Mark J. Edwards and Penelope Talelli

24.7.2 Parkinsonism and other extrapyramidal diseases  5946 Elisaveta Sokolov, Vinod K. Metta, and K. Ray Chaudhuri

24.7.3 Movement disorders other than Parkinson’s disease  5956 Bettina Balint and Kailash Bhatia

24.7.4 Ataxic disorders  5976 Nicholas Wood 24.8 Headache  5987 Peter J. Goadsby 24.9 Brainstem syndromes  6006 David Bates 24.10 Specific conditions affecting the central nervous system  6010

24.10.1 Stroke: Cerebrovascular disease  6010 J. van Gijn (revised by Peter M. Rothwell)

24.10.2 Demyelinating disorders of the central nervous system  6026 Alasdair Coles and Siddharthan Chandran

24.10.3 Traumatic brain injury  6042 Tim Lawrence and Laurence Watkins

24.10.4 Intracranial tumours  6048 Jeremy Rees

24.10.5 Idiopathic intracranial hypertension  6054 Alexandra Sinclair 24.11 Infections of the central nervous system  6060

24.11.1 Bacterial infections  6060 Diederik van de Beek and Guy E. Thwaites

24.11.2 Viral infections  6082 Fiona McGill, Jeremy Farrar, Bridget Wills, Menno
De Jong, David A. Warrell, and Tom Solomon

24.11.3 Intracranial abscesses  6097 Tim Lawrence and Richard S.C. Kerr

24.11.4 Neurosyphilis and neuro-​AIDS  6100 Hadi Manji

24.11.5 Human prion diseases  6109 Simon Mead and R.G. Will 24.12 Disorders of cranial nerves  6120 Robert D.M. Hadden 24.13 Disorders of the spinal cord  6127

24.13.1 Diseases of the spinal cord  6127 Anu Jacob and Andrew J. Larner

24.13.2 Spinal cord injury and its management  6135 Wagih El Masri(y) and Michael Barnes 24.14 Diseases of the autonomic nervous system  6150 Christopher J. Mathias and David A. Low 24.15 The motor neuron diseases  6166 Tom Jenkins, Alice Brockington, and Pamela J. Shaw 24.16 Diseases of the peripheral nerves  6176 Robert D.M. Hadden 24.17 Inherited neurodegenerative diseases  6197 Swati Sathe 24.18 Disorders of the neuromuscular junction  6295 David Hilton-​Jones and Jacqueline Palace 24.19 Disorders of muscle  6304

24.19.1 Structure and function of muscle  6304 Michael G. Hanna and Enrico Bugiardini

24.19.2 Muscular dystrophy  6310 Kate Bushby and Chiara Marini-​Bettolo

24.19.3 Myotonia  6328 David Hilton-​Jones

24.19.4 Metabolic and endocrine disorders  6334 David Hilton-​Jones and Richard Edwards

24.19.5 Mitochondrial disease  6343 Patrick F. Chinnery and D.M. Turnbull 24.20 Developmental abnormalities of the central nervous system  6350 Chris M. Verity, Jane A. Hurst, and Helen V. Firth 24.21 Acquired metabolic disorders and the nervous system  6368 Neil Scolding 24.22 Neurological complications of systemic disease  6376 Neil Scolding

Contents xxxii 24.23 Paraneoplastic neurological syndromes  6384 Jeremy Rees 24.24 Autoimmune encephalitis and Morvan’s syndrome  6393 Camilla Buckley and Angela Vincent SECTION 25 Disorders of the eye Section editor: Christopher P. Conlon 25.1 The eye in general medicine  6399 Tasanee Braithwaite, Richard W.J. Lee, and Peng T. Khaw SECTION 26 Psychiatric and drug-​related disorders Section editor: Michael Sharpe 26.1 General introduction  6445 Michael Sharpe 26.2 The psychiatric assessment of the medical patient  6447 Jane Walker, Roger Smyth, and Michael Sharpe 26.3 Common psychiatric presentations in medical patients  6454

26.3.1 Confusion  6454 Bart Sheehan and Thomas Jackson

26.3.2 Self-​harm  6457 Kate E.A. Saunders and Keith Hawton

26.3.3 Medically unexplained symptoms  6460 Michael Sharpe

26.3.4 Low mood  6462 Jane Walker 26.4 Psychiatric treatments in the medically ill  6465

26.4.1 Psychopharmacology in medical practice  6465 Philip J. Cowen

26.4.2 Psychological treatments  6470 Michael Sharpe and Simon Wessely 26.5 Specific psychiatric disorders  6475

26.5.1 Delirium  6475 Bart Sheehan

26.5.2 Dementia  6478 Bart Sheehan

26.5.3 Organic psychoses  6482 Curtis McKnight and Jason Caplan

26.5.4 Alcohol misuse  6486 Jonathan Wood

26.5.5 Substance misuse  6490 Stephen Potts

26.5.6 Depressive disorder  6493 Joseph Cerimele and Lydia Chwastiak

26.5.7 Bipolar disorder  6498 Kate E.A. Saunders and John Geddes

26.5.8 Anxiety disorders  6501 Ted Liao and Steve Epstein

26.5.9 Acute stress disorder, adjustment disorders,
and post-​traumatic stress disorder  6506 Jonathan I. Bisson

26.5.10 Eating disorders  6509 Christopher G. Fairburn

26.5.11 Schizophrenia  6513 Stephen M. Lawrie

26.5.12 Somatic symptom and related
disorders  6517 Michael Sharpe

26.5.13 Personality disorders  6520 Iain Jordan 26.6 Changing unhealthy behaviours  6524

26.6.1 Brief interventions for excessive alcohol consumption  6524 Amy O’Donnell, Eileen Kaner, and Nick Heather

26.6.2 Obesity and weight management  6529 Susan Jebb and Paul Aveyard

26.6.3 Smoking cessation  6533 Paul Aveyard 26.7 Psychiatry, liaison psychiatry, and
psychological medicine  6536 Michael Sharpe SECTION 27 Forensic medicine Section editor: John D. Firth 27.1 Forensic and legal medicine  6541 Jason Payne-​James, Paul Marks, Ralph Bouhaidar, and
Steven B. Karch

Contents xxxiii SECTION 28 Sport and exercise medicine Section editor: John D. Firth 28.1 Sport and exercise medicine  6565 Cathy Speed SECTION 29 Biochemistry in medicine Section editor: Christopher P. Conlon 29.1 The use of biochemical analysis for diagnosis
and management  6577 Brian Shine and Nishan Guha SECTION 30 Acute medicine Section editor: John D. Firth 30.1 Acute medical presentations  6591 Sian Coggle, Elaine Jolly, and John D. Firth 30.2 Practical procedures  6644 Elaine Jolly, Sian Coggle, and John D. Firth Index

18.14.9 Lipoid (lipid) pneumonia 4263 S.J. Bourke

18.14.9 Lipoid (lipid) pneumonia 4263 S.J. Bourke

18.14.9  Lipoid (lipid) pneumonia 4263 Other manifestations Exudative pleural effusions can occur from amyloid deposits directly involving the pleura. Transudative pleural effusions and pulmonary oedema are often complications of amyloid cardiomyopathy or neph- rotic syndrome. Respiratory muscle weakness has been reported due to infiltration of the diaphragm and skeletal muscles by amyloid. Lymph node enlargement may be seen on CT images. Macroglossia may cause or aggravate obstructive sleep apnoea. The pulmonary vas- culature often contains deposits of amyloid at post-​mortem examin- ation. This is usually of no clinical consequence but has been reported to cause pulmonary hypertension and may be associated with an in- creased risk of bleeding when amyloid tissue is biopsied. Management and prognosis Local deposits of amyloid in the larynx, trachea, or bronchi may require treatment by endoscopic interventions, with mechanical debulking by forceps resection or laser therapy. This is effective in re- lieving airway obstruction, but there is a risk of provoking bleeding and recurrence is common. Stenting may also be used to maintain airway patency. Radiotherapy has also been deployed successfully, and in certain circumstances may be a better option with less risk of bleeding or recurrence. Amyloid deposits in the lung parenchyma often do not give rise to symptoms and may not require treatment, but they simulate bronchial carcinoma and may therefore be resected. Systemic AL amyloidosis may be treated by chemotherapy, using agents such as melphalan to reduce the production of immunoglobulin light chains. Diffuse alveolar amyloidosis has a poor prognosis, particularly be- cause it is associated with cardiac and renal amyloidosis. Lung trans- plantation has very rarely been performed for pulmonary amyloidosis. FURTHER READING Borie R, et  al. (2012). Tracheobronchial amyloidosis:  evidence for local B-​cell clonal expansion. Eur Resp J, 39, 1042–​5. Gillmore JD, Hawkins PN (1999). Amyloidosis and the respiratory tract. Thorax, 54, 444–​51. Jaccard A, et al. (2007). High-​dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med, 357, 1083–​93. Lachmann HJ, et al. (2007). Natural history and outcome in systemic AA amyloidosis. N Engl J Med, 356, 2361–​71. McLaughlin AM, et al. (2006). Amyloidosis in cystic fibrosis: a case series. J Cyst Fibrosis, 5, 59–​61. Milani P, et al. (2017). The lung in amyloidosis. Eur Respir Rev, 26, 170046. doi.org/10.1183/1600617.0046-2017. Neben-​Wittich MA, Foote RL, Kalra S (2007). External beam radiation therapy for tracheobronchial amyloidosis. Chest, 132, 262–​7. Pinney JH, Lachmann HJ (2011). Amyloidosis and the lung. Eur Respir Mon, 54, 152–​70. Santiago RM, Scharnhorst D, Ratkin G, Crouch EC (1987). Respiratory muscle weakness and ventilatory failure in AL amyloidosis with muscular pseudohypertrophy. Am J Med, 83, 175–​8. Ware LB, et al. (1998). Lung transplantation for pulmonary amyloid- osis: a case report. J Heart Lung Transplant, 17, 1129–​32. 18.14.9  Lipoid (lipid) pneumonia S. J. Bourke ESSENTIALS Exogenous lipoid pneumonia occurs when animal, vegetable, or mineral oils are aspirated or inhaled into the lungs, provoking a for- eign body reaction with chronic inflammation. Typical symptoms are cough and breathlessness. The chest radiograph and CT may show interstitial thickening, with areas of consolidation that may coalesce into a mass (paraffinoma) which simulates carcinoma. Bronchoalveolar lavage and biopsy show lipid-​laden macrophages. In endogenous lipoid pneumonia the lipids are derived from surfactant and cholesterol released from decaying cells distal to bronchial obstruction. Introduction Lipoid pneumonia is an unusual form of lung disease resulting from the accumulation of lipids in the alveoli, where they provoke a for- eign body reaction with associated inflammation and sometimes local fibrosis. The lipids may be endogenous or exogenous in origin, and the clinical mechanisms and circumstances differ accordingly. Endogenous lipoid pneumonia is usually part of another lung dis- ease, notably bronchial obstruction from carcinoma or bronchio- litis, where cholesterol and lipid–​rich surfactant accumulate in the alveolar macrophages. Exogenous lipoid pneumonia is caused by the aspiration or inhalation of animal, vegetable, or mineral oil, or hydrocarbons such as petroleum-​based substances (Box 18.14.9.1). When ex- ogenous mineral or vegetable lipids are deposited in the lung, they Fig. 18.14.8.2  Alveolar–​interstitial type amyloidosis of the lung. Staining with Congo red stain under polarized light (high magnification) demonstrates the characteristic dichroic birefringence. By courtesy of Dr T. Ashcroft.

section 18  Respiratory disorders 4264 are usually relatively inert but difficult to remove. Lung lipases have little effect, and macrophages are slow to transport the free or emulsified material into the lymphatics, such that they are re- tained in the lung for a long time. The result is often a chronic low-​grade inflammatory response that may lead to local fibrosis. Animal lipids are more readily degraded by lung lipases, releasing irritating fatty acids and causing a brisk and more widespread pneumonitis, particularly if lipid material is inhaled in large quantities. Exogenous lipoid pneumonia Aetiology Acute lipoid pneumonia Acute lipoid pneumonia is the result of an episode of massive ex- posure to petroleum-​based products. This usually occurs as a result of an accident or specific circumstances, such as ‘fire eater’s lung’ or ‘petrol-​siphoner’s lung’. In fire eating the performer blows out a mouthful of a flammable petroleum-​based liquid against a burning stick, creating an aerosol that burns around the stick. In siphoning petrol, fluid may be sucked into the mouth and aspirated during in- gestion or when vomiting. Shipwrecked sailors have suffered lipoid pneumonia from aspirating floating oil in the sea. A high level of lipid deposition in the lung can produce severe acute respiratory failure, as well as systemic effects involving other organs. Chronic exogenous lipoid pneumonia Chronic exogenous lipoid pneumonia is an indolent disease re- sulting from repeated aspiration or inhalation of lipids into the lung. Diagnosis is based upon identifying a history of exposure to exogenous lipid, and this has been described in a diverse range of settings and circumstances. In infants and children exogenous lipoid pneumonia has occurred as the result of feeding debilitated mal- nourished children with milk, ghee (clarified butter), or liquids with a high lipid content. Administration of cod liver oil to reluctant chil- dren has also resulted in deposition of lipid in the lungs. Sometimes repeated use of petroleum-​based nasal jelly is the source of the ex- ogenous lipid. In parts of India there was a common practice of cleaning the mouth, throat, and nose of infants with oil, and this resulted in a high incidence of lipoid pneumonia. In older people lipoid pneumonia has most often occurred from the regular use of li- quid paraffin as a laxative, taken each night for chronic constipation. Nasogastric feeding can also result in repeated deposition of lipid in the lungs. Often there are associated problems which predispose to aspiration, such as an impaired cough reflex, gastro-​oesophageal reflux, or neurological disease, causing difficulties in swallowing or impaired consciousness. In the occupational setting lipid inhalation may occur in fire- fighters exposed to oil mists and burning fats, and in factory workers inhaling metal working fluid contaminated with lubri- cant oils. Local customs and habits may cause lipid pneumonia in particular circumstances, such as the blackfat tobacco smokers of Guyana. Blackfat is a tobacco leaf to which mineral oil and Vaseline are added for flavouring, leading to recurrent inhalation of lipids. Clinical features The clinical features depend on the irritant properties of the lipid material and the dose retained in the lung, and whether any add- itional materials have been aspirated into the lungs. Chronic low-​grade aspiration of lipid often produces no imme- diate symptoms and the affected subject may present by chance with an abnormal chest radiograph. However, in about 50% of cases there is a chronic pneumonic illness with productive cough, low-​grade fever, and occasionally haemoptysis. Repeated aspiration may lead to fibrotic shrinkage of the affected segments, usually in the lower lobes or the middle lobe. Sometimes the radiographic appearances may closely simulate bronchial carcinoma and surgical resection may be undertaken, revealing a characteristic granulomatous mass (paraffinoma). When more substantial quantities are aspirated the radiographic abnormalities are more diffuse, and when the lipid material is more reactive an acute pneumonic illness occurs. CT may allow the iden- tification of lipid material by its low density (similar to body fat, –​ 150 to –​80 Hounsfield units, compared with + 50 to + 150 units for solid tumours) and also show patchy areas of ground-​glass attenu- ation and interstitial thickening, thereby producing a ‘crazy paving’ pattern. Diagnosis is crucially based on identifying exposure to ex- ogenous lipid, and this often requires a detailed history, con- centrating on particular risk factors. Identifying lipid material and lipid-​laden macrophages in bronchoalveolar lavage fluid or sputum is helpful, but this must be interpreted in the context of the full clinical circumstances and the presence of any diseases asso- ciated with endogenous lipoid pneumonia. Transbronchial biopsy or surgical lung biopsy may be needed, and typically shows lipid-​ laden macrophages, multinucleated giant cells, and interstitial fi- brosis (Fig. 18.14.9.1). Box 18.14.9.1  Lipoid pneumonia Exogenous lipoid pneumonia Aspiration • Liquid paraffin laxatives • Paraffin-​based nasal jelly • Cod liver oil • Milk feeds • Ghee feeds • Nasogastric feeding • Cosmetic oils • Petrol-​siphoner’s lung Inhalation • Metal working fluid • Oil mists • Blackfat tobacco smoking • Fire fighters • Fire eater’s lung Endogenous lipoid pneumonia • Bronchial obstruction • Bronchiolitis • Niemann–​Pick disease • Fat embolism

18.15 Chronic respiratory failure 4282 Michael I.

18.15 Chronic respiratory failure 4282 Michael I. Polkey and P.M.A. Calverley

ESSENTIALS Chronic respiratory failure describes a clinical state when the ar- terial Po2 breathing air is less than 8.0 kPa, which may or may not be associated with hypercapnia (defined as Pco2 more than
6.0 kPa (45 mm Hg)). Four processes cause arterial hypoxaemia due to inefficient pulmonary gas exchange—​ventilation–​perfusion (V/​Q) mismatch, hypoventilation, diffusion limitation, and true shunt, with the most important of these being V/​Q mismatching. The arterial CO2 is increased by inadequate alveolar ventilation and/​or V/​Q abnormality. A wide range of disorders can cause chronic respiratory failure, with the commonest being chronic obstructive pulmonary disease, interstitial lung diseases, chest wall, and neuromuscular diseases and morbid obesity. Diagnosis—​the detection of mild/​moderate hypoxaemia rests on an awareness of the possibility rather than any specific clinical finding. Central cyanosis may be apparent when there is an increase in the circulating deoxygenated haemoglobin to approximately 5 g/​dl, but this is an unreliable clinical sign. Measurement of arterial blood gases is required, preferably when the patient is breathing air. Fingertip oxim- etry is now ubiquitous and is a valuable screening tool Management—​the treatment of stable chronic respiratory failure involves: (1) making a firm diagnosis; (2) correction of the underlying disorder (when possible); (3) increasing the inspired oxygen con- centration; and (4) increasing alveolar ventilation. The benefits of regular oxygen treatment on breathlessness are marginal and there are no data to suggest that the severity or subsequent progres- sion of breathlessness is influenced by chronic oxygen treatment. Regular ‘continuous’ treatment with oxygen of patients with chronic obstructive pulmonary disease and stable hypoxaemia (Pao2 <7.3 kPa (55 mm Hg)) prolongs life. NIV prolongs admission free survival in patients with COPD who remain hypercapnic two weeks after an admission with acute hypercapnic exacerbation. Noninvasive nasal positive-​pressure ventilation has generally superseded other methods of providing chronic mechanical ventilatory support, but the patient–​mask interface remains a significant problem in some cases. Introduction Although respiration is ultimately a biochemical process involving the generation of ATP, the term ‘respiratory failure’ is used more loosely to describe the failure of gas exchange within the lung to maintain arterial blood gas homeostasis. Defining normal blood gas tensions is harder than it may appear initially, as Pao2 falls with age and the extent of this is debated. The most commonly applied formula to describe this is: PaO2(kPa) = 13.86 [0.036 age(years)]. Thus, a Pao2 of 10.6 kPa may be abnormal in a man of 24 years but a ‘normal’ value in a woman of 80. Subnormal levels of arterial oxygenation are described as hypoxaemia, whereas arterial CO2 ten- sions, which do not show similar age dependence, are considered to be hypercapnic when they exceed 6.0 kPa (45 mm Hg). Respiratory failure is defined primarily in terms of hypoxaemia and is arbitrarily considered to be present when the arterial Po2
(at sea level) is less than 8.0 kPa (60 mm Hg). It need not be accom- panied by hypercapnia, but when this develops it leads to acidosis due to the accumulation of carbonic acid by the Henderson–​ Hasselbalch equilibrium. If the acidosis is not rapidly progressive, and in the presence of intact renal compensatory mechanisms that generate bicarbonate ions, it becomes ‘chronic’—​a compensated state where the arterial pH returns to normal. In summary, chronic respiratory failure describes a clinical state when the arterial Po2 breathing air is less than 8.0 kPa, which may or may not be associated with hypercapnia, but is accompanied by a normal arterial pH and has been present for several days or more. This definition emphasizes the physiological determinants of gas exchange that characterize the problem. Unlike some other forms of organ system failure, such as car- diac or hepatic failure, the clinical symptoms and signs of chronic respiratory failure are relatively undramatic, but its development is equally significant, both as a marker of disease progression and in producing serious complications beyond those normally seen with the underlying disease. This chapter reviews the causes, clinical features, and assessment of chronic respiratory failure, as well as specific means of treatment. 18.15 Chronic respiratory failure Michael I. Polkey and P.M.A. Calverley

18.15  Chronic respiratory failure 4283 However, to do so logically requires some understanding of the principles underlying the development of this condition, as well as the factors relevant to the selection of the threshold values used in defining this state. Physiological determinants of blood gas tensions In health there is a predictable fall in the partial pressure of oxygen from that in the room air to that in mixed venous blood. This re- flects the effect of diluting room air with resident gas in the alveoli, the efficiency of pulmonary oxygen exchange, and the consump- tion of oxygen by metabolizing tissues. Conversely, there is a pre- dictable increase in the amount of CO2 added to the circulation and subsequently removed from the lungs during expiration. This simple system is reliant on a range of physical processes that differ somewhat for oxygen and CO2. Within the lungs, gas transport is largely by convective bulk transport, and in the alveoli by diffusion. In the blood oxygen combines with haemoglobin, which augments transportation to the tissues where diffusion is the final process in- volved. By contrast, CO2 transport begins with diffusion from rela- tively high tissue concentrations and is buffered in solution in the blood. This complex mechanism can be deranged in some predict- able ways that are discussed next. Analysis of pulmonary gas exchange In the last 30 years the analysis of pulmonary gas exchange has been revolutionized by the use of the complex multiple inert gas elimination techniques in research laboratories around the world. This gives a relatively complete description of the distribution of gas exchange abnormalities within the lungs. However, for an understanding of the general principles involved in disease states the traditional three-​compartment model is easier to follow. This assumes that alveolar air within the lungs is either ideally matched to pulmonary arterial blood flow within the pulmonary capillary bed or is totally mismatched, meaning that either the ventilation–​ perfusion (V/​Q) ratio is unity (ventilation without perfusion—​ physiological dead space, VD) or zero (perfusion without ventilation—​shunt effect). The physiological dead space includes a component due to dilution of the resident gas in the airways, the anatomical dead space, while the shunt fraction incorporates the very small amount of cardiac output (<1%) not passing through the pulmonary capillary bed. Hypoxaemia The principal mechanisms leading to arterial hypoxaemia are shown in Table 18.15.1. Individuals resident at altitude (e.g. in the high Andes or Himalayas), experience significantly lower in- spired oxygen tensions than those at sea level and in these cir- cumstances even individuals with normal lungs can develop clinically significant hypoxaemia, especially during sleep. Even minor degrees of respiratory impairment in these circumstances can produce dramatic changes in blood gas tensions and the early onset of cor pulmonale. Conversely, people with established hyp- oxaemia at sea level can occasionally experience worsening symp- toms when travelling by air, where cabin pressurization is 75% of atmospheric. However, in clinical practice, this is relatively infrequent. Four processes cause arterial hypoxaemia due to inefficient pul- monary gas exchange: • V/​Q mismatch • hypoventilation • diffusion limitation • true shunt Ventilation/​perfusion mismatching Much the most important cause of arterial hypoxaemia is V/​Q mismatching. In many diseases where minute ventilation is in- creased, the additional inspired gas is distributed to well-​perfused areas of the lungs, but when the opposite occurs and perfusion exceeds effective ventilation (low V/​Q states), arterial Pao2 falls. At first this might seem surprising as most diseases associated with V/​Q imbalance are of patchy distribution and compensa- tion from areas of high V/​Q ratios might be expected. However, this does not occur because of an important feature of the oxy- haemoglobin dissociation curve (Fig. 18.15.1), whose sigmoid shape means that well-​perfused parts of the lung cannot increase the arterial oxygen saturation of the blood leaving them beyond Table 18.15.1  Determinants of a reduced arterial oxygen tension Inspired oxygen concentration Reduced at altitude and iatrogenically Pulmonary factors V/​Q mismatching Alveolar hypoventilation Diffusion limitation Arteriovenous shunts Extrapulmonary factors Increased oxygen uptake Reduced mixed venous Po2 Low cardiac output Reduced mixed venous Po2 Reduced pulmonary capillary transit time Reduced end-​capillary Po2 Oxygen saturation (%) 100 80 60 40 20 0 Partial pressure of oxygen (mm Hg) v 0 20 40 60 80 100 a Fig. 18.15.1  The haemoglobin–​oxygen dissociation curve. (a) Partial pressure of oxygen of 8 kPa (60 mm Hg), which is the definition of arterial hypoxia. (v) Partial pressure of oxygen of 5.3 kPa (40 mm Hg), which is typical of mixed venous blood. Note that once the Pao2 falls below 8 kPa small further falls dramatically decrease the arterial oxygen saturation.

section 18  Respiratory disorders 4284 100%, hence the saturation of the pulmonary venous blood must fall if low V/​Q areas are present. Clinical examples of this process might include pulmonary embolus, where the lung is ventilated but not perfused, or pneumonia where the lung is perfused but cannot be ventilated. Alveolar hypoventilation The second important mechanism contributing to arterial hypox- aemia is alveolar hypoventilation, where the supply of fresh oxygen is globally reduced because of generally inadequate minute ventila- tion. This process often coexists with V/​Q mismatching and tends to exacerbate it. In some situations, such as during exercise, total mi- nute ventilation may lie within the normal range but can still be in- appropriately low for the subject’s metabolic requirements, thereby leading to hypoxaemia. Anatomical shunting and diffusion limitation Anatomical shunting and diffusion limitation are less important mechanisms for hypoxia. The former occurs predominantly with intrapulmonary arteriovenous malformations. Congenital cardiac anomalies such as ventricular septal defects with reversed flow are often lumped in with this problem, although technically they are extrapulmonary in origin. The failure to increase Pao2 to more than 40 kPa (300 mm Hg), even when exposed to 100% oxygen, is diagnostic. Diffusion limitation has gone in and out of fashion as an explanation for arterial hypoxaemia. It was initially believed to be important in many diseases, the assumption being that passive diffusion of oxygen was reduced to the point where equilibration with haemoglobin during red-​cell transit of the pulmonary capil- laries was incomplete. Detailed studies with modern techniques of gas exchange analysis have shown that this is seldom the case, except for small falls in arterial oxygen tension at maximum levels of performance in elderly athletes. Recent data suggest that dif- fusion limitation contributes to some of the resting and most of the exercise-​induced hypoxaemia in some forms of interstitial lung disease. Although it is not the sole explanation of arterial hypoxaemia, the degree of hypoxaemia can be worsened when the mixed venous arterial oxygen tension is significantly reduced as occurs in low car- diac output states or conditions where peripheral oxygen consump- tion is increased. Hypercapnia Analysis of the pulmonary causes for changes in arterial CO2 tension is much simpler, the relevant relationship being: PaCO K VCO VA 2 2

× / , where Vco2 is the CO2 production by the body, VA is the alveolar ventilation, and K is a constant. Alveolar hypoventilation It is easy to see that inadequate alveolar ventilation, due to either low total alveolar ventilation or an inability to increase VA in re- sponse to an increase in metabolic CO2 production, will increase the arterial CO2. Alveolar ventilation is influenced by a range of factors, reflecting the balance of the intrinsic capacity of the venti- latory pump and the demands placed on it (Fig. 18.15.2). Ventilation/​perfusion abnormality The second important mechanism for hypercapnia is V/​Q
abnormality, although here the important component is the increased physiological dead space. This can be seen by a rearrangement of the earlier equation to: PaCO K VCO V V V D T 2 2 1

× × / ( / ), where VD/​VT is the ratio of the physiological dead space to the tidal volume and V is the total minute ventilation. An increase in VD occurring when V/​Q ratios are high can lead to an increase in CO2 tension. Rather surprisingly, low V/​Q units are much less important in producing CO2 retention than they are in producing hypoxia since CO2 transport from the blood to the al- veolar gas is linear (Fig. 18.15.3). This means that in areas of normal V/​Q ratios an increase in overall minute ventilation will increase CO2 elimination and compensate for the CO2 that is not excreted from areas of reduced perfusion. Combined effects In most cases of chronic respiratory failure with CO2 retention, both alveolar hypoventilation and ventilation/​perfusion abnor- mality operate and the patient is unable to sustain the high overall levels of ventilation needed to maintain CO2 tension within the normal range. An important compensatory mechanism in the trade-​off be- tween the increased chemical drive to breathing and the mechanical limitations on ventilation is the breathing pattern. In both chronic obstructive and restrictive lung disease, a rapid shallow breathing pattern is adopted to minimize respiratory discomfort while maintaining minute ventilation. However, the relative fall in tidal volume further worsens the VD/​VT ratio and can itself contribute to CO2 retention. Some of these problems are resolved when the buf- fering capacity of the blood rises as compensation for respiratory acidosis occurs. Special circumstances As already noted, residence at altitude and exercise pose particular problems for gas exchange and may induce temporary respiratory failure. There is now a wealth of data indicating that similar changes Ventilatory failure Respiratory muscle pump Load Capacity Sleep CNS drive Fig. 18.15.2  Alveolar ventilation reflects the balance of the intrinsic capacity of the ventilatory pump and the demands placed on it. A reduced respiratory drive, particularly during sleep, reduces alveolar ventilation but does not produce significant hypercapnia.

18.15  Chronic respiratory failure 4285 can occur during sleep. All healthy people show an approximately 15% reduction in minute ventilation in the transition from wakeful- ness to stable nonrapid eye movement (REM) sleep, and this may be greater still in phasic REM sleep. The ventilatory responses to both hypoxia and hypercapnia decline as sleep deepens and upper airway resistance rises, especially in those who snore. Despite this the blood gas tensions vary little in health during sleep, but dramatic abnor- malities can develop during periods of repetitive upper airway ob- struction (see Chapter 18.5.2), or when coexisting neuromuscular weakness leads to excessive dependence on muscle groups whose activity declines with sleep (see next). Persistent nocturnal hypoxaemia can ‘feed forwards’ to contribute to daytime hypoxaemia in patients with otherwise normal lungs by its adaptive effect on chemoreceptor responsiveness. This occurs in a few people with obstructive sleep apnoea, but its relevance to most patients with this disease is debatable, usually being noted when there is coexisting severe obesity (see next). Gas transport to the tissues Oxygen delivered to the tissues depends on the oxygen saturation of arterial blood (Sao2), the haemoglobin concentration (Hb), and the cardiac output (CO), related as follows: Oxygen delivery

1.34 /100 . ( ) 2 2 ( ) DO CO Hb SaO

× × × ( ) This is influenced only indirectly by the effectiveness of gas ex- change. Since oxygen delivery is the clinically relevant outcome of oxygenation, decisions about when and how much to intervene therapeutically will be influenced by this variable. Small changes in saturation become clinically more important in individuals with impaired cardiac function and/​or reduced haemoglobin concentra- tion, and a higher Sao2 should be maintained. In general, there is little to be gained by increasing Sao2 to the high 90s, especially as this may cause secondary CO2 retention in some diseases. As is clear from Fig. 18.15.1, desaturations below 90% only occur when the ar- terial oxygen tension is below 8.0 kPa (60 mm Hg), and this is also influenced by certain other factors that determine the position of the dissociation curve (Table 18.15.2). This provides the rationale for the choice of 8.0 kPa as the cut-​off point for the onset of respira- tory failure. Causes of chronic respiratory failure The principal causes of chronic respiratory failure are summarized in Box 18.15.1, with the commonest causes discussed next. Chronic airflow limitation This term covers the most important cause of chronic respiratory failure, chronic obstructive pulmonary disease (COPD), but is also relevant to diseases such as chronic bronchial asthma, which is now excluded from the definition of COPD, and bronchiectasis, where airflow obstruction is a frequent finding as the disease ad- vances. In all these conditions there is a reduction in the forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio below 70% and a reduction in the FEV1, which is commonly below 35% predicted before chronic respiratory failure is noted clinically. In chronic airflow limitation hypoxaemia is the earliest abnor- mality and largely due to V/​Q mismatching. Attempts at relating these changes to structural patterns of airway and alveolar disease in COPD have proved unsuccessful. As lung mechanics worsen (commonly when FEV1 falls below 1.5 litres or 35% of the pre- dicted value), arterial CO2 increases. This has been related to the development of inspiratory threshold loading (PEEPi) with the onset of chronic hyperinflation, but the degree of CO2 retention varies between subjects suggesting that individual variations in chemoresponsiveness/​perception of ventilatory load contribute to this process. There is no predictable relationship between the se- verity of impaired lung mechanics below the thresholds indicated and the degree of hypoxaemia or hypercapnia, and many patients who maintain arterial CO2 tensions within the normal range de- velop acute CO2 retention during exacerbations of their disease. These changes can be relatively short lived and the hypercapnia kPa 0 600 4 400 200 Concentration (ml/l) 50 100 Partial pressure (mm Hg) 12 8 0 0 O2·CO O2 CO CO2 Blood Plasma Fig. 18.15.3  Concentration of oxygen (O2), carbon monoxide (CO), and carbon dioxide (CO2) in blood and plasma at differing partial pressures of these gases. Table 18.15.2  Important facts about the oxygen dissociation curve Pao2 = 100 (13.3), Sao2 = 97.5% Normal values for arterial blood Pao2 = 80 (10.7), Sao2 = 96% Lower limit for normal arterial blood Pao2 = 60 (8.0), Sao2 = 89% Dissociation curve changes shape Pao2 = 40 (5.3), Sao2 = 75% Mixed venous blood, or severe arterial hypoxaemia Increased temperature, Pco2, acidosis, 2,3-​DPG shifts the curve to the right
and vice versa Reduces O2 uptake from pulmonary venous blood but increases O2 delivery in the tissues 2,3-​DPG, s-​diphosphoglycerate in red cells; Sao2, arterial oxygen saturation. Figures for Pao2 are mm Hg (kPa).

section 18  Respiratory disorders 4286 resolves by the time of discharge. Coexisting left ventricular impair- ment reduces cardiac output and increases venous admixture, which can cause severe hypercapnia and acidosis, which none the less re- spond rapidly to appropriate treatment. Patients with COPD in association with persistent hypercapnic respiratory failure have a worse prognosis than those with intermit- tent hypercapnia during exacerbations (Fig. 18.15.4). The pattern in chronic asthma and bronchiectasis appears similar to COPD, indicating that lung mechanics rather than individual pathology dictates the severity of the gas exchange disorder. Interstitial lung disease Despite the wide range of primary pathologies covered by the term ‘interstitial lung disease’, they present with a relatively stereotyped physiological picture. A  restrictive physiological disorder (FEV1/​ FVC >75% with a reduced absolute FEV1 and FVC) is usual, although patients with sarcoidosis commonly show airways involvement and can present with severe airflow limitation or a mixed physiological pattern. Near normal spirometry can be seen with significant exer- cise limitation and exercise-​induced oxygen desaturation in some patients where COPD and interstitial lung disease coexist. Typically, resting gas exchange is relatively preserved in interstitial lung disease until late in the course, whereas exercise-​induced desaturation is an early finding, often seen when spirometric changes are unimpressive. Studies using the multiple inert gas technique have described a bimodal pattern of V/​Q distribution, with some areas of lung having normal V/​Q relationships and others relatively little ventila- tion (increased physiological shunting), a situation which worsens during exercise. A few patients with severe interstitial lung disease develop CO2 retention and cor pulmonale in the terminal phase of their illness. The physiological mechanisms underlying this are poorly studied, but are probably similar to those in COPD. Chest wall and neuromuscular disease Here the underlying lung structure and potential for gas exchange are unimpaired, but the ability to maintain adequate alveolar ventilation Box 18.15.1  Causes of chronic hypoxaemia alone or with hypercapnia With normal or low PaCO2 Pulmonary diseases • Obstructive ventilatory disorders -​ COPD -​ Chronic asthma • Mixed ventilatory disorders -​ Bronchiectasis -​ Sequelae of tuberculosis • Interstitial lung disorders -​ Idiopathic pulmonary fibrosis -​ Pneumoconiosis -​ Sarcoidosis -​ Extrinsic allergic alveolitis • Pulmonary vascular diseases -​ Pulmonary vascular hypertension -​ Chronic or acute pulmonary thrombosis -​ Arteriovenous malformations Nonpulmonary diseases • Severe heart failure • Right to left cardiac shunt • Hepatopulmonary syndrome With hypercapnia Pulmonary diseases • Obstructive ventilatory disorders -​ COPD • Mixed ventilatory disorders -​ Bronchiectasis -​ Sequelae of tuberculosis Nonpulmonary diseases • Dysfunction of respiratory centres (e.g. central congenital hypoventi- lation syndrome) • Obesity hypoventilation syndrome • Depressant drugs • Lesion of brainstem • Neuromuscular diseases -​ Poliomyelitis -​ Amyotrophic lateral sclerosis (syn. Motor Neurone Disease) -​ Myasthenia gravis -​ Muscular dystrophies, polymyositis -​ Metabolic respiratory muscle weakness (e.g. hypothyroidism, adult onset Pompe disease) • Chest wall deformities -​ Kyphoscoliosis -​ Ankylosing spondylitis -​ Chest trauma -​ Thoracoplasty • Limitation of chest wall movement -​ Massive obesity - Pleural thickening • Obstructive sleep apnoea COPD, chronic obstructive pulmonary disease. 40 100 80 60 Cumulative percentage Interval (years) 20 0 1 2 3 4 5 11% 26% 33% 0 2.2 2.1 1 Fig. 18.15.4  Survival after index admission in three groups of patients with COPD who had similar initial spirometry. Group 1 never exhibited CO2 retention; group 2.1 retained CO2 during the admission but this resolved; group 2.2 had persistent arterial hypercapnia. Based on data from Costello R, et al. (1997). Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis. Am J Med, 102, 239–​44.

18.15  Chronic respiratory failure 4287 is reduced. This can be due to increased chest wall stiffness, as in kyphoscoliosis, or reduced inspiratory muscle force, as in neuro- muscular disease. In this latter group the reduction in maximum inspiratory pressure can be global, such as in Duchenne muscular dystrophy, or more specific, such as isolated diaphragmatic weak- ness, where gas exchange abnormalities may only be present during specific sleep stages. Significant abnormalities of gas exchange at rest only occur with advanced disease and not in every patient. Alveolar hypoventilation is the dominant mechanism of both hypoxaemia and hypercapnia, although secondary changes such as pulmonary microatelectasis may contribute an element of V/​Q mismatching. Assessing exercise hypoxaemia is difficult in these patients due to their generalized muscle weakness. However, sleep-​ related oxygen desaturation, particularly during REM sleep when the inspiratory system is most dependent on diaphragm function, is a common finding in patients with mild daytime hypoxaemia due to chest wall problems or neuromuscular diseases. Occasionally these changes are dramatic, but in boys with muscular dystrophy the presence of transient hypoxaemic episodes was no better guide to prognosis than was measurement of the vital capacity (Fig. 18.15.5). Arterial CO2 tensions often lie in the high normal range, daytime hypercapnia only being seen in advanced disease. Obesity–​hypoventilation syndrome As obesity becomes more prevalent in developed countries, so the incidence of the ‘obesity–​hypoventilation’ syndrome rises. This con- dition is characterized by waking hypercapnia and mild hypoxemia in the absence of factors known to cause CO2 retention. Overnight polysomnography shows marked and sustained hypoventilation, with a rise in the CO2 retention throughout the night. Many of these patients have coexisting obstructive sleep apnoea with repetitive upper airway obstructions, which worsens both their hypoxemia and sleep disruption. However, the arterial oxygen tension before sleeping may still be low, with a waking saturation below 90% as a result of closure of the dependent airways during tidal breathing and a consequent worsening of the V/​Q relationships. Nonpulmonary disorders Patients with stable congestive cardiac failure often show mild re- ductions in Pao2 and a normal or low Paco2 due to premature airway closure secondary to pulmonary oedema. Some patients with severe liver cirrhosis develop the so-​called hepatopulmonary syndrome, with otherwise unexplained hypoxaemia due to V/​Q mismatching and true anatomical shunting through arteriovenous communica- tions in the pulmonary circulation. A rare, but often overlooked, clinical cause of extrapulmonary hypoxia is the post-​pneumonectomy syndrome in which anatomical change inherent to the surgery causes opening of a patent foramen ovale with consequent right to left shunting Morbidly obese individuals can develop hypoxaemia and hypercapnia due to profound nocturnal hypoventilation and chemoreceptor resetting. Rather more common are the problems of patients with severe obstructive sleep apnoea who develop day- time hypoxaemia and hypercapnia secondary to recurrent noc- turnal upper airway obstruction and oxygen desaturation. Careful review of these ‘Pickwickian’ patients may shows coexisting hypothyroidism or obstructive lung disease, and this diagnosis should be suspected in any patient with COPD with significant re- spiratory failure and an FEV1 greater than 1.5 litres. Correction of the sleep apnoea by nasal continuous positive airway pressure can produce significant improvement in daytime blood gases, but in most patients with obstructive sleep apnoea no significant abnor- malities of waking gas exchange are seen. Pulmonary vascular disease This is an uncommon cause of hypoxaemia, and at the time of diag- nosis CO2 retention is rare. Rather variable changes in DLco are re- ported, but as pulmonary hypertension becomes more advanced, exercise and resting hypoxaemia develops, a significant component being secondary to the reduced cardiac output and increase in mixed venous oxygen tension. See Chapter 16.15.2 for further discussion. Assessment of chronic respiratory failure The diagnosis of mild/​moderate hypoxaemia rests on an awareness of the possibility rather than any specific clinical finding. Impair­ ment of concentration and memory can be demonstrated when the arterial Po2 is below 8.0 kPa, but these features are extremely non-​ specific. Although tempting to ascribe to hypoxaemia, the principal 50 100 75 25 min SaO2 (%) Survival (months) 0 r =0.62 0 25 50 75 100 2.0 1.5 1.0 0.5 0.0 Vital capacity (litres) r =0.65 Survival (months) 0 25 50 75 100 Fig. 18.15.5  Survival of boys with respiratory failure due to neuromuscular disease plotted against minimum arterial oxygen saturation recorded during sleep and vital capacity. Based on data from Phillips MF, et al. (1999). Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy. Am J Respir Crit Care Med, 160, 198–​202.

section 18  Respiratory disorders 4288 cause of breathlessness in these patients is usually the underlying disease. Reduction of peripheral chemoreceptor activity by supple- mentary oxygen can be beneficial, but this is usually secondary to a fall in minute ventilation rather than to any specific ‘dyspnogenic’ effect of hypoxia itself. Hypercapnia is equally nonspecific, with headache the most com- monly attributed symptom. There are no good data to support this in compensated respiratory failure, although a generalized degree of vasodilatation is seen in some patients with CO2 retention, which may be accompanied by a large-​volume pulse and warm peripheral extremities. On examination, central cyanosis may be apparent as a bluish dis- coloration of the mucous membranes associated with an increase in the reduced circulating haemoglobin to approximately 5 g/​dl, but this is an unreliable clinical sign in some ethnic groups and in the presence of artificial illumination. Chronic hypoxaemia can lead to secondary polycythaemia due to increased renal secretion of erythropoietin. This may be exacer- bated if the patient is also a heavy smoker. The resulting increase in haemoglobin concentration contributes to a ruddy complexion, which increases the ability to detect cyanosis clinically. When right heart failure develops the jugular venous pressure may be elevated, and ankle swelling develops as CO2 retention worsens. The principal diagnostic steps are listed in Box 18.15.2. Measure­ ment of arterial blood gases, preferably breathing air, is the most reliable way of diagnosing chronic respiratory failure, although the widespread availability of fingertip oximetry provides a useful screening measure. Substantial hypoxia is unlikely where the SpO2 breathing room air is 94% or more. Measurement of fingertip SpO2 during a corridor walk or stair climb can be a useful bedside screen for exercise-​induced hypoxia. Arterialized earlobe gases are an ac- ceptable alternative to an arterial sample in the management of chronic respiratory failure and may be less painful for some patients. If an arterial (or arterialized) blood sample is taken when a patient is breathing supplementary oxygen, it is essential to record at what inspired concentration: without this information the Pao2 simply cannot be interpreted sensibly. Patients with chronic airflow limitation treated with broncho- dilators nebulized in oxygen may show unexpectedly high Pao2 for some time after this treatment. Noninvasive measurement of arterial oxygen saturation using pulse oximetry can be used to screen indi- viduals at risk of chronic respiratory failure and to monitor patients in hospital or overnight, but it is no substitute for assessing blood gas tensions to make the diagnosis correctly. Management of chronic respiratory failure Managing stable chronic respiratory failure involves several steps: 1 Making a firm diagnosis 2 Correcting the underlying disorder (when possible) 3 Increasing the inspired oxygen concentration 4 Increasing alveolar ventilation Making a firm diagnosis This is essential for rational management. It is important to re- member that more than one process may contribute to the devel- opment of chronic respiratory failure (e.g. poor left ventricular function due to cardiac disease and COPD together). The relative importance of each factor should be determined. Correction of the underlying disorder In general, treatment of the primary pathology improves both V/​Q relationships and hence oxygenation, and respiratory system mechanics, which increases ventilatory capacity and lowers the Paco2. In patients with COPD this usually involves administration of inhaled bronchodilators and corticosteroids (see Chapter 18.8), but marked improvement is the exception rather than the rule in patients where chronic respiratory failure has developed. Medical therapy tends to be ineffective by the time chronic respiratory failure has developed in interstitial lung disease and the neuro- muscular disorders. Specific pulmonary vasodilator treatment has been used to treat pulmonary hypertension, with most evidence of improvement seen after infusion of prostacyclin in primary pulmonary hyper- tension, and this field is rapidly evolving (see Chapter 16.15.12). Attempts to improve gas exchange in secondary pulmonary hypertension by the use of inhaled nitric oxide, a specific pul- monary arterial vasodilator, have been disappointing, and resting gas exchange has usually deteriorated rather than improved after this treatment. There is no specific treatment for most neuromuscular diseases or the abnormalities of the thoracic skeleton which produce chronic respiratory failure. Dramatic weight loss after bariatric surgery is possible in patients with obesity–​hypoventilation. Increasing the inspired oxygen concentration Hypoxaemia secondary to V/​Q mismatch or global hypoventilation is relatively easily corrected by supplementary oxygen. In chronic airflow limitation and especially COPD, where respiratory time constants for gas exchange are long, it may take 30 min before a new steady state is reached when breathing relatively low concen- trations of oxygen. Monitoring of blood gases should be adjusted accordingly. In the chronic stable state, treatment with oxygen is given to pre- vent or reverse the chronic consequences of hypoxaemia. The bene- fits of regular oxygen treatment on breathlessness are marginal and there are no data to suggest that the severity or subsequent progres- sion of breathlessness is influenced by chronic oxygen treatment. Almost all data about oxygen therapy in chronic respiratory failure are based on observations in hypoxaemic COPD, treatment in other conditions being offered by analogy with this more common problem. Box 18.15.2  Diagnostic steps in detecting respiratory failure 1 Consider the possibility—​see Box 18.15.1 2 Look for central cyanosis and other clinical signs, measure fingertip oximetry 3 If the probability is high or unanticipated signs are present, measure arterial blood gases while breathing air 4 If it is not possible to measure arterial blood gases on air, note the in- spired oxygen concentration 5 Blood gas tensions can change with the clinical state of the patient and measurements need to be repeated when this happens 6 Noninvasive pulse oximetry and capnometry is useful for monitoring progress but cannot diagnose acidosis

18.15  Chronic respiratory failure 4289 Long-​term oxygen therapy Two well-​performed randomized clinical trials have shown that regular treatment of patients with COPD and stable hypoxaemia (Pao2 <55 mm Hg) prolongs life (Fig. 18.15.6a). These data sug- gest that patients using more oxygen (the ‘continuous’ limb of the Nocturnal Oxygen Therapy Trial Group) do better than either the United Kingdom Medical Research Council treatment group or the North American patients using oxygen only at night. A more re- cent Polish study found no benefit when patients with COPD with a Pao2 of 7.3–​8.8 kPa were treated with oxygen at home for 15 h/​day (Fig. 18.15.6b), emphasizing that chronic oxygen therapy is only of value when the oxygen saturation falls below 90%. These studies showed that progression of secondary pulmonary hypertension can be halted by regular oxygen treatment and sec- ondary polycythaemia can be corrected. However, secondary polycythaemia in COPD is influenced by the amount of carboxy- haemoglobin from cigarettes, and patients who continue to smoke do not show a fall in red-​cell mass or packed cell volumes with oxygen treatment. Neuropsychological effects of chronic hypoxaemia have been described and may be improved by regular oxygen treatment, although the evidence for this is limited. Most authorities consider therapeutic venesection is indicated when the haemoglobin exceeds 175 g/​litre with a packed cell volume greater than 55%. Oxygen therapy during exercise Giving oxygen during exercise increases performance and par- ticularly endurance in patients with COPD who are relatively normoxaemic, as well as those with resting hypoxaemia. Again, carbon monoxide from cigarette smoking reduces this response, and whether oxygen desaturation during exercise is necessary for the benefit to occur has not been conclusively established, although it is used as a reimbursement criterion for portable oxygen in North America. Delivery of oxygen Oxygen concentrators are the most cost-​effective way of delivering oxygen for near-​continuous use. These devices have proved reliable and safe; they use the ability of zeolite cells to separate nitrogen from room air and so generate an oxygen-​enriched inspirate. Portable battery-​operated concentrators are now available, which can im- prove patients’ quality of life by enhancing their mobility. Liquid oxygen has the advantage of allowing relatively easy refilling of port- able oxygen units for use during exercise. Oxygen masks are the most accurate way of delivering oxygen, with a range of inspired concentrations (24, 28, 35%) available. However, these are easily dislodged during sleep, and plastic nasal prongs with a long extension pipe offer an easier system for use in the home. Occasional patients, especially those with severe interstitial lung disease, may have difficulties obtaining a Pao2 greater than 8.0 kPa with these systems. Transtracheal oxygen delivery may have a role here, but early enthusiasm for this has been tempered by problems with cannula occlusion, infection, and bleeding. A variety of oxygen-​conserving devices that deliver oxygen only during inspiration have been developed: these increase the time be- tween refills of portable oxygen equipment as well as having finan- cial advantages in some healthcare systems. Improving alveolar ventilation Mechanical methods These are potentially valuable ways of reducing arterial CO2 in dis- orders like COPD and can increase arterial oxygen tension as well, especially in conditions such as neuromuscular disease where hypo- ventilation predominates. The use of tank respirators in neuromuscular weakness has now been superseded by the development of noninvasive nasal positive-​ pressure ventilation (NIPPV), which is normally only needed at night. This therapy is used increasingly in the management of acute-​ on-​chronic respiratory failure in patients where the primary problem is ventilatory, without coexisting pneumonia/​acute lung injury. Its chronic use arose from the belief that respiratory muscle fatigue was an important cause of CO2 retention in COPD and the empirical ob- servation that gas exchange and survival were better in patients with kyphoscoliosis treated with night-​time cuirass ventilation. Newer 100 (a) 80 40 Cumulative survival (%) 0 Time (years) 60 20 1 2 3 4 5 6 0 (b) 1.0 0.8 0.2 0.5 0.3 12 24 36 48 60 72 84 96 Long-term oxygen therapy Controls Cumulative survival (%) Survival (months) 0 0.7 Nocturnal oxygen therapy trial-oxygen 24 h/day Nocturnal oxygen therapy trial-oxygen 12 h/day MRC trial-oxygen 15 h/day MRC trial-control (no oxygen) Fig. 18.15.6  The effect of regular domiciliary oxygen on survival in COPD. Panel (a) combines data from the MRC and NIH oxygen trial in the United States of America: survival was greatest in those receiving oxygen for 24 h/​day. Panel (b) is based on the study of Gorecka et al. for COPD patients with a Pao2 between 7.3 and 8.5 kPa who were treated with oxygen or normal medical therapy: there was no survival benefit in the oxygen treated group, confirming the importance of the 7.3-​kPa threshold in selecting patients for this therapy.

section 18  Respiratory disorders 4290 studies have shown that respiratory muscle function is well pre- served in COPD when allowance is made for the muscle shortening secondary to pulmonary hyperinflation. Chronic obstructive pulmonary disease Several trials of NIPPV in stable hypoxaemic but normocapnic COPD have reported relatively unimpressive results. In studies con- fined to those with persistent hypercapnia, randomized controlled trials have as yet failed to provide unanimous evidence of efficacy of this approach. A recent multicentre UK trial (HOT-HMV) has demonstrated that NIV (in addition to oxygen) tripled admission- free survival compared with oxygen alone. This finding was in con- trast to prior studies but important differences in HOT-HMV was were selection of patients who remained hypercapnic 2 weeks after an index admission with acute hypercapnic respiratory failure, and the use of a high pressure ventilation strategy. Kyphoscoliosis Significant symptomatic and blood gas improvements with NIPPV have been demonstrated in patients with kyphoscoliosis, but again no randomized clinical trial data are available. At present, it appears unlikely that trials will be set up, given the significant and sustained symptomatic benefits seen clinically. Muscular weakness The only study to report prospective data on muscular dystrophy found no effect of regular NIPPV on survival in normocapnic patients, but use of this therapy as supportive treatment in the terminal phases of advanced muscular dystrophy appears to be as- sociated with prolonged survival. A carefully constructed random- ized control trial has shown improvements in survival and quality of life with NIPPV in patients with motor neuron disease who are free from bulbar problems. However, it is always important in the face of progressive disease such as muscular dystrophy or motor neuron disease that the patient should be fully informed of the complications of NIPPV and the fact that it is unlikely to influ- ence the underlying progression of the condition. Provided a good dialogue between patient, carer, and physician is established, then reasonable decisions about the use of this ethically difficult treat- ment are still possible. Types of ventilator support Although volume-​cycled ventilation was initially preferred, most patients are now managed with a bilevel pressure-​cycled patient-​ triggered device. This may have some advantages in obstructive lung disease, where PEEP can be added to offset static PEEPi. Adequate peak inspiratory pressure generation, certainly in excess of 20 cmH2O, is needed in both COPD and kyphoscoliosis, where total respiratory system compliance is reduced. The patient–​mask interface remains a major problem, espe- cially for those with unusual craniofacial structure, where getting a comfortable mask fit without excessive tightness can be difficult. Progress should be assessed by regular blood gas measurements, and overnight monitoring of oxygenation and CO2 tensions is useful at the start of therapy. Patience and trained respiratory therapists are the best way of ensuring long-​term compliance with treatment. Chronically ventilator-​dependent patients In most patients with chronic respiratory failure who require ven- tilatory support the instigation of this treatment is a considered de- cision as part of the patient’s ongoing management. However, for a few, chronic ventilation becomes necessary when they have pre- sented with an acute life-​threatening illness which has led to ventila- tory support in the intensive care unit. Many of these patients would have previously succumbed from diseases with a poor initial prog- nosis (e.g. adult respiratory distress syndrome), but now survive to leave the intensive care unit, and inevitably some do not recover the level of lung function or independence which they had experienced before hospitalization. There is no universally agreed definition for such ‘ventilator de- pendence’, but a patient who requires at least 6 h/​day of ventilatory support for 21 or more days meets the most widely used operational approach. Patients of this type raise important ethical, logistical, and economic issues, but it is possible to offer them a good quality of life and a reasonable prognosis if they are cared for by appropriately trained staff in specialized units. In this setting many patients can be transferred from tracheostomy-​dependent ventilation to NIPPV, with a significant improvement in personal well-​being and the op- tions for community care. Given the continuing developments in critical care medicine, an increase in the number of patients with chronic respiratory failure who meet these criteria appears likely. Specific pharmacological therapy Although mechanical ventilatory support is effective, it is also cumbersome, uncomfortable, and restricting, hence a drug treat- ment for chronic respiratory failure would be invaluable. Although medroxyprogesterone acetate has nonspecific ventilatory stimulant effects and can produce small falls in CO2 tension in patients with COPD, its oestrogen-​like side effects limit its use. Methylxanthines like theophylline have some chemoreceptor stimulant effects, but are mainly of use for their bronchodilator and anti-​inflammatory prop- erties. Almitrine bismethylate is an interesting specific peripheral chemoreceptor stimulant drug, which also modifies intrapulmonary V/​Q matching and increases arterial oxygen while reducing CO2 tensions in patients with resting hypoxaemia. These properties have led to its use in parts of Europe, but it is associated with the develop- ment of peripheral neuropathy, and possibly increasing pulmonary artery pressure during exercise, which has limited its more wide- spread application. Despite the attractions of a pharmacological approach, the recog- nition that, in most diseases, the central drive to breathe is already high, mean that treatment with respiratory stimulant therapy is likely to have only limited clinical application. FURTHER READING Anonymous (1980). Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group. Ann Intern Med, 93, 391–​8. Anonymous (1981). Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and em- physema. Report of the Medical Research Council Working Party. Lancet, i, 681–​6.

18.15  Chronic respiratory failure 4291 Bourke SC, et al. (2006). Effects of non-​invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomized control trial. Lancet Neurol, 2, 40–​7. Calverley PM, Leggett RJ, Flenley DC (1981). Carbon monoxide and exercise tolerance in chronic bronchitis and emphysema. BMJ, 283, 878–​80. Calverley PM, et al. (1982). Cigarette smoking and secondary polycy- themia in hypoxic cor pulmonale. Am Rev Respir Dis, 125, 507–​10. Costello R, et al. (1997). Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis. Am J Med, 102, 239–​44. Gorecka D, et al. (1997). Effect of long-​term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with mod- erate hypoxaemia. Thorax, 52, 674–​9. Haluszka J, et al. (1990). Intrinsic PEEP and arterial Pco2 in stable patients with chronic obstructive pulmonary disease. Am Rev Respir Dis, 141, 1194–​7. Iftikhar IH, Roland J (2018). Obesity hypoventilation syndrome. Clin Chest Med, 39, 427–36. MacIntyre NR, et al. (2005). The management of patients requiring prolonged mechanical ventilation: report of a NAMDRC consensus conference. Chest, 128, 3937–​54. Meecham JD, et al. (1995). Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med, 152, 538–​44. Ming DK, et al. (2014). The ‘anatomic shunt test’ in clinical practice; contemporary description of test and in-​service evaluation. Thorax, 69, 773–​5. Murphy PB, et al. (2017). Effect of home noninvasive ventilation with oxygen therapy vs oxygen therapy alone on hospital readmission or death after an acute COPD exacerbation: A randomized clinical trial. JAMA, 317, 2177–86. Olson AL, Zwillich C (2005). The obesity hypoventilation syndrome. Am J Med, 118, 948–​56. Phillips MF, et al. (1999). Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy. Am J Respir Crit Care Med, 160, 198–​202. Powell FL, Wagner PD, West JB (2015). Ventilation, blood flow, and gas exchange. In: Broaddus VC, et al. (eds) Murray and Nadel’s Textbook of Respiratory Medicine, 6th edn, pp. 44–75. Elsevier Saunders, Philadelphia. Raphael JC, et al. (1994). Randomised trial of preventive nasal ven- tilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation Assistance in Duchenne de Boulogne Muscular Dystrophy. Lancet, 343, 1600–​4. Struik FM, et al. (2014). Nocturnal non-​invasive ventilation in COPD patients with prolonged hypercapnia after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-​group study. Thorax, 69, 826–​34.

18.16 Lung transplantation 4292 P. Hopkins and A.J

18.16 Lung transplantation 4292 P. Hopkins and A.J. Fisher

ESSENTIALS Lung transplantation offers the only therapeutic option for many pa- tients with end-​stage pulmonary and cardiopulmonary diseases, but donors are scarce and the major challenge facing lung transplantation (as with all solid organ transplants) is the shortage of donor organs. Recipient selection—​emphysema/​chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis, and pulmonary vascular disease are the main disease groups referred for lung transplant- ation. Most suitable patients are listed for transplantation when their
2-​year survival is estimated to be less than 50% without transplantation. Donor selection—​almost all organs come from cadaveric donors who have sustained brainstem death, but an increasing proportion come after withdrawal of life support leads to donation after circula- tory death (DCD) in those who have sustained irreversible cardiac or neurological injury. Ideal donors have satisfactory lung function and are free of systemic infection and disease. Donor/​recipient matching is on the basis of ABO blood group, and size. Transplant procedure—​three types of transplant are performed: (1) single lung transplantation; (2) bilateral sequential single or double lung transplantation (required for septic lung diseases and pre- ferred for patients with chronic obstructive pulmonary disease); and (3) heart–​lung transplantation (required for Eisenmenger’s syn- drome or those with complex congenital heart disease). Immediate post-​transplantation management—​important issues are early extubation, fluid (crystalloid) restriction and diuresis, early mobilization, ensuring adequate nutrition, and prevention of infection (with antibacterial, antifungal, antipneumocystis, and anticytomegalovirus prophylaxis). Immunosuppression—​most centres employ a combination of an in- duction regimen based on either an antithymocyte globulin or inter- leukin-​2 receptor blocker, followed by triple therapy with a calcineurin inhibitor (ciclosporin or tacrolimus), a cell cycle inhibitor (azathioprine or mycophenolate), and a corticosteroid (usually prednisolone). Longer-​term management—​the incidence of acute rejection and in- fection are highest in the first 3 months. Acute rejection is diagnosed via transbronchial biopsy and defined by perivascular lymphocytic infiltrates of varying severity, graded from minimal (grade 1) to severe (grade 4): it is usually treated with intravenous methylprednisolone.
Chronic rejection is defined histologically by airway fibrosis with/​without accompanying vascular sclerosis (obliterative bronchiolitis), and is the main cause of death in long-​term survivors of lung transplantation, with complicating infection the most common terminal event. Solid organ and lymphoid malignancies affect up to 4% of recipients. Prognosis—​Long term survival beyond 10 years is increasingly common yet development of chronic lung allograft dysfunction is likely to be a major limitation to normal life. The complications of very long term immunosupression use contribute to overall prog- nosis as much as graft function. Introduction For many patients with end-​stage lung disease, the only prospect for long term survival and improved quality of life is through a successful lung transplant. The first lung transplant was performed in 1963 and the first successful heart–​lung transplant in 1981. Since then, over 55 000 pulmonary transplants have been reported to the registry of the International Society for Heart and Lung Transplantation (ISHLT) from 345 participating institutions. This number, however, falls considerably short of the number of patients with advanced lung disease who might benefit from lung transplantation, and the major challenge facing lung transplantation (as with all solid organ transplants) is the critical shortage of donor organs. Increasing pressure on transplant waiting lists has translated into much more liberal donor acceptance criteria, including the use of donors after circulatory death (DCD donors), with donors over the age of 60 now becoming common. Despite this apparent reduction in donor quality, survival following lung transplantation in the modern era (2009–​2016 ISHLT Registry) has improved to the point where a first-​time lung or heart–​lung transplant recipient has a 12-​month survival of 86%, and a 57% chance of surviving for 5 years with a me- dian survival 6.5 years. Infection remains the most significant problem encountered by the lung transplant recipient at any time. The lung allograft is unique within solid organ transplants in that it is in direct contact with the external environment, and recipients have poor cough reflexes and impaired mucociliary clearance. These factors continuously expose the allograft to potential infections and allergens, which predispose to many of the problems encountered both early and late after transplantation. Obliterative bronchiolitis (OB) remains the most significant long-​term challenge faced by lung transplant recipients and lung 18.16 Lung transplantation P. Hopkins and A.J. Fisher

18.16  Lung transplantation 4293 transplant physicians, with most deaths after the first year attribut- able to this complication. However, the impact of OB is lessening, and recipients are enjoying improved quality of life for many years. The transplant process The transplant process comprises an amalgamation of six separate steps: • recipient selection • donor selection • donor/​recipient matching • the transplant (surgical) procedure • immediate post-​transplantation care • longer-​term monitoring Each of these steps is critical, and a compromise in any one of these areas can spell disaster for the overall outcome. Lung transplantation is unique among solid organ transplants in that several transplant options are available (single lung, bilateral lung, and combined heart–​lung) with the choice of procedure deter- mined primarily by the recipient’s underlying disease process. Recipient selection Type of pulmonary disease Most pulmonary diseases can be considered for transplantation, with emphysema/​chronic obstructive pulmonary disease (COPD, including α1-​antitrypsin deficiency), cystic fibrosis, idiopathic pul- monary fibrosis, and pulmonary vascular disease (idiopathic pul- monary arterial hypertension (iPAH) and Eisenmenger’s syndrome) being the main disease groups referred for lung transplantation. The ISHLT Registry, from January 1995 to June 2017, recorded that 30.6% of lung transplants were performed for emphysema, 25.7% for idiopathic pulmonary fibrosis, 15.4% cystic fibrosis, 4.9% α-1 antitrypsin deficiency, and 4.4% pulmonary vascular disease. Disease (or the major impact of any disease process) should be confined to the thorax, although in carefully selected patients some systemic diseases with predominantly pulmonary manifestations (scleroderma, sarcoidosis, and others) can be transplanted successfully. There are also limited opportunities (largely dictated by donor organ availability and allocation policies) for combined organ transplant- ation, such as lung–​liver transplantation in patients with cystic fibrosis. Prognosis at time of listing Most patients are listed for transplantation when their 2-​year survival is estimated to be less than 50% without a transplant. The prognosis of patients with cystic fibrosis, idiopathic pulmonary arterial hyper- tension, and idiopathic pulmonary fibrosis can be estimated within this sort of time frame. In patients with Eisenmenger’s syndrome and emphysema, however, survival on the waiting list is less predict- able, and in some cases can be as good if not better than following a transplant. There is continued debate as to whether transplantation in this setting should be performed primarily for quality-​of-​life issues. Box 18.16.1 summarizes the specific disease referral recom- mendations, based on guidelines published by the ISHLT. Box 18.16.1  Disease-​specific indications for lung transplantation (based on ISHLT guidelines 2014) Patients with the following characteristics should be considered for referral for transplant assessment. Obstructive lung disease • BODE index of 5–​6 • FEV1 <25% predicted • Diffusing capacity of the lung for carbon monoxide (DLco) <20% • Homogenous emphysema unsuitable for lung volume reduction surgery • Respiratory failure with pO2 <60 mm Hg or 8 kPa and/​or pCO2 >50 mm Hg or 6.6 kPa • Cor pulmonale Cystic fibrosis The following parameters are associated with 20% 2-​year survival on the waiting list, and ideally patients will be referred for assessment before reaching them: • FEV1 <30% predicted • Severe reduction in exercise capacity—​≤400 m on a 6-​min walk or equivalent • Development of pulmonary hypertension In addition, early referral should be considered for: • Adolescent females with rapidly declining lung function • Patients with increasingly frequent and difficult infective exacerbations • Patients with recurrent severe haemoptysis or pneumothorax • Patients with multiple antibiotic resistant organisms Idiopathic pulmonary arterial hypertension • WHO functional class III or IV • Requirement for increasing doses of prostacyclin The following parameters are associated with a median survival of only 12 months and/​or an overall survival of less than 20% at 3 years and are also indications for referral: • Mean right atrial pressure >15 mm Hg • Mixed venous oxygen saturation <60% • Cardiac index <2.0 litres/​min per m2 • 6-​min walk test <350 m Eisenmenger’s syndrome • Severely compromised quality of life • Refractory right heart failure • Frequent presyncopal or syncopal events • Poorly controlled arrhythmia Eisenmenger’s syndrome patients with complex lesions and/​or re- pairs tend to require or benefit from transplantation in their third decade: those with ‘simple’ lesions such as ventricular septal defects (VSD) and patent ductus arteriosus (PDA) tend to come to transplant- ation later, in their fourth decade. Idiopathic pulmonary fibrosis These patients often deteriorate rapidly, with no effective treatment and up to a 30% death rate on the waiting list after only 12 months. Early referral is therefore warranted in the following circumstances: • Radiology or histopathology evidence of usual interstitial pneumonia (UIP) or fibrotic nonspecific interstitial pneumonia (NSIP) regardless of function • Forced vital capacity (FVC) <80% predicted • Transfer factor (DLCO) <40% predicted • Ambulatory oxygen requirement • Dyspnoea or exercise limitation due to lung disease

section 18  Respiratory disorders 4294 Contraindications to transplantation Lung transplantation is a complex undertaking, associated with sig- nificant mortality and the potential for significant morbidity, and patients with a bigger burden of disease (including age) simply do not fare as well after a lung transplant as younger and (in rela- tive terms) fitter patients. Most contraindications are relative and are considered in the context of the patient’s overall status and ex- pected outcome. Patients are generally considered up to 65 years of age, but many units have expanded age criteria so that 13.5% of all lung transplants worldwide are now in recipients 65 years of age or over. The compromise with older recipients is inferior 12 month and longer-​term survival given the burden of immunosuppression and indices of frailty in older people. Major contraindications include patients with untreatable psy- chiatric conditions, or social issues associated with an inability to cooperate or comply with a complex medical regime; substance addiction including cigarette smoking within 6 months; active or incurable extrapulmonary infection; pulmonary infection with pan-​ or multiresistant pathogens; significant chest wall or spinal de- formity; and significant extrathoracic organ dysfunction. Relative contraindications include severe osteoporosis, frailty, and active replicating viral infection with hepatitis B or C.  Successful lung transplantation has been reported in individuals with HIV infection provided their CD4 count is more than 200, undetectable viral load, and no AIDS-​defining illness. Disease recurrence Some diseases for which lung transplantation is applicable can recur after transplantation, including sarcoidosis and some hard metal pneumoconioses, pulmonary lymphangioleiomyomatosis, histiocytosis, α-​1 antitrypsin deficiency, and desquamative intersti- tial pneumonitis. As a general rule, recurrence of these conditions does not significantly affect the transplant outcome, but on occa- sions they do cause diagnostic dilemmas. Cystic fibrosis does not directly affect lung allografts (which do not carry the CFTR genetic abnormality), and idiopathic pulmonary arterial hypertension has not been documented to recur after transplantation Donor selection Types of donor Most lung allografts are procured from cadaveric donors who have sustained brainstem death, typically from spontaneous intra- cranial haemorrhage, ischaemic stroke, or traumatic head injury. Nonethe­less, up to 30% of all lung transplants (depending on re- gion) are performed from DCD donors. DCD donors have suffered catastrophic neurological or cardiac injury and have no prospect of recovery, with withdrawal of life-​supporting measures under- taken in a controlled environment such as the Intensive Care Unit or operating theatre setting. Following cessation of cardiac activity and declaration of death, the deceased donor is transferred to the- atre for organ procurement. Marginal lung donors (defined as at least one of age >60 years, smoking >20 pack years, abnormal chest radiograph, or pO2 less than 300 mm Hg on 100% oxygen) may be accepted for donation and are a source in 45% of all lung transplants. The development of ex-​vivo lung perfusion (EVLP), enabling human lungs to be placed on an external circuit after organ retrieval, has demonstrated ability to expand the donor pool further (see Fig. 18.16.1). Perfusion with fluid with a high albumin content reduces interstitial and alveolar oedema, the key consequences of neurogenic pulmonary oedema in the donor, and thereby facilitates improved gas exchange. Other manoeuvres including ventilation and toilet bronchoscopy may be performed while the lungs are placed on the EVLP circuit to ad- dress areas of atelectasis, consolidation, and retention of secretions. Fig. 18.16.1  (a) Ex vivo lung perfusion (EVLP) machine incorporating an oxygenator, rotator pump, ventilation connections, leukocyte filter, and fluid chamber. (b) A human lung placed on the EVLP circuit being perfused with Steen solution. (a) Reproduced with permission from Vivoline Medical.

18.16  Lung transplantation 4295 A small number of living related lung transplants are performed internationally each year, predominately by adult parents donating a lower lobe to their child with cystic fibrosis. Other criteria The following details refer primarily to donors sustaining brainstem death, but the principles applying to the selection of a lung allograft from any type of donor are the same. All donors should be free of systemic infection or disease. The donor lung is assessed on the basis of function (gas exchange and compliance) and appearance (macroscopic, bronchoscopic, and radiographic). In heart–​lung transplantation, cardiac function is as- sessed via haemodynamic performance based on systemic arterial and venous pressures, urine output, and via Swann–​Ganz cath- eterization. The donor lung is assessed on the basis of function. If indicated (and available), coronary angiography and/​or echocar- diography may be performed, but these investigations are not rou- tinely available at every donor hospital. Lung donors are generally under 60 years of age, although because of the critical shortage of donor organs there is an increasing trend to accept organs from donors significantly older than this. Older donors are more prone to early graft dysfunction, and this is particularly the case in combination with longer organ ischaemic times. Unlike the situation in heart transplantation, there are limited options for improving donor lung function in the donor prior to retrieval. Nonetheless, it is important to optimize function by employing venti- lator strategies that minimize barotrauma, promote alveolar recruit- ment, perform active airway clearance to prevent accumulation of secretions and basal collapse, and use cautious fluid resuscitation of the donor to avoid pulmonary oedema. A potential donor lung will generally be considered acceptable if, just before retrieval, the arterial oxygen level is at least 300 mm Hg (35 kPa) on 100% inspired O2, airways are free of purulent se- cretions, and a chest radiograph is free of consolidation. However, suitability is always considered in the light of donor age, projected ischaemic time, and condition of the potential recipient. EVLP can be used to further assess marginal lungs not meeting traditional cri- teria for acceptance at time of retrieval. Donor/​recipient matching Matching the donor organ with a suitable recipient is done simply on the basis of ABO blood group, with the same principles of ABO matching applying in solid organ transplantation as in blood transfusion practice, and size based on predicted total lung cap- acity calculated from donor sex and height. Perfect size matching is rarely achieved because recipients will have either a restricted or hyperinflated chest cavity reflecting their underlying disease pro- cess (e.g. pulmonary fibrosis and emphysema, respectively). Size-​ matching algorithms are largely based on the experience of the lung transplant team, who need to take into account measured and pre- dicted total lung capacity (TLC) of the recipient, predicted TLC of the donor, CXR measurements from apex to diaphragm, and the type of transplant being performed (single or bilateral lung transplant). As a general rule, oversizing should be avoided as the resultant lung compression and atelectasis predisposes to postoperative infection. By contrast, undersizing creates the opportunity for development of hyperinflation physiology of the lung allograft. The transplant (surgical) procedure Management of the donor, donor lung preservation, and surgical re- trieval of donor lungs are outside the scope of this chapter (but for information, see ‘Further reading’). Surgical options There are three basic options available when replacing diseased lung tissue—​single lung transplantation, bilateral sequential single lung (or double lung) transplantation, and heart–​lung transplantation. The choice of procedure is determined by the recipient’s underlying disease process, by the expected outcome of the procedure in terms of survival and functional result, and on occasions by surgical pref- erence. The commonest disease indications for bilateral lung trans- plantation have been COPD/​emphysema (26.4%), cystic fibrosis (22.3%), and interstitial lung disease (25.7%) and for single lung transplantation, COPD/​emphysema (39.4%) and interstitial lung disease (37.1%). However, it is now recognized that bilateral sequen- tial single lung transplantation is superior to single lung transplant- ation in terms of both long-​term survival and functional status for recipients with emphysema/​COPD. Thus, for patients with emphy- sema/​COPD (including α1-​antitrypsin deficiency), bilateral lung re- placement is now the preferred transplant option. Individuals with severe hyperinflation (TLC >150% predicted) are best served with a bilateral procedure to reduce the risk of native lung hyperinflation causing compression of the transplanted single lung. When this does occur, patients may require surgical lung volume reduction of the na- tive lung with attendant risks of prolonged air leak and infection. Septic lung diseases such as cystic fibrosis and bronchiectasis re- quire the replacement of both lungs (either bilateral lung transplant- ation or heart–​lung transplantation). Diseases such as Eisenmenger’s syndrome that involve both the heart and lungs mandate combined heart–​lung replacement. Some centres/​surgeons also prefer heart–​ lung transplantation for idiopathic pulmonary arterial hyperten- sion, which avoids issues in the immediate post-​transplantation period with a severely dysfunctional right ventricle. Single lung transplantation can be applied to most other diseases but is most effectively used in patients with pulmonary fibrosis (Fig. 18.16.2). In this situation, the underlying restrictive lung dis- ease allows hyperinflation of the allograft, and as a consequence these recipients will often achieve near-​normal spirometry des- pite only receiving a single lung. Older patients with emphysema can also benefit from single lung transplantation because longer-​ term functional requirements in this group are not as demanding as those in younger individuals. Additional benefits of single lung replacement include less blood loss, reduced cardiopulmonary by- pass time, and decreased phrenic nerve injury. Bilateral lung transplantation is performed as two sequential single lung transplantations and can be done via a sternotomy, a bilat- eral thoracotomy, or a ‘clamshell’ incision which involves a bilateral thoracotomy with transection of the lower sternum (Fig. 18.16.3). Heart–​lung transplantation mandates cardiopulmonary bypass and is performed via a sternotomy or clamshell approach. Bilateral sequential single lung transplantation can be performed with or without cardiopulmonary bypass or with extracorporeal lung sup- port (ECLS) depending on the underlying disease (e.g. severe pul- monary hypertension almost always requires cardiopulmonary bypass), and surgical/​anaesthetic preference.

section 18  Respiratory disorders 4296 Surgical principles Successful outcome from any form of lung transplantation requires observation of key surgical principles. Careful and unhurried dis- section minimizes intra-​ and postoperative bleeding, and avoids damage to mediastinal (phrenic, vagus, and recurrent laryngeal) nerves. Careful implantation reduces the chances of vascular or airway anastomotic complications after transplantation. For ex- ample, trimming the donor main bronchus flush with the upper lobe take off and preserving the recipient airway enhances the bronchial circulation and promotes better airway healing. Technical compli- cations, are responsible for 11.8% of the early deaths reported in the latest ISHLT Registry. Implantation and reperfusion should ideally be achieved within 6–​8 hours, because shorter ischaemic times are generally associ- ated with better immediate and short-​term results, particularly when older donors are utilized, as there is less propensity for de- velopment of ischaemia/​reperfusion injury (see next). Likewise, controlled reperfusion of the allograft(s) using low pressures over a prolonged (≥10 min) period is also associated with reduced risk of severe reperfusion injury and therefore improved early allograft function and outcome. Immediate post-​transplantation care The first 24–​48 h after reperfusion of the allograft(s) are critical for minimizing early complications and setting the scene for a good long-​term result. Ischaemia/​reperfusion injury Immediate postoperative care is aimed specifically at reducing the impact of the ischaemia/​reperfusion injury that is sustained by all lung allografts to some degree, and is the underlying cause of pri- mary lung allograft dysfunction, reported in the ISHLT Registry to be the most common cause (24.0%) of death within 30 days of transplantation. The pathophysiology of this process involves injury to and con- sequent dysfunction of the pulmonary vascular endothelium, re- sulting in a breakdown of the normal alveolar–​capillary endothelial barrier, the endothelial injury itself being perpetuated by ventilator-​ induced barotrauma and infection. This manifests as leakage of fluid into alveoli (pulmonary oedema) and impaired gas exchange and is essentially a form of acute lung injury, which in its severest form results in diffuse alveolar damage with all its consequences. Severe pulmonary oedema can be precipitated by injudicious fluid man- agement, even in cases where the initial injury is only mild. Severe Fig. 18.16.2  Chest radiograph of a patient with a left single lung transplant for pulmonary fibrosis. Note the relative hyperinflation of the allograft compared to the native lung. Fig. 18.16.3  Chest radiographs taken before (left panel) and after (right panel) bilateral sequential single lung transplant in a patient with cystic fibrosis.

18.16  Lung transplantation 4297 injury inevitably results in prolonged mechanical ventilatory sup- port with the increased risk of infection and barotrauma, thus per- petuating the injury and potentially leading to irreversible damage to the allograft. Any bleeding requiring significant fluid resuscitation inevitably results in severe pulmonary oedema, the requirement for increased ventilatory support, which again will be associated with the aforementioned problems; hence all efforts should be made to ensure haemostasis at the conclusion of the transplant procedure. With careful management, most cases of severe primary graft dys- function will resolve over a few days. There is no specific treatment, although there are reports of the effective use of exogenous surfactant therapy instilled into distal airways via a fibre-​optic bronchoscope. Nitric oxide can improve gas exchange and thus reduce ventilation pressures, but as yet has not been shown to alter outcomes. In the most severe cases, temporary support with extracorporeal lung sup- port (ECLS) may be required while waiting for allograft recovery. In addition to severe primary graft dysfunction, the other major cause of postoperative morbidity and mortality is infection, pre- dominantly bacterial sepsis, which accounts for 19.1% of reported 30-​day mortality. Key issues in early postoperative management Early extubation Extubation is possible within 12 h of the procedure in most patients, and in many cases much earlier than this, which permits active coughing and clearance of secretions, the institution of enteral nu- trition, and the early commencement of rehabilitation. Fluid restriction and diuresis This minimizes the development of pulmonary oedema, thus op- timizing gas exchange and enabling early extubation. Colloid so- lutions are used for haemodynamic requirements, with vigorous diuresis achieved by regular administration of a loop diuretic (fur- osemide). Diuresis (removal of water) should not be discontinued simply because colloid is required to maintain filling pressures, and total input of oral fluids and intravenous crystalloid (combined) should be rigorously restricted to 1500 ml/​24 h (or thereabouts) in association with vigorous diuresis for at least the first 48 h. Achieving a central venous pressure target of 4–​6 mm Hg is critical early post-​transplant. Early mobilization Patients with end-​stage lung disease are usually debilitated and it is important they are mobilized and commence rehabilitation as early as possible. This prevents complications such as basal atelectasis and deep venous thrombosis, improves appetite, and promotes sleep. Most patients are able to sit out of bed within 24 h and can partici- pate in a gymnasium programme by day 3. Adequate analgesia is im- perative for effective rehabilitation at this early stage, with epidural anaesthesia very effective for pain control following thoracotomy or clamshell incisions. With a sternotomy approach, patient-​controlled analgesia is normally sufficient. Nutrition Patients with end-​stage lung disease are usually nutritionally com- promised and an adequate calorie intake is necessary to overcome the severe catabolism stimulated by surgery. Enteral feeding can usually be started within 24 h (either orally or via a nasogastric tube), but parenteral nutrition may be considered if the gut is not functioning as a result of gastroparesis or postoperative ileus. A new issue that has been increasingly recognized as a potential cause of early allograft dysfunction is gastro-​oesophageal reflux. This can be a particular problem in patients with cystic fibrosis, and can be exacerbated by mediastinal nerve injury (usually revers- ible) sustained during the transplant procedure. Such neural injury may contribute to the development of oesophageal dysmotility and gastroparesis. The problem is discussed in more detail next. Prevention of infection Bacterial infection remains one of the commonest problems en- countered in the perioperative period and responsible for many deaths during the first 30 days. It is a significant factor in the ex- acerbation of ischaemia/​reperfusion injury and acute lung injury, and is the final common pathway of death in most cases affected by this problem. The organisms encountered can be either donor or recipient derived, hence antibiotic prophylaxis (started immediately before transplantation) is tailored according to the recipient’s known or likely microbiology, but can be modified once donor culture re- sults are available. Antibiotics are commonly administered until the patient is mo- bile, all drains have been removed, and respiratory secretions are clear. Antibiotics are chosen to cover Pseudomonas aeruginosa and Staphylococcus aureus in cystic fibrosis and other septic lung dis- eases, and patients with these conditions will usually have well-​ documented microbiology, antibiotic sensitivity, and drug allergy data available to aid in the choice of antibiotic. In other patients, community-​acquired respiratory pathogens (pneumococcus, haemophilus, and others) and Staphylococcus aureus are targeted. Many units administer a broad-​spectrum antibiotic such as vanco- mycin to cover the transplantation procedure and peri-​transplant period until methicillin-​resistant Staphylococcus aureus (MRSA) cultures are confirmed negative. However, despite the availability of effective antibiotics it should be stressed again that the most effective strategy for prevention of bacterial infection after transplantation is early extubation and mobilization. Oropharyngeal candidiasis is common after transplantation and is effectively controlled with topical nystatin or amphotericin: rou- tine systemic prophylaxis against candida is not generally necessary. Aspergillus is the commonest cause of invasive fungal disease in the early postoperative period, and in both single and bilateral lung transplantation, any airway ischaemia renders patients at particular risk of developing this infection and its associated complications. They are at increased risk if exposed to high aspergillus loads, such as can occur in the setting of hospital building work (Figs. 18.16.4 and 18.16.5). Nebulized amphotericin prophylaxis given for the first month after transplantation is effective in reducing aspergillus-​related problems. Added prophylaxis with azole preparations is dependent on local policy and experience. Documented aspergillus infection is treated with either liposomal amphotericin B or voricona­zole, with an echinocandin (caspofungin or anidulafungin) or posaconazole used if these agents are ineffective or not tolerated. Widespread inva- sive disease may require combination therapy. Systemic azole therapy interacts with calcineurin inhibitors and an appropriate dose reduc- tion is required to avoid drug toxicity.

section 18  Respiratory disorders 4298 Viral infections (specifically herpesviruses) tend to occur later in the recovery period, but prophylaxis must be administered from the early stages to be effective. Ganciclovir is very effective in reducing both the incidence and severity of cytomegalovirus (CMV)-​related illness. There is no consensus on the optimal prophylaxis regimen. Some units have opted for a combination of intravenous for the first week followed by oral therapy with valganciclovir for 3–​6 months. The oral formulation of ganciclovir (valganciclovir) is well absorbed and achieves equivalent blood concentrations to intravenous therapy. CMV mismatched transplant recipients (donor CMV posi- tive, recipient CMV negative) are at the highest risk of developing CMV disease and will require a period of prophylaxis, often fol- lowed by a period of monitoring of CMV viral load by polymerase chain reaction. Herpes simplex virus, which most commonly causes mucocutaneous infection and occasionally lower airway infection, is also effectively covered by ganciclovir. Fig. 18.16.4  Chest radiograph and CT showing invasive aspergillosis after bilateral lung transplant. Fig. 18.16.5  (a) Hyphae of aspergillus seen in sputum. (b) Hyphae of aspergillus seen within a heart valve in a case of aspergillus endocarditis after bilateral sequential single lung transplant. (c) Aspergilloma in the upper lobe of an explanted lung.

18.16  Lung transplantation 4299 Co-​trimoxazole prophylaxis is effective in preventing both pneumocystis infection and toxoplasma reactivation. Standard therapy is 480 mg daily or 960 mg three times a week. Therapy is usually continued for a minimum of 12 months but in some units is given lifelong. Nebulized pentamidine or oral dapsone are effective alternatives for those who cannot tolerate co-​trimoxazole. Immunosuppression Three phases of immunosuppression are used in lung transplantation—​ induction, consolidation, and maintenance. Although the details of the exact combinations and doses of agents used vary from unit to unit, the principles are similar. Most regimens employ a combination of three agents: a calcineurin inhibitor (CNI—​ciclosporin or tacrolimus); a lymphocyte prolif- eration inhibitor (azathioprine or mycophenolate); and a cortico- steroid (usually prednisolone). Induction therapy, given either immediately before or after transplantation, is used variably in lung transplantation according to individual unit protocols and/​or in- dividual patient requirements. There is no consistent or conclusive evidence that induction with any agent is associated with better or worse outcomes compared with no induction therapy, but data from the ISHLT Registry shows a small favourable impact of induction therapy on long-​term survival (conditional on 14-​day survival) in lung transplant recipients. There are, however, other benefits of using an induction regimen, such as the ability to introduce CNI therapy more slowly in patients with renal dysfunction, and a reduction in the number of episodes of acute rejection. Induction agents Induction agents commonly used are antithymocyte/​antilymphocyte globulin (ATG/​ALG) and interleukin-​2 receptor (IL-​2R) antagon- ists. ATG and ALG are polyclonal immunoglobulin preparations de- rived from animals (typically rabbit or horse) and directed at CD3 positive cell including T-​lymphocytes. Use of one of these agents for 3–​7 days is associated with profound depletion of circulating T cells, as well as nonspecific immunomodulatory effects which also appear to affect B-​cell functions. Use of these agents can be associated with an increased incidence of side effects, the most important being in- fection and malignancy, but these are much reduced with shorter (3-​day) and less intense courses such that the risk of infection at 1 year and malignancy at 10 years is no different from a cohort who received no induction therapy. Monoclonal antibodies directed at IL-​2R are increasingly being used for induction in lung transplantation, with evidence for this practice being extrapolated from other solid organs, particularly kidney, or taken from small clinical series. IL-​2 is an important signalling molecule leading to the proliferation of activated T cells, hence blocking this signal is very effective at reducing T-​cell alloreactivity. The safety and side effect profile of these agents (either daclizumab or basiliximab) appears to be excellent. Calcineurin inhibitors Calcineurin inhibitors (CNIs) are the cornerstone of immuno- suppressive regimens in all solid organ transplants: they work by preventing IL-​2 production by T cells. Ciclosporin and tacrolimus are the two agents used from this class of drugs. Although they have similar immunosuppressive efficacy, there are several important differences in side effect profiles which dictate use of one or other agent in individual patients. Ciclosporin causes upregulation of TGF​β production and as such contributes to the growth of tissue in general. This can result in cosmetic issues with hirsutism and gum hypertrophy, and overgrowth of nasal polyps, particularly in patients with cystic fibrosis. For this reason, tacrolimus is often substituted for ciclosporin at the onset of bronchiolitis obliterans syndrome in an attempt to reduce airway scarring (see next). Tacrolimus is also diabetogenic, whereas ciclosporin is not. Both agents list nephro- toxicity, hypertension, and dyslipidaemia among their extensive side effect profiles. Cell cycle inhibitors These agents act to directly suppress lymphocyte proliferation at the bone marrow level. Azathioprine is a purine analogue, converted to 6-​mercaptopurine in the liver. It inhibits the early stages of purine metabolism, as well as blocking several enzyme systems, leading to a reduction in the synthesis of nucleic acids. Its major side ef- fects are bone marrow suppression and gastrointestinal (including liver) toxicity. Approximately 1 in 300 patients have a deficiency of thiopurine methyltransferase, the main enzyme in azathioprine me- tabolism. Such individuals are at heightened risk of adverse events with azathioprine and doses need to be reduced. Mycophenolate mofetil (MMF) is an inhibitor of inosine-​5′-​ monophosphate dehydrogenase (IMPDH) and works in a similar fashion to azathioprine, interfering with de novo DNA synthesis. Major side effects are gastrointestinal toxicity and bone marrow suppression. Mycophenolate may have additional clinical bene- fits in transplantation as it has a potent anti-​B-​cell effect, including inhibition of the Epstein–​Barr (EBV)-​driven B-​cell replication re- sponsible for post-​transplantation lymphoproliferative disorders. Furthermore, in heart transplantation the use of MMF in standard immunosuppressive regimens has been shown to be associated with a significantly lower risk of developing malignancy in general. Corticosteroids Corticosteroids have several effects on the immune system, disrupting a variety of signalling and transcription pathways. This results in a nonspecific anti-​inflammatory response, with a predom- inantly lympholytic action when used in high doses. Prednisolone is most commonly used in small oral doses in combination with a CNI and a cell cycle inhibitor as part of a triple immunosup- pression maintenance regimen, or in high doses as intravenous methylprednisolone as part of the transplant induction regimen or for treatment of episodes of acute rejection or nonspecific allograft dysfunction, including organizing pneumonia. mTOR inhibitors Other immunosuppressive agents in clinical use include the mTOR (mammalian Target Of Rapamycin) inhibitors sirolimus and everolimus. These drugs are structurally similar to tacrolimus but work downstream of CNIs, interfering with the T-​cell response to IL-​2 signalling by preventing the progression of the T cell from the G1 to the S phase of the cell cycle. They also have a powerful antiproliferative action and hence are generally not used immedi- ately after transplantation because of their adverse effect on wound healing, including airway anastomotic healing. Other major side ef- fects include oral ulceration, skin rash, haematological (thrombo- cytopaenia, anaemia) disturbances, and dyslipidaemia.

section 18  Respiratory disorders 4300 In lung transplantation mTOR inhibitors have mainly been used in bronchiolitis obliterans syndrome because of their antiproliferative profile, and also as CNI-​sparing agents in cases of significant renal impairment. However, caution should be exercised if these agents are used for the latter indication: some (but not all) trials in kidney and heart transplantation, and anecdotal reports in lung trans­ plantation, have highlighted an unacceptably high rate of acute rejection when mTOR inhibitors have been used without any ad- junctive CNI therapy. Longer-​term monitoring The incidence of acute rejection and infection is highest in the first 3 months. Acute rejection episodes are uncommon after 6 months unless immunosuppression strategies are changed (either inten- tionally or through noncompliance), but infection remains an ever-​ present threat. Baseline lung function is usually established by 6–​9 months after transplantation, this level being used to define subsequent devel- opment of chronic lung allograft dysfunction in the form of bron- chiolitis obliterans syndrome, discussed in detail next, which is the greatest threat to long-​term survival and quality of life faced by lung transplant recipients. The thrust of long-​term management is to maintain allograft function and to minimize the side effects of immunosuppression. As a general principle, immunosuppression should be gradually re- duced, but dose adjustments of all agents must be tailored to indi- vidual requirements, balancing the need to prevent acute rejection against minimization of adverse effects. As time from the transplant increases, outpatient visits to the transplant centre occur less frequently. Monitoring of symptoms, chest radiography, and spirometry are the basis of lung allograft surveillance. Small handheld spirometers are used in some centres and enable daily home monitoring of lung function, with a 10% or greater fall in the forced expiratory volume in 1 second (FEV1) prompting review and investigation of the cause. Bronchoscopy and transbronchial biopsy are performed in the event of new onset allograft dysfunction. Acute rejection and in- fection cannot be distinguished clinically and may occur simul- taneously, hence histopathological confirmation of the cause(s) of dysfunction is highly desirable. Some units perform regular surveillance transbronchial biopsies but there is no evidence that this improves long-​term outcome compared to symptom-​driven biopsies. Specific complications Many of the complications experienced by lung transplant recipients are common to all forms of solid organ transplantation and relate to immunosuppressive drug side effects, including the increased risk of infection. The following discussion focuses on issues specific to lung transplantation. Rejection As in all solid organ transplantation, the lung allograft is at risk of both acute and so-​called ‘chronic’ rejection. These are defined not by their timing of occurrence after transplantation but by their histo- pathology and/​or clinical presentation. Acute rejection can occur at any time after transplantation and is directly related to the effi- cacy of the immunosuppression strategy used. Chronic rejection can occur early (in the first year after transplantation), but is more commonly seen after 2–​3  years. The two processes can coexist. Histopathological criteria for the diagnosis and grading of rejection have been published by the ISHLT. Hyperacute rejection This is a very rare cause of primary graft failure in lung transplant- ation. It is caused by preformed anti-​HLA antibodies in the re- cipient, which activate complement, leading to rapid destruction of the allograft. Plasma exchange, intravenous immunoglobulin, and specific anti-​B-​cell therapies such as intravenous cyclophosphamide and rituximab are used in this scenario. Acute rejection There are two types of acute allograft rejection:  cellular and hu- meral (antibody-mediated). Acute cellular rejection is diagnosed via transbronchial biopsy and defined by perivascular or airway wall lymphocytic infiltrates of varying severity. Perivascular in- filtrates are graded from minimal (grade A1) to severe (grade A4) and airway wall infiltration, also termed lymphocytic bronchiolitis, from mild to moderate (grade B1R) to severe (grade B2R). It is con- ventionally treated with high-​dose intravenous methylprednisolone followed by an oral taper back to the maintenance dose, which is effective in most cases. Steroid resistant acute rejection is usually treated with adjunctive ATG, and if moderate to severe acute re- jection occurs on two or more occasions it is now usual practice to change the background immunosuppression by either substituting tacrolimus for ciclosporin, or mycophenolate for azathioprine (or both), and/​or adding an mTOR inhibitor. Another emerging category of acute rejection is acute humeral re- jection, also known as antibody-​mediated rejection, involving the for- mation of donor specific antibodies generally against HLA antigens. It is defined by the presence of allograft dysfunction, detection of cir- culating donor specific antibodies, and complement deposition with C4d staining on transbronchial lung biopsy. Treatment consists of B-​cell depletion using rituximab and antibody removal with plasma- pheresis followed by intravenous immunoglobulin therapy. Chronic lung allograft dysfunction In lung transplantation, the term ‘chronic rejection’ is something of a misnomer, as both alloimmune and nonalloimmune processes may result in fibrotic obliteration of the airway lumen or fibrotic remod- elling of the lung parenchyma. The term ‘chronic lung allograft dys- function’, or CLAD, is therefore preferred. There are now two main phenotypes of CLAD recognized (see Fig. 18.16.6). The commonest is bronchiolitis obliterans syndrome (BOS), which is a physiological entity defined by airflow obstruction on spirometry and histologically by airway fibrosis with or without accompanying vascular sclerosis. The other phenotype is restrictive allograft syndrome (RAS) which is characterized by a restrictive de- fect on spirometry and extensive parenchymal fibrosis, particularly in the upper lobes. The fibroproliferative scarring characteristic of obliterative bron- chiolitis leads to either total or subtotal obliteration of the affected airway lumen. This translates clinically into progressive airflow ob- struction of varying severity, which can be easily measured using

18.16  Lung transplantation 4301 spirometry, providing a useful noninvasive marker of the both the presence and severity of the condition. Bronchiolitis obliterans syn- drome is defined and graded by a fall in FEV1, as measured from baseline, defined as the average of the two best FEV1 measure- ments achieved after transplantation, taken at least 1 month apart (Table 18.16.1). Reversible causes of a fall in lung function should be excluded before a diagnosis of BOS is made. It has been confirmed in a number of large series that bronchiolitis obliterans syndrome accurately reflects the presence and severity of obliterative bron- chiolitis, and it is widely used in clinical practice for this purpose. The number of severe acute rejection episodes remains the strongest risk factor for the development of obliterative bronchio- litis. However several nonalloimmune factors are increasingly rec- ognized as independent risk factors including gastro-​oesophageal reflux disease, infection with community respiratory viruses, Pseudomonas aeruginosa, or Aspergillus species. Obliterative bron- chiolitis is the main cause of death in long-​term survivors of lung transplantation, with complicating infection precipitating respira- tory failure being the most common terminal event. The rate of progression of CLAD is variable. In some cases of BOS, the disease arrests spontaneously and patients can live for many years with significant airflow obstruction. In many cases the condition slowly progresses, and increases morbidity and contributes to early mortality. In a subgroup of patients, BOS may progress very rapidly and lead to early onset respiratory failure and death despite all attempts to inter- vene. The prognosis in patients who develop the RAS form of CLAD is now recognized to be worse than that in most cases of BOS. Although CLAD is often given a label of ‘chronic rejection’, aug- mented immunosuppression is rarely effective and substantially increases the risk of infection. Most experienced centres change immunosuppression early in the disease process, focusing on antiproliferative strategies, with the substitution of ciclosporin with tacrolimus and the use of mycophenolate and mTOR inhibitors. It is common practice to reduce immunosuppression levels in an attempt to minimize the impact of infections. Other immunomodulatory therapies used to treat BOS include total lymphoid irradiation or extracorporeal photopheresis (ECP), which have both been shown in single centre experiences to slow or even halt disease progression. Selected patients may be considered for retransplantation. The biggest advance in the treatment of potential BOS has come from the use of low-​dose azithromycin to modulate airway inflamma- tion. It is now accepted that approximately 30–​40% of patients who develop clinical features of BOS will show a response to azithromycin by either stabilizing or partially/​fully reversing their fall in lung func- tion. Two randomized controlled trials have confirmed the beneficial effects of azithromycin given either early after transplant to reduce the (a) (b) Fig. 18.16.6  Representative high-​resolution computer tomography (HRCT) images of lung transplant recipients with chronic lung allograft dysfunction. (a) HRCT chest section through the lower lobe in a patient with bronchiolitis obliterans syndrome. Findings include mild bronchiectasis, focal mucous plugging peripherally, peribronchial thickening, and mosaic attenuation indicative of airways disease. (b) HRCT chest section through the upper lobe in a patient with restrictive allograft syndrome. Findings include patchy consolidation, relative volume loss in the right upper lobe and subtle interstitial thickening. Subsequent lung biopsy confirmed organizing pneumonia, diffuse alveolar damage, and interstitial fibrosis with accompanying cellular infiltrate. Table 18.16.1  Classification of bronchiolitis obliterans syndrome Baseline Average of two best FEV1 measurements achieved
post-​transplantation, taken at least 1 month apart Bronchiolitis obliterans syndrome Grade 0 FEV1 >80% baseline Grade 1 FEV1 66–​79% baseline Grade 2 FEV1 51–​65% baseline Grade 3 FEV1 <50% baseline

section 18  Respiratory disorders 4302 incidence of BOS and also given after BOS diagnosis to improve lung function. Unfortunately, some of those who initially responded to azithromycin will subsequently develop progressive BOS again. Malignancy Solid organ and lymphoid malignancies occur at an increased fre- quency in lung transplantation, affecting up to 4% of recipients. Post-​transplant lymphoproliferative disease (PTLD) is frequently related to EBV-​driven B-​cell proliferation and to the intensity of im- munosuppression, and in a small number of cases to primary EBV infection in EBV-​naive recipients. In lung transplantation most cases of lymphoproliferative disorder are focused in the allograft, with most occurring in the first 12–​18 months after transplantation. Patients are usually treated with dramatically reduced background immunosuppression, which involves reducing calcineurin inhibitor levels to 30–​50% of previous maintenance levels, stopping the cell cycle inhibitor, and reducing prednisolone. Careful monitoring for acute rejection is required once levels of immunosuppression have been substantially reduced. If the PTLD does not show regression with reduce immunosup- pression or if the disease is threatening organ function, rituximab is administered for B-​cell dominant tumours and CHOP-​based chemotherapy is indicated for those who do not respond, or if hist- ology demonstrates high-​grade lymphoma. There are no evidence-​ based data to support these recommendations, which are based on clinical experience only. The prognosis of these disorders is surprisingly good, especially if confined to a single organ system and if disease responds to a reduction in immunosuppression, but patients diagnosed with advanced disease invariably have a poor outcome. Occasionally, despite thorough donor screening, a lung malig- nancy will be transplanted into the recipient. Inevitably this will lead to the development of clinically significant disease, although sur- prisingly this may not occur for many years. Airway complications The bronchial anastomosis is devoid of its normal bronchial ar- terial supply and therefore prone to the development of problems relating to ischaemia and subsequent scarring (Fig. 18.16.7). These range from asymptomatic narrowing (often related to size mismatching of the donor and recipient airway) to severe sten- osis requiring intervention, and occasionally to dehiscence and death. Areas of ischaemic airway are at increased risk of infec- tion, particularly with fungi, and care is needed to ensure organ- isms such as Aspergillus species do not worsen the viability of the anastomosis. Most units experience an airway complication rate of between 5 and 10%. Bronchial artery revascularization procedures are time-​consuming, technically demanding, and not widely per- formed. Bronchial stenoses are effectively treated with airway dilatation and stenting, which is optimally performed after the early inflammation related to ischaemia and infection has re- solved (Fig. 18.16.8). Heart–​lung transplantation is rarely associated with airway complications as the tracheal anastomosis has a collateral blood supply derived from the coronary arteries and is generally not ischaemic. Gastro-​oesophageal reflux Gastro-​oesophageal reflux disease (GORD) is common in lung transplant recipients. There is a high prevalence of GORD in pa- tients with severe chronic lung disease before transplant but the risk of intraoperative vagal nerve injury and the side effects of post-​transplant medication can cause sphincter dysfunction and delayed gastric emptying, which significantly exacerbate the problem. It can be strongly suspected if transbronchial biopsy of the allograft reveals food matter or highly positive Oil Red O staining, and should be considered if there are recurrent acute epi- sodes of allograft dysfunction, particularly if associated with or- ganizing pneumonia. The condition is asymptomatic in upwards of 60% of lung transplant recipients because of the widespread use of proton pump inhibitors. It is a particular problem in the pa- tient with cystic fibrosis. There are no standardized approaches to screening for GORD after lung transplant. Some centres refer all patients for routine 24 h pH monitoring and oesophageal manometry at 3 months post-​transplant, whereas others will refer Fig. 18.16.7  Appearance at 2 weeks of bronchial anastomosis with mucosal slough secondary to ischaemia: this airway would be expected to heal well.

18.16  Lung transplantation 4303 symptomatic patients or those with unexplained allograft dysfunc- tion. Laparoscopic fundoplication is the treatment of choice if sig- nificant reflux is demonstrated. Outcome Many studies have shown that lung transplantation confers signifi- cant survival and quality-​of life-​benefits. Survival figures of 90% at 1 year, 70% at 5 years, and 50% at 10 years are now achievable for all types of lung transplant and underlying disease categories. The main contributor to mortality in the first 12 months is in- fection (predominantly bacterial). Acute rejection rarely causes death directly. CLAD is the main factor determining long-​term survival in most lung transplant recipients. Coronary artery vasculopathy affecting the cardiac allograft in a heart–​lung trans- plant occurs predominantly in the setting of CLAD, and it is the airway disease that dominates the clinical picture long term in all forms of lung transplantation. Survival is usually associated with markedly improved lung function that translates into improved functional capacity. As long as lung function is maintained (implying an absence of bron- chiolitis obliterans syndrome), quality and quantity of life are maintained. Many patients are able to return to work and live a near-​normal life. FURTHER READING Barr ML, et al. (1998). Recipient and donor outcomes in living related and unrelated lobar transplantation. Transplant Proc, 30, 915–​22. Boehler A, Estenne M (2003). Post-​transplant bronchiolitis obliterans. Eur Respir J, 22, 1007–​18. Chambers DC, et al. (2017). The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung and Heart-Lung Transplantation Report – 2017; Focus Theme: Allograft ischaemic time. J Heart and Lung Transplant, 36, 1047–60. Charman SC, et al. (2002). Assessment of survival benefit after lung transplantation by patient diagnosis. J Heart Lung Transplant, 21, 226–​32. Christie JD, et al. (2005). ISHLT Working Group on Primary Lung Graft Dysfunction Parts I—​VI. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction. J Heart Lung Transplant, 24, 1451–​500. Crespo M, et  al. (2018). ISHLT Consensus Statement on adult and paediatric airway complications after lung transplantation: Definitions, grading system and therapeutics. J Heart and Lung Transplant, 37, 548–64. Dennis CM, et al. (1993). Heart–​lung transplantation for end-​stage respiratory disease in patients with cystic fibrosis at Papworth Hospital. J Heart Lung Transplant, 12, 893–​902. Dennis CM, et al. (1996). Heart–​lung–​liver transplantation. J Heart Lung Transplant, 15, 536–​8. Heng D, et al. (1998). Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors. J Heart Lung Transplant, 17, 1255–​63. Herrera JM, et al. (2001). Airway complications after lung transplant- ation:  treatment and long-​term outcome. Ann Thorac Surg, 71, 989–​93. Higgins R, et al. (1994). Airway stenosis after lung transplantation: management with expanding metal stents. J Heart Lung Transplant, 13, 774–​8. Hopkins PM (2006). Pharmacological manipulation of the rejection response. Methods Mol Biol, 333, 375–​400. Hulbert AL, et al. (2018). Current challenges and opportunities in the management of antibody-mediated rejection in lung transplant- ation. Curr Opin Organ Transplant, 23, 308–15. Jackson CH, et al. (2002). Acute and chronic onset of bronchiolitis obliterans syndrome (bronchiolitis obliterans syndrome): are they different entities? J Heart Lung Transplant, 21, 658–​66. Jonas M, Oduro A (1997). Management of the multi-​organ donor. In:  Higgins RSD, et  al. (eds) The multi-​organ donor. Selection and management, pp. 123–​9. Blackwell Scientific Publications, Oxford. Kulkarni H, et  al. (2019). Bronchiolitis obliterans syndrome-free survival after lung transplantation: An International Society for Heart and Lung Transplantation Thoracic Transplant Registry ana- lysis. J Heart and Lung Transplant, 38, 5–17. Levine D, et al. (2016). Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation. J Heart and Lung Transplant, 35, 397–407. Fig. 18.16.8  An expanding metal ‘ultraflex’ stent in a bilateral sequential single lung transplant recipient.

section 18  Respiratory disorders 4304 McNeil K, Dennis CM (1998). Heart–​lung transplantation: inten- sive care. In: Klinck JR, Lindop MJ (eds) Anaesthesia and inten- sive care for organ transplantation, pp. 115–​20. Chapman & Hall, London. McNeil K, Wallwork J (1997). Principles of lung allocation. In: Collins GM, et al. (eds) Procurement, preservation and allocation of vascula- rised organs, pp. 223–​6. Kluwer, Dordrecht. Orens JB, et al. (2006). A consensus document for the selection of lung transplant candidates: 2014—​an update from the Pulmonary Transplantation Council of the International society for Heart and Lung Transplantation. J Heart Lung Transplant, 34, 1–​15. Sharples LD, et al. (2002). Risk factors for bronchiolitis obliterans: a systematic review of recent publications. J Heart Lung Transplant, 21, 271–​81. Studer SM, et  al. (2004). Lung transplant outcomes:  a review of survival, graft function, physiology, health-​related quality of life and cost-​effectiveness. Eur Respir J, 24, 674–​85. Verleden GM, et al. (2014). A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant, 33, 127–​33. Yeatman M, et al. (1996). Lung transplantation in patients with sys- temic diseases:  an eleven year experience at Papworth Hospital.
J Heart Lung Transplant, 15, 144–​9. Yousem SA, et al. (1996). Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant, 15, 1–​15. Yusen R, et al. (2014). Registry of the International Society for Heart and Lung Transplantation: thirty-​first official adult lung and heart–​lung transplantation report. J Heart and Lung Transplant, 33, 1009–​24.

18.17 Pleural diseases 4305 D. de Fonseka, Y.C. Ga

18.17 Pleural diseases 4305 D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell

ESSENTIALS Pleural effusion—​general considerations This is a common clinical problem which can complicate a range of lung and systemic diseases. Most cases can be diagnosed by pleural fluid analysis and pleural biopsy. Light’s criteria enables discrimin- ation between transudates and exudates. These state that a pleural effusion is an exudate if any of the following are present: (1) pleural fluid to serum protein ratio greater than 0.5; (2) pleural fluid lactate dehydrogenase (LDH) greater than two-​thirds of the upper limit of normal serum LDH; (3) pleural fluid to serum LDH ratio greater than 0.6. Aetiology—​common causes of a transudative effusion are heart failure and liver cirrhosis; common causes of an exudative effusion are malignancy, empyema/​parapneumonic effusion, and tuberculosis. Diagnosis—​low pH and low glucose levels are found in pleural fluid caused by very intense inflammatory processes, most com- monly pleural infection, or malignancy. A single cytological test of pleural fluid for malignant cells is about 50% sensitive for malignancy, with a second sample increasing the sensitivity to about 60%. Where cytology is negative, image-​guided pleural cutting needle biopsy or thoracoscopy are the most sensitive techniques to identify ma- lignancy (c.80%) and are superior to closed pleural biopsy (c.45%). A  high pleural fluid adenosine deaminase (ADA) activity strongly supports the diagnosis of tuberculosis in TB endemic regions. A low pleural fluid ADA level effectively excludes TB pleuritis in a low inci- dence setting. Alternatively, tuberculosis can be diagnosed by pleural biopsy (closed biopsy c.80% sensitive vs. thoracoscopy c.100%). Where an effusion remains undiagnosed, specifically treatable con- ditions such as pulmonary embolism and drug-​induced pleuritis should be reconsidered. Pleural effusion—​particular diseases Pyogenic pleural infection—​community-​acquired infection is usu- ally due to Streptococci (50% of cases, including the milleri group, and S. pneumoniae), enterobacteria, anaerobes, and Staphylococci; hospital-​acquired infection is most commonly due to Staphylococcus aureus (50% of cases, of which many can be methicillin-​resistant (MRSA)), enterobacteria, or enterococci. Clinical features can range from fulminant sepsis to an indolent presentation with weight loss. Diagnosis depends on sampling pleural fluid to identify purulence, the presence of bacteria or low pleural pH/​glucose levels. The treatment depends on effective chest tube drainage, appropriate antimicrobials (usually for at least 3 weeks), adequate nutrition, and prompt thoracic surgical drainage where clinical recovery is delayed. The associated mortality is greater than 20%. A recent randomized trial has suggested the usefulness of intrapleural administration of tissue plasminogen activator (tPA) and deoxyribonuclease (DNase) in improving radiographic and clinical outcomes. Tuberculous pleural effusion and empyema—​hypersensitivity tu- berculous pleurisy is due to a delayed hypersensitivity reaction to mycobacteria in the pleural space, often occurs in cases of pri- mary infection, and is associated with a low pleural mycobacterial load. Diagnosis is often dependent on pleural histology revealing caseating granulomas. Tuberculous empyema is caused by rupture of cavitating tuberculosis into the pleural space and usually involves coinfection with mycobacteria and pyogenic bacteria (due to inocu- lation of the pleural space from the infected lung tissue). Treatment is as for tuberculosis elsewhere. Antibiotics for pyogenic bacteria are required in addition to antituberculous treatment in tuberculous empyema. Chylothorax and pseudochylothorax—​turbid or white pleural fluid has three common causes, with diagnosis established by lipid ana- lysis of pleural fluid: (1) true chylothorax—​due to leaking of chyle from a damaged thoracic duct, usually caused by lymphoma, other can- cers, and trauma (including surgery); treatment is of the underlying disease where possible, and talc pleurodesis or thoracic duct repair for fluid control. Nutrition is a high priority; (2) pseudochylothorax—​ due to chronic pleural inflammation; and (3) empyema. Haemothorax—​most commonly caused by chest trauma or iatrogenically, haemothorax is distinguished from heavily blood stained pleural effusion by the pleural fluid haematocrit being greater than 0.5 of that in blood. Traumatic haemothorax is not detectable on a presentation chest radiograph in 20% of cases, when it subse- quently evolves over a few days. Initial treatment is by large-​bore chest tube drainage. About 20% of patients require surgery (video-​ assisted thoracoscopic surgery, or thoracotomy) to control blood loss, repair organ injury, and evacuate the blood. Failure to evacuate a large haemothorax can lead to late extensive pleural fibrosis (‘fibrothorax’). 18.17 Pleural diseases D. de Fonseka, Y.C. Gary Lee, and N.A. Maskell

section 18  Respiratory disorders 4306 Benign asbestos-​induced pleural disease—​the commonest benign asbestos-​induced pleural disease is pleural plaque. These are fibrotic and sometimes calcified pleural thickenings on the lateral chest wall and the dome of the diaphragm that have no clinical significance. Diffuse pleural fibrosis is less common and occurs due to asbestos-​ mediated pleural inflammation, sometimes following benign as- bestos pleural effusion. There is no specific treatment and care is supportive. When visceral pleural thickening causes the lung to en- fold it forms a characteristic lesion known as ‘rounded atelectasis’. Pneumothorax Pneumothoraces, defined as air in the pleural space, are classified as traumatic (including iatrogenic) or spontaneous, with the latter being primary (where the lung is largely normal) or secondary (where the pneumothorax is due to an underlying lung disease, most commonly chronic obstructive pulmonary disease). The diagnosis is usually es- tablished by visualization of a lung edge—​a pleural line—​on the chest radiograph. Treatment involves removing air from the pleural cavity and preventing recurrence. Primary pneumothorax—​associated with smoking, tall stature, and the presence of macroscopic subpleural apical lung blebs; gener- ally a benign disease; usually treated conservatively. Supplementary oxygen can be given (where the patient is an inpatient) to hasten reabsorption. Aspiration is recommended for symptomatic large pneumothorax of greater than 50% of hemithoracic volume, with chest tube drainage required if this fails. Recurrence rate is approxi- mately 40%, with video-​assisted thoracic surgery typically recom- mended to prevent recurrence in patients who have had two events. All should be advised to stop smoking as this is a major risk factor for recurrence. Secondary pneumothorax—​can sometimes be difficult to differen- tiate from a large bulla; CT is useful in this setting. All patients require hospitalization for a period of observation and most require chest tube drainage and recurrence prevention. Tension pneumothorax—​a rare but important variant of pneumo- thorax where a ‘flap valve’ mechanism at the visceral pleural sur- face results in the development of increasing positive pressure in the pleural space. Diagnosis is based on the clinical features of a large pneumothorax with mediastinal shift away from the affected side, cardiovascular compromise, and severe progressive dyspnoea. Tension pneumothorax should be treated by urgent thoracic decom- pression, followed by placement of a chest tube. Introduction Pleural disease is a common problem, affecting 3000 per million population each year, contributing to a significant workload for every chest physician. Pleural effusion is the commonest pleural pathology, closely followed by pneumothorax. Anatomy and physiology of the pleura The pleura is a serous membrane that covers the lung parenchyma, rib cage, mediastinum, and the diaphragm. The visceral pleura covers the lung parenchyma, including the interlobar fissures. The parietal pleura covers the mediastinal structures, chest wall, and diaphragm. The pleural membrane consist of a monolayer of mesothelial cells that are metabolically active and are capable of synthesizing numerous inflammatory mediators in response to stimuli, which regulate biological responses within the pleural cavity and facilitate transport of molecular and particulate material across the pleural surfaces. The parietal pleura, particularly the costal and diaphragmatic portions has sensory nerve endings and is innervated by the intercostal nerves. Trauma or inflammation irritating the par- ietal pleura can be perceived as pain on the chest wall at this level. The visceral pleura, although contains sensory receptors, does not contain pain fibres. The normal pleural cavity contains a very small volume of fluid for lubrication (c.0.13 ± 0.06 ml/​kg body mass, per pleural cavity). The fluid is mostly filtered from the systemic blood supply of the intercostal arterial circulation of the parietal pleura, with a bio- chemical composition resembling that of other interstitial fluids. The bronchial circulation of the visceral pleura is unlikely to con- tribute significantly to the fluid formation process in humans as the visceral pleura is thick and the microvascular pressure for fluid filtration in the bronchial circulation is low. Fluid filters between mesothelial cells and into the pleural space according to the net hydrostatic–​oncotic pressure gradient, and some molecules can be actively transported through the mesothelial cells. Pleural fluid accumulates when the rate of pleural fluid formation exceeds the rate of fluid reabsorption. The drainage capacity of the parietal pleural lymphatics can increase up to 30-​fold from its baseline values observed during normal physiological states, hence signifi- cant increase in fluid formation and/​or impairment of pleural fluid reabsorption is usually needed for diseases to produce a pleural effusion. Pleural imaging A chest radiograph (CXR) is a simple and easy imaging modality as a first assessment for suspected pleural disease. The normal parietal and visceral pleurae are not visible on the CXR, except for the double layer of visceral pleurae of the fissures. CT, MRI, and PET Three-​dimensional imaging is very helpful in the differential diag- nosis of pleural effusion. CT and MRI are equally effective in defining pleural anatomy, though CT is favoured for cost and convenience reasons. MRI is preferred where minimizing radiation dosage is particularly important (e.g. a young woman with benign disease, to avoid irradiating breast tissue). CT technique is important to achieve effective delineation of pleural abnormality. Images should be gathered with pleural fluid in situ and following intravenous contrast administration. The contrast medium should be given time to enter the tissue phase (60–​90 s after injection), to allow for the enhancement of abnormal parietal pleural tissue which is then easily seen against the lower attenuation pleural fluid (Fig. 18.17.1). Pleural thickening which is nodular and circumferential, extending over the mediastinal pleural surface, involving the interlobar fissures or is more than 1 cm in thickness is suggestive of malignant disease, and CT scan approaches 100% specificity for malignancy where all these criteria are fulfilled. The use of MR imaging to differentiate between malignant and benign pleural disease is increasing. The absence of ionizing radi- ation and high soft tissue contrast and intrinsic flow sensitivity are

18.17  Pleural diseases 4307 some of the features that make MRI more attractive. Combination of morphological and functional imaging sequences using diffusion weighted and dynamic contrast-​enhanced MRI can increase the sensitivity and specificity of MRI when used to diagnose malignant pleural disease. Positron emission tomography (PET) scanning is sensitive for pleural malignancy but of limited specificity as it cannot dif- ferentiate tumour from pleural inflammation (including em- pyema, tuberculosis, and the effects of pleurodesis). Some centres now use PET scanning in the staging of mesothelioma. It has a role in predicting survival in malignant mesothelioma, particu- larly when used to assess response to treatment for those having chemotherapy. Ultrasound examination Ultrasonography is simple portable and able to provide real-​time point-​of-​care imaging with no radiation. It is increasingly per- formed at the bedside by appropriately trained respiratory phys- icians (Fig. 18.17.2). Following an unsuccessful ‘blind’ attempted pleural aspiration, subsequent ultrasound directed aspiration is successful in 87% of the cases. Pleural ultrasound offers vital infor- mation with regards to size of effusion, other characteristics such as septations and loculations, and location with regards to other nearby structures. Patients with effusions that are small or appear loculated on the chest radiograph should have pleural fluid sam- pling performed under ultrasound guidance. Pleural fluid that ap- pears septated on ultrasound is consistently exudative, although Fig. 18.17.1  Identification of malignant pleural tumour by CT scanning. Imaging was performed in the same patient without contrast administration (a) and 90 s after the administration of intravenous contrast to allow it to enter the ‘tissue phase’ (b). Parietal pleural thickening (due to pleural malignancy) which was invisible on the unenhanced images is clearly seen following contrast enhancement (arrow). (a) (b) Fig. 18.17.2  The appearances of a free-​flowing right pleural effusion on ultrasound (a) the large echo free area is the pleural effusion (PE). The diaphragm (D), liver (Li) and lung (Lu) are shown. Fig. (b) shows multiple septae (S) in a complicated parapneumonic effusion.

section 18  Respiratory disorders 4308 free-​flowing effusions can be transudates or exudates. Nodularity of the pleura or diaphragm, which is suggestive of malignancy, can also be identified on ultrasound. Pleural effusion—​general considerations Pleural effusions are common, with an incidence of greater than 0.3% of the population each year. It is a common medical problem com- plicating a range of lung and systemic diseases, hence establishing the cause can be challenging. Approximately 75% of pleural effu- sions are caused by malignancy, pneumonia, heart failure, and tuberculosis. Formation of pleural effusion Pleural fluid accumulates when the rate of pleural fluid forma- tion exceeds the rate of pleural fluid removal due to a combination of intravascular pressures (positive driving pressure), increased pleural fluid protein levels (pleural oncotic pressure), and de- creased intrapleural pressure (e.g. due to lung collapse). Changes in pressure gradients produce a transudate with a low protein con- centration, and changes in vascular permeability produce an ex- udate with a high protein level. Inflammatory cellular debris and pleural fluid protein increase oncotic pressure, further promoting fluid collection. Fluid may also enter the pleural cavity by leaking from other structures. Abdominal fluid (ascites or peritoneal dialysis fluid) may cross the diaphragm. Chyle can enter from a ruptured thoracic duct (chylothorax), blood from a blood vessel (haemothorax) or, rarely, urine from the kidney (urinothorax) or bile from the biliary tract (bilo or chylothorax). Occasionally a pleural effusion could be due to a direct communication with another organ such as an oesophago-​ pleural fistula. The most common cause of decreased pleural fluid absorption is parietal pleural malignancy or obstruction of the lymphatics draining the parietal pleura due to inflammation (e.g. empyema or tuberculosis). Pleural effusion development often involves both an increase in fluid formation and a decrease in its absorption. Physiological consequences The accumulation of pleural fluid is usually accompanied by an increase in pleural pressure in the thoracic cavity. The degree of dyspnoea induced by a pleural effusion is related to the effect of the increased pleural pressure on the hemidiaphragm and the loss of functioning lung parenchyma. If the hemidiaphragm is domed and is functioning normally, dyspnoea is mild and worsens as the hemidiaphragm flattens or everts. High pleural pressures due to a large effusion can impair cardiac function by reducing venous return. In animals, right ventricular diastolic collapse begins when mean pleural pressure is increased about 5 mm Hg, and cardiac output falls about 30% if mean pleural pressure reaches 15 mm Hg. Clinical features Establishing a diagnosis begins with history and examination (Table 18.17.1), particularly seeking any history of asbestos or tu- berculosis exposure, previous or current malignancy, smoking his- tory, and a drug history (Box 18.17.1). Clinical assessment can often reliably identify the causes of transudative effusions, and effusions in the context of heart failure do not need to be sampled unless there are atypical features (e.g. fever, chest pain, bilateral effusions of disparate sizes, and so on) or they fail to respond to therapy. Approximately 75% of effu- sions related to cardiac failure will resolve within a few weeks with optimum diuretic therapy. Effusions that persist require further investigation. Investigation—​imaging The aim when investigating a patient with a pleural effusion is to reach an accurate diagnosis with the least invasive procedure and as few invasive pleural procedures as possible, thus reducing symptoms (i.e. dyspnoea, pain, cough), the risk of infection, the risk of pleural fluid loculation and septation (making later fluid control difficult), and the frequency of chest wall tumour invasion in patients who ultimately prove to have malignant pleural mesothelioma, which is common in the United Kingdom. Table 18.17.1  Causes of transudative and exudative pleural effusions Transudative effusion Exudative effusion Common Heart failure Malignancy Liver cirrhosis Empyema/​parapneumonic effusion Hypoalbuminaemia Tuberculosis Uncommon Atelectasis Pericardial diseases Peritoneal dialysis Pulmonary embolism Nephrotic syndrome Post-​surgery (cardiac, thoracic, or abdominal) Pulmonary arterial hypertensiona Post-​cardiac injury syndrome Chylothoraxa and cholesterol effusions Viral pleuritic Haemothorax Acute and chronic pancreatitis Autoimmune rheumatic diseases Rare Glomerulonephritis Drugs (see Box 18.17.1) Superior vena cava obstruction Fungal and parasitic infections Hypothyroidism Meigs’ syndrome Urinothoraxa a These effusions may meet transudative or exudative criteria. Box 18.17.1  Drugs particularly associated with pleural effusion Cabergoline Pergolide Amiodarone Dasatinib/​Bosutinib Nitrofurantoin Phenytoin Methotrexate

18.17  Pleural diseases 4309 Chest radiography The clinical history and examination are supplemented by an erect, plain chest radiograph (Fig. 18.17.3). Characteristically an effusion forms a basal opacity, drawn into a fluid meniscus by surface tension, and the costophrenic angle is lost, which helps differentiate pleural fluid from dense lung consolidation. The radiograph may also demonstrate pleural calcification, due to be- nign asbestos-​related pleural plaques, or previous chronic pleural inflammation (particularly tuberculous treated with an artificial pneumothorax, or a chronic bacterial empyema, Fig. 18.17.4). Failure of the pleural fluid to form a typical basal opacity sug- gests loculation of the fluid, which most commonly occurs in exudative effusions, particularly those that are heavily inflamed (see section on ‘Pyogenic pleural infection’, next). In patients imaged supine, free-​flowing pleural fluid lies posteriorly, and is seen as a hazy opacity of one hemithorax (Fig. 18.17.3). Bilateral effusions associated with an enlarged cardiac silhouette are usually due to heart failure, whereas the absence of cardiomegaly should raise suspicion of alternative diagnoses. Two-​thirds of effusions that opacify the entire hemithorax have a malignant origin, although parapneumonic effusions, tuberculosis, and hepatic hydrothoraces may also mani- fest as massive effusions. Concurrent causes of pleural pathologies can coexist. Fig. 18.17.3  Chest radiograph appearances of a free-​flowing left pleural effusion imaged erect (a); a massive right pleural effusion with mediastinal shift (b); and a pleural effusion radiographed supine (c) and erect (d) in the same patient.

section 18  Respiratory disorders 4310 Investigation—​Pleural fluid analysis The first investigation of an undiagnosed pleural effusion should be a diagnostic aspiration, whereby a small volume of pleural fluid is as- pirated through a fine bore (c.21 G) needle, under ultrasound guid- ance. In a very large symptomatic effusion, 1–​2 litres of fluid may be removed to reduce breathlessness, but the thorax should not be completely drained as leaving some fluid can help with subsequent CT or pleural biopsy if necessary. The odour and colour of pleural fluid should be noted. Bloodstained pleural fluid suggests malignancy, trauma, pulmonary infarction or embolism, benign asbestos effusion, or post-​cardiac surgery syndrome. Milky pleural fluid suggests a chylothorax, pseudochylothorax (see later in this chapter) or occasionally, em- pyema. Foul-​smelling fluid suggests anaerobic pleural infection and pleural fluid that smells like urine suggests urinothorax. Fluid should be sent for estimation of protein and lactate de- hydrogenase (LDH) concentrations (to differentiate pleural transu- dates and exudates); cytological assessment for malignant cells, and dominant cell type (e.g. neutrophilic vs. lymphocytic) and pH and/​ or glucose levels, Gram smear for bacteria, and microbial culture. Additional tests can be ordered if clinically appropriate, including adenosine deaminase (ADA) and TB culture for TB, and flow cytometry for lymphoma. Transudative and exudative effusions Differentiating if an effusion is a transudate or an exudate is a useful first step as this can guide the best investigational pathway to obtain a diagnosis. A transudate is unlikely to be due to a primary pleural pathology and usually resolves when the underlying cause is treated. Exudative effusions with a high protein and/​or LDH content are commoner and can be manifestation of range of pleural and sys- temic diseases. Transudative and exudative effusions are usually differentiated using ‘Light’s criteria’. A pleural effusion is an exudate if it satisfies any of the following criteria: • Pleural fluid to serum protein ratio more than 0.5 • Pleural fluid LDH more than 2/​3 of the upper limit of normal serum LDH • Pleural fluid to serum LDH ratio more than 0.6 Analysing pleural fluid protein and LDH concentrations as con- tinuous variables improves their diagnostic accuracy slightly, but the traditional simple threshold criteria are generally robust in clinical practice. The leading causes of transudates are heart failure (80%) and liver cirrhosis (13%). Light’s criteria are highly sensitive (98%) in identifying exudates, but misclassify 20–​30% of transudates as ex- udates, almost exclusively in patients receiving diuretic therapy. In those thought to have heart failure or cirrhosis whose pleural fluid meet exudative Light’s criteria, a serum to pleural fluid albumin gra- dient more than 1.2 g/​dl or a pleural fluid to serum albumin ratio less than 0.6, respectively, points to a truly transudative effusion. Serum or pleural fluid levels of the natriuretic peptide NT-​proBNP more than 1300 pg/​ml indicates that the effusion is almost certainly secondary to heart failure. Pleural fluid cytology for malignant cells Overall, only 60% of patients with malignant pleural disease will have a positive diagnosis established by a single cytological test of pleural fluid. This is increased if both cell blocks and smears are pre- pared. A further 5–​10% are identified by a second fluid sample, but a third examination adds little. The sensitivity of pleural cytology depends on tumour cell type, a low yield being common for diseases like lymphoma and malignant mesothelioma. Malignant mesothelioma is particularly difficult to diagnose with cytology, and only about 20% of cases are positive. Immunocytochemistry helps distinguish between benign and ma- lignant cells, as well as between different cancer types. Diagnosis of pleural infection Pleural fluid Gram’s smear for bacteria and microbial culture should be performed in all cases of exudative pleural effusion. Inoculation of pleural fluid into culture medium bottles (widely used for blood cultures) will improve the sensitivity of bacterial culture but at least 40% of cases of pleural infection are negative by standard culture techniques. Where there is a reasonable sus- picion of mycobacterial disease, pleural fluid should be tested for acid-​ and alcohol-​fast bacilli, ADA, and TB culture ordered. Intense pleural inflammation reduces pleural fluid pH as lactate is produced by leucocyte and bacterial metabolism. A pleural fluid pH of less than 7.2 (measured on a heparinized pleural fluid sample with a blood gas analyser), in association with a clinical presentation suggestive of pleural infection, is a clinic- ally robust diagnostic test that predicts the need for pleural effu- sion drainage, as well as antibiotic therapy, hence measurement of pleural fluid pH should be routine in the assessment of all non-​ purulent pleural effusions. The interpretation of a pleural acidosis should always consider the differential diagnosis of other diseases that cause intense pleural inflammation and so lower pleural pH, particularly rheumatoid disease, oesophageal perforation Fig. 18.17.4  Right pleural calcification following treatment of tuberculosis with an artificial pneumothorax in the prechemotherapy era.

18.17  Pleural diseases 4311 (which is causing pleural infection), advanced malignancy, and tuberculosis. The inflammatory processes that produce pleural acidosis also reduce pleural fluid glucose as it is consumed by metabolically ac- tive cells and bacteria, and raise the pleural fluid LDH level as this is released from apoptotic leucocytes. Quantifying these indices are alternative ways of identifying intense pleural inflammation, but in practice they add little to the measurement of pleural fluid pH alone. Other pleural fluid analyses to diagnose exudative
pleural effusion A pleural fluid amylase level is useful for diagnosing the cause of exudative pleural effusion associated with pancreatitis, which can sometimes occur without abdominal pain. Isoenzyme analysis shows that the amylase is pancreatic in origin. Oesophageal perfor- ation allows amylase of salivary origin to enter the pleural space, and identification of this can suggest an oesophageal leak. Some adeno- carcinomas also secrete amylase (usually salivary), hence amylase rich effusions are seen in some cases of carcinoma. Measurements of pleural fluid triglyceride, lipid profiles, and cholesterol levels are valuable in the differential diagnosis of chylo/​ pseudochylothorax. Adenosine deaminase levels are raised in pleural tuberculosis, which is diagnostically valuable in TB endemic areas. However, even in areas with low prevalence of tuberculosis, a low pleural ADA test is useful for ruling out the disease due to its high negative predictive value. High pleural fluid ADA activity can also occur with empyema, connective tissue diseases, and lymphoma. The demonstration of a pleural fluid to serum creatinine ratio greater than 1 is diagnostic of the rare syndrome of urinothorax, where urine has extravasated from an obstructed kidney through the retroperitoneal space and into the pleural cavity. Similarly, the finding of a very elevated glucose level in a pleural effusion in a patient on peritoneal dialysis suggests the presence of a diaphragmatic leak. In general, the measurement of tumour markers for the evalu- ation of patients with suspected malignant effusions is not recom- mended. When 100% specific cut-​off levels are set, tumour markers are very insensitive. Mesothelin is a potential biomarker of meso- thelioma that can be measured in pleural fluid or serum (sensitivity 70–​80%, specificity 90%). Investigation—​pleural biopsy Pleural malignancy Exudative pleural effusions where pleural fluid analysis has not yielded a diagnosis usually require the sampling of pleural tissue to make a specific diagnosis, particularly of malignancy, tuberculosis, and some rarer conditions such as amyloidosis and sarcoidosis. There are three common approaches to gaining this tissue: thoracoscopy (under general or local anaesthesia), image-​guided pleural biopsy (where pleural thickening or nodules have been shown on contrast-​ enhanced CT), or blind closed pleural biopsy (using an Abrams or Cope’s biopsy needle). For malignant pleural disease, thoracoscopic and image-​guided cutting needle biopsy of pleural tissue are 95% and 87% sensitive, respectively, which is superior to the sensitivity of closed pleural biopsy (about 45%). Whereas image-​guided pleural biopsy is a less invasive procedure, thoracoscopy allows for drainage of pleural effusion and pleurodesis in order to control pleural fluid recurrence, all in one setting. The histological differential diagnosis of malignant pleural meso- thelioma from reactive mesothelium and metastatic carcinoma by morphological examination is not reliable: accurate diagnosis often relies on a panel of immunohistochemical markers. Prophylactic ra- diation to pleural puncture sites to reduce the risk of tumour inva- sion into needle tracts is controversial, with conflicting results from three small randomized trials. If used, radiotherapy should be ad- ministered within 2 weeks of the biopsy or drainage procedure. Tuberculosis The choice of biopsy method is more finely balanced when possible tuberculosis is the indication for the procedure. Closed (Abrams) pleural biopsy with acid-​fast bacillus staining and culture of a bi- opsy sample for mycobacteria is diagnostic of tuberculosis in about 90% of cases when histological appearances and mycobacterial cul- ture results are combined. This is less sensitive than thoracoscopic pleural biopsy, which is nearly 100% sensitive, although the diag- nostic advantage to thoracoscopy is smaller than it is in malignant disease. Pleural effusion—​specific conditions Pyogenic pleural infection Infection of the pleural space has been known for millennia. Hippocrates was credited for its recognition as long ago as 500 BC, and it remains a significant problem with an incidence of more than 65 000 cases in the United Kingdom and United States combined. Pleural infection is still associated with a high mortality and mor- bidity. The median length of stay in hospital is 12–​15 days, and 25% of patients stay in hospital for over one month, with a mortality rate of up to 20%. The incidences of pleural infection have been rising worldwide in recent decades despite the introduction of multivalent pneumococcal vaccines. Aetiology Risk factors for developing empyema are similar to those for pneu- monia, with paediatric and elderly populations being particularly susceptible. Men are affected twice as often as women. Diabetes mellitus, immunocompromise, alcohol abuse, and intravenous drug use are all risk factors for the development of empyema. Poor orodental hygiene is commonly seen in anaerobic pleural infections. Most cases of pleural infection are secondary to underlying par- enchymal lung infection. Up to half the cases of pneumonia will develop a parapneumonic effusion, and up to 10% of these can subsequently become infected. However, there is no radiological evidence of pneumonia in a third of cases, raising the likelihood of other routes of entry (e.g. micro-​aspiration, haematogenous or transdiaphragmatic invasion). Other causes of pleural infection include trauma, iatrogenic causes, and proximal bronchial tree obstruction. Pathophysiology An uncomplicated sterile exudative effusion is formed as a result of increased vascular permeability of the visceral pleural membranes

section 18  Respiratory disorders 4312 during the parenchymal infection. Pro-​inflammatory cytokines such as interleukin (IL)–​6, IL-​8 and tumour necrosis factor alpha (TNF​α) facilitate the formation of pleural fluid. At this initial stage, the sterile effusion can be managed with antibiotic treatment alone. However, secondary bacterial infection of the effusion leads to the pleural in- fection syndrome, which often fails conservative management. With invasion of the pleural space the bacteria multiply leading to increased metabolic activity and neutrophil phagocytic activity, resulting in increased production of lactic acid and consumption of pleural fluid glucose. The characteristic features in the diagnosis of pleural infection; pH less than 7.2, pleural fluid glucose less than 3.0 mmol/​litre, and LDH less than 1000 IU/​litre are a result of the increased metabolic activity. Along with the increased production of pro-​inflammatory cytokines, a rising level of inhibitors of fibrin- olysis such as tissue plasminogen activator inhibitor leads to in- creased production of fluid and deposition of fibrin. This thin fibrin layer coats the visceral and parietal pleural surfaces which can lead to formation of pockets or locules that complicates the management of these effusions even further. Bacteriology Pleural fluid microbiological culture is only positive in approxi- mately 45% of cases. The yield can be increased significantly by pla- cing a pleural fluid sample in blood culture bottles. The bacteriology of pleural infection varies significantly between community-​ and hospital-​acquired pleural infection (Fig. 18.17.5), and empirical antibiotics should be tailored accordingly. The mortality of hospital-​ acquired pleural infection is twice that of community-​acquired infection. Community-​acquired pleural infections are predominantly Streptococcal and Staphylococcal species with up to 65% culture positive cases being attributable to these two groups. In addition, at least 20% of cases are associated with anaerobic organisms. In con- trast Staphylococcus aureus (including MRSA) and Gram negative organisms are often associated with hospital-​acquired cases. Clinical features and investigations Pleural infection commonly present with cough, breathlessness, chest pain, fever, and a clinical examination suggestive of effusion. Occasionally a more indolent course may follow with lethargy and anorexia where diagnosis and hence treatment can be delayed. A chest radiograph may give information as to the presence of fluid or parenchymal infection. CXR appearance in pleural infection may be of a simple effusion with blunting of the costophrenic angle with a meniscus sign confirming fluid or it may have a lobulated appear- ance depicting a mass, which is not uncommon in a loculated em- pyema (Fig. 18.17.6). Community acquired Staph Strep milleri group Strep pneumoniae Other Strep Enterobacteriacea Anaerobes MRSA H. influenzae Enterococci Pseudomonas 11% 12% 13% 14% 31% 10% Hospital acquired Enterococci Staph MRSA Anaerobes Enterobacteriacea Strep S. Milleri Pseudomonas 36% 15% 13% 15% 7% 5% 5% Fig. 18.17.5  Pie charts showing the proportions of different bacterial classes in community-​acquired and hospital-​acquired pleural infection. Fig. 18.17.6  Chest radiograph showing a typical pleural infection with a severely loculated pleural effusion, which mimics a lung mass.

18.17  Pleural diseases 4313 Thoracic ultrasound is useful when investigating pleural infec- tion, not only to confirm the presence of fluid in the pleural space and guide a diagnostic aspiration, but also to characterize the na- ture of the effusion as to the presence or absence of septations and loculations (Fig. 18.17.7). Diagnostic aspiration is essential to ex- clude pleural infection when there is clinical suspicion of this diag- nosis (Fig. 18.17.8). CT can be useful where diagnostic uncertainty remains following the investigations described earlier (Fig. 18.17.9). CT with contrast swallow is particularly useful where oesophageal perforation is sus- pected as the cause of low pleural fluid pH, or advanced malignancy. A contrast CT acquired in the pleural phase, approximately 60 sec- onds post contrast injection, will provide good pleural enhance- ment. Smooth pleural thickening, parietal pleural enhancement, and attenuation of the extrapleural fat are common features seen in pleural infection. Risk stratification A recently published prediction model (the RAPID score) derived from two large prospective randomized trials of patients with pleural infection offers some promise in prognostication in pleural infec- tion. Increasing age, raised blood urea level, low serum albumin, hospital-​acquired infection, and nonpurulence of the pleural fluid were all associated with a poorer outcome. (See Table 18.17.2). This score is now the subject of a large multicentre observational study aimed at validating it. Management Timely diagnosis and initiation of treatment is crucial in the man- agement of pleural infection. Empirical intravenous antibiotic treatment, directed by likely source of acquisition, is required Fig. 18.17.7  Fibrinous septations due to pleural infection shown on ultrasonography (a) and directly observed at thoracoscopy (panel b). Fig. 18.17.8  Pleural fluid samples obtained from locules with varying echogenicity on ultrasound in a case of pyogenic bacterial pleural infection. Those with greater echogenicity contain fluid of greater purulence, thus emphasizing that the pleural inflammatory process is not uniform. Fig. 18.17.9  Thoracic CT scan showing an empyema complicating an aspirated foreign body (marked A). A piece of lamb chop was later removed at bronchoscopy. A chest drain is also seen (marked B).

section 18  Respiratory disorders 4314 ahead of pleural fluid culture results. Community-​acquired in- fections should be treated with an antibiotic agent that has good Gram-​positive and anaerobic cover. Hospital-​acquired infections will require both Gram-​positive (including possible MRSA) cover, Gram-​negative cover, and anaerobic cover. Early nutritional support is an important cornerstone of manage- ment and often overlooked at initial presentation. While it has not been subject to a randomized controlled trial in this setting, nutri- tional support is likely to be important in counteracting the cata- bolic state associated with infection. Early full nutrition assessment is strongly advised in all cases. Frank pus on aspiration is diagnostic of pleural infection and tube drainage should be initiated to drain the pleural space. Pleural fluid culture positive for organisms, a positive Gram stain or low pleural fluid pH/​glucose with history suggestive of pleural infec- tion would necessitate intercostal tube drainage of the fluid. There is no consensus on the optimum size of the chest tube, but smaller bore chest tubes (10–​14 F) are just as effective as larger bore drains, and are better tolerated due to less discomfort. It is important to note that small bore chest tubes must be flushed regularly with normal saline to maintain tube patency. The MIST2 study, a double-​dummy, double-​placebo, ran- domized, controlled trial in pleural infection, utilizing tPA as a directly-​acting fibrinolytic to disrupt septations and DNase to reduce fluid viscosity within the pleural space and enhance drainage. This four arm study (n = 210) showed that intrapleural tPA and DNase therapy resulted in significant reduction in chest radiographic opacification, whereas single-​agent tPA or DNase had no effect compared to placebo. A recently published pro- spective series of over 100 patients treated with this regime highlighted its safety. The need for surgical intervention was limited to only a handful of patients, and the mortality rate was extremely low. In some cases resolution following tube drainage can be slow (Fig. 18.17.10), but patients with ineffective tube drainage and persistent clinical features of sepsis will require assessment by thoracic surgery. Most pleural infection cases requiring surgical intervention are now treated with video-​assisted thoracoscopic surgery (VATS). VATS allows disruption of the adhesions and clearance of the infected pleural collection, although some cases still require open thoracotomy and decortication. Rib resection with open drainage is an option in those that are very frail. Tuberculous pleural effusion and empyema The general treatment of tuberculosis is discussed in detail else- where (see Chapter 8.6.26). Tuberculous related pleural effusions are predominantly due to a delayed hypersensitivity reaction to mycobacteria or mycobacterial Table 18.17.2  RAPID risk stratification score for pleural infection Parameter Measure Score Renal –​ Urea (mM) <5 5–​8

8 0 1 2 Age (years) <50 50–​70 70 0 1 2 Purulence of pleural fluid –​ purulent – nonpurulent –​ –​ 0 1 Infection source –​ community-​acquired –​ hospital acquired –​ –​ 0 1 Dietary factors –​ Albumin (g/​litre) ≥27 <27 0 1 Risk categories Score 0–​2 Score 3–​4 Score 5–​7 –​ –​ –​ Low risk Medium risk High risk Fig. 18.17.10  Chest radiographs in a patient with a left lung that has not re-​expanded due to visceral pleural thickening following drainage and treatment of a pleural infection (a). The patient was clinically well and the radiographic changes resolved spontaneously over 3 months (b).

18.17  Pleural diseases 4315 antigens in the pleural space. In most cases these effusions resolve spontaneously without treatment. Rarely, patients can develop tu- berculous empyema due to direct communication between infected lung parenchyma and the pleural space, such as a ruptured cavity. Clinical features and diagnosis Hypersensitivity pleuritis may be asymptomatic in some cases, or acute or subacute symptoms may develop depending on the duration of the inflammation of the pleura and presence of effusion. Patients may have symptoms of cough, pleuritic chest pain, and fever. Pleural fluid analysis reveals high protein and lactate dehydro- genase level content. Pleural fluid glucose level can be moderately depressed. Lymphocyte predominant effusions are common where the effusions have been present for a few days. It is not uncommon to see a neutrophil predominance at early stages of effusion or in empyema. Pleural fluid ADA levels have a role in excluding a diagnosis of tuberculous pleuritis where the level is less than 35 U/​litre in low endemic areas. Sensitivity of ADA is low as it can be elevated in non-​ tuberculous related empyema and in patients with HIV. Pleural fluid smear and culture yields are low especially in im- munocompromised patients. Pleural biopsy with Abrams needle is a relatively safe procedure with a high sensitivity, with granuloma of the parietal pleura demonstrated in 95% of cases due to pleural TB (Fig. 18.17.11). Thoracoscopy is nearly 100% sensitive for diagnosing pleural TB, but it is a more invasive procedure. Management Most cases of tuberculous related pleural effusions resolve spon- taneously. Left untreated, half the cases may develop some form of active tuberculosis, mostly pulmonary, over the ensuing few years. Treatment is therefore mainly aimed at preventing recurrence. The Fig. 18.17.11  Histological appearances of pleural biopsies in patients with tuberculosis. The appearance in an immunocompetent patient (a) shows a typical caseating granuloma (G). Panel b shows staining for acid-​ and alcohol-​fast bacilli (AAFB) and demonstrates Mycobacterium tuberculosis (later confirmed by culture). The appearance in a patient with immunosuppression due to HIV disease (c) shows no granulomas.

section 18  Respiratory disorders 4316 same antibiotic regimes as per pulmonary TB are used to treat tuber- culous pleural effusions (see Chapter 8.6.26). Use of corticosteroids for tuberculous pleuritis and effusions re- main controversial. Small studies and a recent Cochrane review failed to show sufficient evidence to recommend adjuvant use of cor- ticosteroids in TB pleurisy. A short course of steroid can be justified in those with large recurrent effusions, and those with troublesome symptoms (e.g. fever and chest pain). Steroid may increase the risk of subsequent Kaposi’s sarcoma in HIV patients. Coinfections of the pleural space with other bacteria are not un- common in TB empyema, hence adequate cover should be insti- gated for these patients alongside their TB treatment. Tuberculous empyema can cause significant pleural thickening/​calcification and long-​term disabling sequalae in some patients. Surgery is an op- tion for these patients, but can be difficult due to underlying paren- chymal infection and poor respiratory reserve. Other specific causes of exudative pleural effusion Rheumatoid arthritis Up to 5% of patients with rheumatoid arthritis can develop pleural effusions. They are more common in men and those with subcuta- neous nodules. The timing of the effusions in relation to the diag- nosis of rheumatoid arthritis can be variable: they can rarely precede joint symptoms, but often occur more than 10 years after the initial joint symptoms. One of the most striking features of rheumatoid related effusions is the very low glucose level. It is postulated that this is due to the significant inflammatory reaction of the pleura. Rheumatoid re- lated effusions can also contain a high level of cholesterol leading to rheumatoid related pseudochylothoraces (see later). Cytological analysis of fluid reveals one or more of the following features: slender elongated multinucleated macrophages, giant round multinucleated macrophages, or necrotic background material. Many agents (e.g. NSAIDS, steroids—​oral or intrapleural—​and pleurodesis) have been attempted for the management of recurrent rheumatoid effusions; none have been well studied. Pleural thick- ening may develop over time. Systemic lupus erythematosus The pleura is often involved in systemic lupus erythematosus (SLE), with reports of up to 56% of patients experiencing pleuritic pain at some point during the course of their disease. Reports of SLE related pleural effusions range widely from 9% to 44% of patients in some case series, although these tend to be of patients with severe disease. Joint symptoms usually precede pleuritis. Pleural fluid levels of antinuclear antibody (ANA) and lupus erythematosus (LE) cells are not useful in diagnosis. Differential white cell count reflects a high proportion of polymorphonuclear leucocytes. Nonsteroidal anti-​ inflammatory drugs and corticosteroids often control mild and se- vere SLE pleurisy, respectively. Occasionally cyclophosphamide may be tried. Pleural effusion secondary to IgG4 related disease IgG4 related pleural effusion is a newly recognized entity that has been increasingly cited in case series. This is a systemic fibro-​inflammatory disease associated with elevated circulating levels of IgG4. The underlying pathophysiology involves dense lymphoplasmacytic infiltrates containing IgG4 positive plasma cells. It is more common in men, with an average age 69 years old at pres- entation. Most patients respond to steroids. Pulmonary embolism Pleural effusions are present in up to 50% of cases of pulmonary embolism. These effusions have no specific diagnostic features, but most tend to be small, and larger effusions should be investigated for other underlying causes. Pleural fluid analysis is important to ex- clude concurrent malignancy or pleural infection. Analysis of fluid often reveals a high polymorphonuclear leucocyte count and occa- sionally an elevated eosinophil count. Physicians must maintain a high index of suspicion for this diagnosis and should pursue appro- priate diagnostic tests as required. Persisting but undiagnosed pleural effusion About 15% of exudative pleural effusions remain undiagnosed, even after careful investigation, including thoracoscopic biopsy. About 10% of these will eventually prove to have a malignant cause, par- ticularly mesothelioma. In cases of undiagnosed effusion, those diagnoses where there is specific therapy to prevent significant morbidity/​mortality should be reconsidered. CT pulmonary angi- ography for pulmonary embolism, ADA testing for tuberculosis, and lymphocyte subset analysis of the pleural fluid to help exclude lymphoma are particularly worthy of consideration. Chylothorax Pleural fluid that is white or milky in colour and does not clear with centrifugation almost always has a high lipid content. This occurs when chyle enters the pleural space following disruption of the thor- acic duct (a true chylothorax), or large amounts of cholesterol or lecithin–​globulin complexes accumulate in a long-​standing inflam- matory effusion (a pseudochylothorax). Pathophysiology About 2 litres of chyle is created daily, with the volume of chyle transported in the thoracic duct increasing by 2–​10 times following a high-​fat meal. The predominant cell type in chyle is small T-​ lymphocytes. Chyle is bacteriostatic, hence the risk of developing empyema in the presence of a chylous effusion is low. It is non-​ irritant to the pleura and thus development of significant pleural thickening is uncommon. Chyle travels in the thoracic duct, which usually passes through the aortic hiatus of the diaphragm on the right, crosses between the T4 and T6 vertebrae to the left, and then continues cephalad on the left side of the oesophagus. A chylothorax forms when the thor- acic duct is disrupted, either before or after it crosses the midline, tending to produce right-​ and left-​sided chylothoraces, respectively. Aetiology The leading cause of chylothorax is trauma, often secondary to oe- sophageal surgical procedures (incidence nearly 4%) or cardiothor- acic surgical procedures (incidence less than 1%). Malignancy is the second commonest cause, with up to 75% of being secondary to lymphoma. Paediatric chylothorax is rare, but when it occurs it tends to be in relation to surgical intervention such as repair of con- genital diaphragmatic hernia, and is usually left sided.

18.17  Pleural diseases 4317 Penetrating injuries of the neck or thorax, and nonpenetrating trauma with spine hyperextension or vertebral fracture, can cause thoracic duct damage. Rupture after weightlifting, severe coughing or vomiting, childbirth, and vigorous stretching while yawning are also occasionally reported. Chylothorax can follow chylous ascites. Pulmonary lym­ phangioleiomyomatosis is one of the common causes of chylothorax and this is discussed in Chapter 18.14.6. Other precipitants include intestinal lymphangiectasis, yellow nail syndrome, superior vena cava, or subclavian vein thrombosis/​obstruction, filariasis, lymph node enlargement, mediastinal fibrosis, lymphangitis of the thor- acic duct, tuberous sclerosis, amyloidosis, and Gorham’s syndrome (disappearing bone disease; massive osteolysis). Clinical features The clinical features are those of a pleural effusion, but chest pain and fever are rare. In traumatic chylothorax, effusion onset is typic- ally delayed for 2–​10 days: during this time chyle may accumulate in the posterior mediastinum as a ‘chyloma’—​sometimes visible on the chest radiograph—​which resolves when it ruptures into the pleural space. The main threat to life with chylothorax is malnutrition if the chyle is drained externally, as the daily loss of 1500–​2500 ml of fluid containing substantial amounts of protein, fats, electro- lytes, and lymphocytes rapidly makes a patient malnourished and immunocompromised. Diagnosis Diagnosis is usually easy from the distinctive white, odourless, milky appearance of aspirated pleural fluid (Fig. 18.17.12) that remains opulent on centrifuging. Chylous effusions may occasionally ap- pear bloody, turbid, or clear yellow. The usual differential diagnoses are empyema fluid and pseudochylothorax. In empyema, the milky appearance is from suspended white blood cells and debris, which sediment on centrifugation and the supernatant remains clear. In pseudochylothorax, the lipids are cholesterol crystals or lecithin–​ globulin complexes rather than chylomicrons (Fig. 18.17.13). Biochemical assessment of the pleural fluid is key to accurate diag- nosis. Patients who have a true chylothorax usually have a pleural fluid triglyceride level above 110 mg/​dl (1.24 mmol/​litre), a ratio of pleural fluid to serum triglyceride of greater than 1.0, and a ratio of the pleural fluid to serum cholesterol of less than 1.0. The demon- stration of chylomicrons on pleural fluid lipoprotein electrophor- esis is diagnostic of a chylothorax. Fasting may significantly reduce the triglyceride level in the pleural fluid and lead to a false-​negative result, hence fluid sampling after a high-​fat meal is helpful if diag- nostic doubt persists. CT scanning of the chest should be obtained in all patients with nontraumatic chylothorax to look for thoracic and abdom- inal lymphadenopathy suggestive of lymphoma (Fig. 18.17.14). In young women the appearance on CT scanning of cystic lung disease may indicate lymphangioleiomyomatosis. Unlike most other pleural effusions, examination of the pleura is not usually diagnostic, and pleural biopsy or thoracoscopy is usually only indicated for fluid control. Fig. 18.17.12  Typical milky pleural fluid from a true chylothorax. Fig. 18.17.13  Microscopy of pleural fluid from a pseudochylothorax showing multiple cholesterol crystals (Giemsa stain with birefringence). Fig. 18.17.14  A case of chylothorax (C) where the thoracic duct has been ruptured by enlarged mediastinal lymph nodes (arrowed).

section 18  Respiratory disorders 4318 Site of injury to the thoracic duct can be localized using lympho­ scintigraphy with Technetium-​99 diethylenetriaminepentaacetic acid human serum albumin (99mTc-​DTPAHSA, 185 MBq/​0.5 ml) injected into the subcutaneous tissue of the dorsum of the foot. A single photon emission computed tomography/​computed tom- ography (SPECT/​CT) performed immediately after the injection will allow localization of the chyle leak. Lymphangiography using lipiodol (iodinated poppy-​seed oil) is a novel method of isolating the site of chyle leakage. Some studies have shown this method may heal the leak where the chyle leak is of small volume: the mechanism of this is unclear but an inflammatory effect of the lipiodol has been postulated. Treatment Treatment aims to correct the underlying disease, maintain nutrition, reduce the flow of chyle, relieve dyspnoea, and (sometimes) close the thoracic duct defect. Malnutrition and a compromised immuno- logical status can quickly follow chest tube drainage through loss of large amounts of protein, fat, electrolytes, and lymphocytes. This means that definitive control of the effusion is required before the pa- tient becomes too debilitated. Spontaneous closure of a thoracic duct leak may follow reduction of the flow of chyle by parenteral feeding or use of a low-​fat diet rich in medium-​chain triglycerides that are ab- sorbed directly into the blood, but this diet is often difficult to tolerate as it tastes unpleasant. Octreotide, a somatostatin analogue, may be effective in hastening the closure of a thoracic duct leak: the mechanism of its action is not clear, but may be through reduced intestinal fat absorption and in- creased faecal fat excretion. If the cause is lymphoma or metastatic carcinoma, a chylothorax often responds to effective chemotherapy or mediastinal radio- therapy. Pleuroperitoneal shunts can be used if a chylothorax fails to settle, which avoids malnourishment and immunodeficiency since lymph is not removed from the body. In traumatic chylothorax, the defect in the thoracic duct often closes spontaneously. The volume of fluid drainage (more or less than c.400 ml/​day) seems to predict the likelihood of such resolution. Thoracoscopic talc pleurodesis is often effective when conservative therapy fails. Embolization of the thoracic duct from the abdomen is nowadays the therapy of choice if the expertise is available. Surgical intervention involves thoracic duct ligation at VATS or thoracotomy. The site of the leak may be identified preoperatively by lymphangiography as mentioned earlier, and identification of the duct at surgery can be facilitated by preoperative drinking of cream. Laparoscopic ligation of the abdominal thoracic duct has also been successful. Pseudochylothorax Pseudochylothorax is less common than chylothorax. The fluid is turbid due to high levels of cholesterol or lecithin–​globulin com- plexes (Fig. 18.17.13). Pathogenesis remains unknown, but most patients with pseudochylothorax have marked pleural thickening and a chronic pleural effusion, and it is hypothesized that inflam- mation increases filtration of cholesterol into pleural fluid and/​or cholesterol is liberated from degenerative inflammatory red and white blood cells within the effusion. The thickened pleura may also inhibit the exit of cholesterol from the pleural space. Pseudochylothorax is most frequently attributable to tubercu- lous (54%) or rheumatoid (10%) pleurisy. The clinical picture is of a stable chronic effusion, although in some cases the effusion grad- ually enlarges with time. Haemothorax Haemothorax is blood in the pleural space, defined as a pleural fluid haematocrit of more than 50% that of blood. A heavily bloodstained pleural effusion often has a haematocrit of under 5%, hence a haem- atocrit should be performed whenever haemothorax is suspected. Traumatic haemothorax Clinical features and diagnosis Traumatic haemothorax should be suspected following any chest trauma, whether penetrating or not. It often develops in the first few days after trauma, is not detectable on 25% of presentation chest radiographs (occult haemothorax, which can be demonstrated by CT), and in patients with multiple or displaced rib fractures late haemothorax may occur up to a week after presentation (delayed haemothorax). Thoracic CT identifies all cases, and bedside ultra- sonography has similar diagnostic sensitivity. The condition is a po- tential surgical emergency and should be managed by a thoracic/​ trauma surgeon. Management Traumatic haemothorax is treated with an immediate large-​bore chest tube (≥28 F) for blood evacuation, which also allows quan- tification of continued bleeding. Blood lost from haemothorax can be autotransfused if necessary, and early effective evacuation of haemothorax may decrease the frequency of empyema and late thoracic contraction due to pleural scarring (‘fibrothorax’). About 20% of patients with haemothorax require surgical inter- vention for suspected cardiac tamponade, vascular injury, pleural contamination, debridement of devitalized tissue, chest wounds, major bronchial air leaks, or continued pleural haemorrhage. Post-​ traumatic haemothorax was managed exclusively by thoracotomy, but advances in VATS have made this minimally invasive tech- nique the procedure of choice in many centres, with thoracotomy reserved for massive haemorrhage or patients with haemodynamic instability. There are no precise criteria for the amount of pleural bleeding that should mandate surgery, and each case must be man- aged on its merits, but surgical intervention is likely to be required if bleeding is more than 200 ml/​h for 4 hours and shows no signs of slowing, or the initial drainage exceeds 1500 ml following tube thoracostomy. Complications The four main pleural complications of traumatic haemothorax are the retention of clotted blood in the pleural space, pleural infection, pleural effusion, and fibrothorax. Most patients with small to mod- erate amounts of clotted blood remaining in their pleural space have no residual pleural abnormalities even if no intervention is under- taken, but evacuation is recommended if the volume of retained haemothorax is greater than 300 ml. In a randomized trial, VATS was more effective than thoracostomy tube drainage, reducing the duration of hospital stay and chest tube drainage. If the volume of clotted blood is more than 900 ml or there is an associated diaphrag- matic injury, thoracotomy is the best choice.

18.17  Pleural diseases 4319 Intrapleural administration of fibrinolytic agents to improve clot drainage may be safe in haemothorax, but there have been no com- parative studies to confirm these agents are efficacious and safe in this setting. The administration of prophylactic antibiotics (cefazolin) before tube thoracostomy in traumatic haemothoraces reduces the inci- dence of pleural infection in randomized trials. Empyema occurs in 1–​4% of cases and should be suspected in the febrile patient. Its treatment is similar to that of other pleural infections. Iatrogenic haemothorax The incidence of iatrogenic haemothorax is highest after cardiac or thoracic surgery, or perforation of a central vein or artery by a per- cutaneous catheter. An occasional haemothorax results from pleural procedures (e.g. thoracentesis, pleural biopsy, chest tube insertion; see Fig. 18.17.15), and percutaneous lung aspiration or biopsy. Rarely, it is associated with endoscopic oesophageal variceal therapy, liver bi- opsy, cardiopulmonary resuscitation, and translumbar aortography. Management is similar to that of traumatic haemothorax. Nontraumatic haemothorax Nontraumatic haemothoraces are uncommon, but most frequently follow malignant pleural disease or anticoagulation (particularly for pulmonary embolism). Rarer causes include abnormal blood vessels (subpleural arteriovenous malformations, Osler–​Weber–​Rendu dis- ease, aneurysm of the aorta or pulmonary artery, aortic dissection, patent ductus arteriosus, coarctation of the aorta), bleeding disorders (haemophilia, severe thrombocytopenia), the use of intrapleural fibrinolytics, spontaneous pneumothorax, bronchopulmonary sequestration, thoracic endometriosis, chickenpox pneumonia, costal exostoses, and intrathoracic extramedullary haematopoiesis. Rarely, neurofibromatosis can cause haemothorax from aneurysmal changes in large arteries or from dysplastic changes in small vessels. Also, other neoplastic processes such as metastatic angiosarcoma to the lung can result in haemothorax. Blood can accumulate in the pleural space from abdominal path- ology (e.g. rupture of a splenic artery aneurysm through the diaphragm, pancreatic pseudocysts, and rupture of hepatocellular carcinoma). The cause of some spontaneous haemothoraces remains un- known despite thoracotomy, although rupture of pleural adhesions has been reported in some cases. Benign asbestos-​related pleural diseases Asbestos is a family of hydrated silicate fibres subdivided into curly (serpentine) and needle-​like (amphibole) types. Chrysotile (white as- bestos) is the main serpentine form; amphiboles include crocidolite (blue asbestos), amosite (brown asbestos), anthophyllite, tremolite, and actinolite. Most benign asbestos-​related pleural diseases are due to occupational exposure, although environmental exposure causes disease in some high-​prevalence asbestos areas such as central and south-​east Turkey, north-​west Greece, and Finland. The benign as- bestos pleural diseases comprise of pleural plaques, benign asbestos pleurisy, diffuse pleural thickening, and rounded atelectasis. Pathogenesis The pathogenesis of benign asbestos-​induced pleural disease is poorly understood. The route by which asbestos fibres transfer to the pleura after inhalation is unclear. Fibre burden studies have shown higher fibre numbers in lymph nodes and pleural plaques than in lung parenchyma, and it is likely that at least some fibres are cleared from the lung parenchyma to the lymph nodes and pleura through lymphatic spread. Amphiboles fibres in particular are associated with ‘black spots’ of anthracotic deposits near lymphatic vessels. Fibre toxicity may be related to a number of factors, including fibre length and diameter, chemical properties such as iron content and surface charge, and durability. Long, thin fibres (e.g. crocidolite) are especially carcinogenic and clear more slowly from the lung, al- though the exact relationship of different fibre types to benign and malignant pleural diseases is still debated. The iron content of as- bestos bodies (Fig. 18.17.16) may influence reactive oxygen species generation, causing pleuropulmonary toxicity. Carbon nanotubes, which have even higher length:width ratio than crocidolite asbestos, have recently been shown to cause significant mesothelial abnor- malities in preclinical models. Fig. 18.17.15  Haemothorax due to laceration of an intercostal artery during chest drain insertion. The CT (a) shows acute haemorrhage (H) into a pleural effusion that was already present (E). The angiogram (b) shows acute haemorrhage (H) from intercostal artery, which was halted by intercostal embolization.

section 18  Respiratory disorders 4320 A primary mechanism of asbestos fibre-​induced injury is pleural inflammation. Fibres induce intrapleural IL-​8 production from pleural mesothelial cells which causes a neutrophil influx that pre- cedes the development of pleural plaques. A prolonged macrophage influx follows, probably due to monocyte chemoattractant protein-​1 (MCP-​1), TNFα, or IL-​1β production. The mechanisms that cause pleural fibrosis and plaque formation following this inflammation are not clearly understood. Clinical manifestations Benign asbestos-​related pleural plaques Circumscribed pleural plaques are the most common manifestation of asbestos exposure and comprise discrete areas of white or yellow thickening on the parietal pleura with a raised ‘beaded’ edge visible at thoracoscopy (Fig. 18.17.17). They are frequently bilateral and occur particularly on the posterolateral chest wall between the fifth and eighth ribs overlying the internal rib surfaces. They also occur on the dome of the diaphragm and over the mediastinal pleura. Histologically they are acellular, with a ‘basket-​weave’ pattern of hyalinized collagen strands, covered by a single layer of normal mesothelial cells on the pleural surface (Fig. 18.17.17). Pleural plaques typically develop 20–​30 years after asbestos ex- posure. They affect up to 50% of exposed workers, with incidence relating to exposure dose, although the extent of plaques within an individual case is not dose related. They are often calcified and can be easily identified on chest radiographs and CT. In fact, a calcified plaque on the diaphragm is highly suggestive of prior asbestos ex- posure, provided there is no previous history of surgery or trauma. Patients with pleural plaques are typically asymptomatic. Pleural plaques do not have any potential for malignant transformation and clinical management consists of patient reassurance. However, their presence indicates significant asbestos exposure and its in- herent risk for mesothelioma. Benign asbestos pleural effusion This is a diagnosis of exclusion when an exudative and often blood- stained, effusion occurs in a patient with asbestos exposure (which can be within the preceding 10 years) and no other cause is found after full investigation, including pleural histology, and at least a 2-​year follow-​up (to exclude malignancy). The effusion is most commonly unilateral and, in few instances, associated with fever and pleuritic chest pain. The risk of benign asbestos effusion is dose dependant with respect to asbestos exposure but can occa- sionally occur after minimal exposure. It usually persists for sev- eral months and resolves completely. However, it could precede the development of diffuse pleural thickening, leaving behind blunting of the costophrenic angle, or recur on the ipsilateral, or contralateral side. Diffuse, benign asbestos-​induced pleural thickening Diffuse pleural thickening consists of extensive fibrosis of the vis- ceral pleura, with areas of adhesion with the parietal pleura and Fig. 18.17.16  An asbestos body where an asbestos fibre (A, arrowed) has become encased in iron-​rich material. Fig. 18.17.17  (a) A pleural plaque (marked P) seen at local anaesthetic thoracoscopy. The raised ‘beaded’ edge of the plaque is clearly
seen. Malignant pleural mesothelioma is also present in this case, with tumour tissue seen infiltrating superiorly to the plaque (marked m).
Fig. (b) shows the typical histological appearance of benign pleural plaque.

18.17  Pleural diseases 4321 consequent obliteration of the pleural space. It is arbitrarily de- fined as a more than 3 mm thick pleura extending more than 8 cm craniocaudally and 5 cm laterally on the thoracic CT. Unlike pleural plaques, the margins of the fibrosis are usually tapered. It fre- quently involves the costophrenic angles, apices, and interlobar fis- sures. Diffuse fibrosis often follows benign asbestos-​related pleural effusion. Diffuse pleural thickening may be asymptomatic or cause breath- lessness. Chest pain, when present, should raise concerns and a thorough investigation should be performed for malignant pleural mesothelioma (see Chapter 18.19.3). Pleural thickening is usually slowly progressive and may cause significant lung function impair- ment, especially if the costophrenic angle is involved. Treatment is largely supportive. Hypercapnoeic ventilatory failure can (rarely) develop. Surgical decortication is generally ineffective in providing clinical or functional improvement. Rounded atelectasis Rounded atelectasis (also known as rolled atelectasis, folded lung, pleuroma, Blesovsky syndrome, or shrinking pleuritis with atelec- tasis) develops as contracting visceral pleural fibrosis rolls and en- snares the underlying lung. This results in the distinctive radiological appearance of a rounded or oval pleural-​based mass 2.5–​5 cm in diameter, with bands of contracted and atelectatic lung radiating out in a whirling fashion (known as ‘comet tails’) on chest radiograph or thoracic CT (Fig. 18.17.18). Although asbestos exposure is the most likely cause, other pleural processes may manifest as rounded atelectasis (e.g. trauma, cor- onary artery surgery, lymphangioleiomyomatosis, tuberculosis, silicosis, histoplasmosis, use of pergolide, Dressler’s syndrome). Rounded atelectasis, which can be multiple and bilateral, is typic- ally asymptomatic and stable or only slowly progressive. It can be confounded, however, with lung cancer or mesothelioma. Specific therapy is rarely required. Serious complications such as obstructive pneumonia and local pulmonary artery thrombosis are rare. Surgical decortication often results in reduced lung volumes and is not gen- erally recommended. Pneumothorax Pneumothorax is air in the pleural cavity, between the lung and the chest wall. Pneumothoraces can be subclassified into spontaneous where there was no preceding insult or an obvious precipitant to the lung, or traumatic following direct or indirect injury to the chest. Iatrogenic pneumothoraces occur following injury to the lung during diagnostic or therapeutic procedures. Pathophysiology During normal tidal breathing the pleural pressure is continuously negative with respect to alveolar/​atmospheric pressure. When a communication develops between the pleural space and the lung (or outside atmosphere via a chest wall injury), then air flows into the pleural space until this negative pressure equilibrates or the air- ways in the collapsing lung occlude to prevent further alveolar gas escape via the airway. This ‘air trapping’ occurs earlier in patients with chronic obstructive pulmonary disease (COPD). The removal of negative pleural pressure also causes the chest wall to ‘spring out’ due to loss of the recoil pressure across the chest wall (by about 8% of vital capacity), hence the overall volume of the hemithorax increases. Primary spontaneous pneumothorax Incidence Incidence is higher in men with a reported rate of 18–​28/​100 000 per annum and in women 1.2–​6/​100 000 per annum. Emergency hos- pital admissions from primary spontaneous pneumothorax (PSP) can be as high as 11.1/​100 000. Fig. 18.17.18  (a) Chest radiograph and (b) CT showing ‘rounded atelectasis’ where visceral pleural fibrosis has contracted to enfold the underlying lung. Characteristic ‘comet tails’ are seen in the lung parenchyma.

section 18  Respiratory disorders 4322 Aetiology Although PSP is said to be in a healthy lung with no apparent re- spiratory disease, macroscopic appearances of the lung suggest otherwise. Apical subpleural blebs or emphysema like changes are present in 75–​100% of cases of PSP, on thoracoscopic visualization of the pleura and on high resolution CT scanning of the chest. These areas represent weakness of the pleura prone to rupture and air leak from the lung to the pleural space. It is unclear whether it is a rup- ture of a bleb or an air leak from the tissue surrounding the bleb, due to anatomical abnormality that causes the air leak, as blebs are seen inflated during thoracoscopy. The development of blebs and em- physema like changes are due to a variety of causes including distal airway inflammation, hereditary disposition, and connective tissue abnormalities. Smoking is a major risk factor for PSP with a lifetime risk of 12% in smokers compared to 0.1% in nonsmokers. Eighty percent of PSPs are in smokers and a dose-​response relationship exists in both men and women. Similarly, cannabis smoking is associated with emphysema like changes that predispose users to an increased risk of PSP. Tall stature and low body mass index are also associated with higher risk of pneumothorax. A tall thin body habitus leads to an in- creased pressure gradient between the apex and the base of the lung, pleural pressure falls by 0.20 cmH2O/​cm of vertical chest height, re- sulting in an increased alveolar distending pressure at the apex. Primary spontaneous pneumothorax has a genetic component in some cases; Marfan syndrome, tuberous sclerosis, α-1 antitrypsin deficiency, homocystinuria, and Birt-​Hogg-​Dubé syndrome and other mutations of the Folliculin gene (FLCN) all showing an in- creased risk of PSP. Birt-​Hogg-​Dubé syndrome is a rare autosomal dominant condition that predisposes to cystic lung disease and hence pneumothorax. Up to 5% of patients with PSP may have underlying Birt-​Hogg-​Dubé syndrome. The frequency of PSP is highest in patients with Marfan syndrome, with reported rates be- tween 4 and 11%, higher in those with chest deformity. Clinical features The peak age of presentation for primary pneumothorax is in the early 20s; the incidence is much lower beyond the age of 40. Predominant symptoms are chest pain and dyspnoea, with up to 64% of patients reporting both symptoms at presentation. Chest pain tends to be of acute onset and localized to the side of the pneumo- thorax. Occasionally patients may not have any symptoms at all. Physical examination is unremarkable in most the cases. A slight to moderate tachycardia, reduced expansion of the affected side, and a hyperresonant percussion note may be found in large pneumothoraces. Rarely a ‘crunching’ noise known as the Hamman’s sign may be heard, this is a noise caused by collections of pleural air being pushed against the chest wall due to the cardiac impulse. Tension Pneumothorax Tension pneumothorax is a rare but important variant of pneumo- thorax where a ‘flap valve’ mechanism at the visceral pleural sur- face results in the development of increasing positive pressure in the pleural space. It is an important diagnosis not to be missed in mechanically ventilated patients with rapidly increasing respira- tory distress. Tension pneumothorax causes progressive medias- tinal shift away from the side of the pneumothorax, and ultimately impedes venous return to the heart—​causing hypotension, shock, and collapse. The diagnosis of tension pneumothorax is based on the clinical features of a large pneumothorax with mediastinal shift away from the affected side, cardiovascular compromise, and severe progres- sive dyspnoea. The pulse rate can exceed 140 beats/​min, and hypo- tension, cyanosis, or pulseless electrical activity may occur. On examination the side of the chest affected is enlarged, moves less during the respiratory cycle, and the trachea and apex beat may be shifted towards the contralateral side. Tactile fremitus is absent, the percussion note is hyperresonant, and the breath sounds are absent or reduced on the affected side. The liver may be shifted inferiorly with a right-​sided pneumothorax. Chest radiographic demonstration of modest deviation of the mediastinum away from the site of pneumothorax and depression of diaphragm ipsilateral to the pneumothorax are not, in the absence of the characteristic clinical features, sufficient to diagnose a tension pneumothorax. These changes are common features of an uncom- plicated pneumothorax (up to 20%) and are due to expansion of the thoracic cavity following the loss of elastic lung recoil pressure. The treatment of tension pneumothorax requires urgent thor- acic decompression, followed by chest tube placement (see Chapter 30.2). Diagnosis of an uncomplicated pneumothorax Chest radiography has been the choice of imaging for the diagnosis of a pneumothorax (Fig. 18.17.19); presence of a ‘lung edge’—​a pleural line—​and absence of lung markings beyond the pleural line supports the diagnosis. Further radiology with Computed tomog- raphy (CT) is rarely needed. Bedside point-​of-​care ultrasound is a quick and portable mode of imaging that can also be used to diag- nose a pneumothorax although the signs seen are subtle and only those who are confident should be using this modality for the diag- nosis. When the lung sliding and the comet tail sign are both present the diagnosis of a pneumothorax can be ruled out. Presence of only one of the signs is not strong enough to exclude the diagnosis on its own. When in doubt, a chest radiograph should be performed. About 15% of radiographs showing a primary pneumothorax also show a small pleural effusion causing a fluid level. This pleural fluid is usually eosinophilic on cytology. Rarely, spontaneous pneumo- thorax causes brisk pleural bleeding from a torn pleural adhesion, with urgent surgery often required to stop this. Estimating the size of a pneumothorax is a contentious issue. The actual size of the pneumothorax is less important than the associated symptoms, as managemessnt decisions rely largely on the severity of the breathlessness. Various methods have been postulated on how to accurately estimate the size of a pneumothorax, one of the most widely used methods assume that the volumes of the lung and the hemithorax are roughly proportional to the cube of their diameters. Estimating the size of a pneumothorax therefore requires the meas- urement of the horizontal diameter of the lung and chest wall and the use of the formula: % pneumothorax volume = 100% × [1 − (lung diameter3/​hemithorax diameter3)]. Management Treatment of pneumothorax aims to drain the pleural cavity of air to relieve the symptoms and prevent recurrence. Detailed guidelines are in place from the British Thoracic Society and American College

18.17  Pleural diseases 4323 of Chest Physicians that may aid clinicians in the management of pneumothorax. A small pneumothorax with few symptoms can be conserva- tively managed provided the air leak has ceased. Air will be reab- sorbed at 2% per day. This process can be expedited by supplemental oxygen. High flow oxygen will increase the capillary partial pressure of oxygen and decrease the partial pressure of nitrogen, resulting in a much higher net gradient for absorption of gas, compared to breathing normal room air. Alternatively, air can be aspirated per- cutaneously using a small catheter (cannula) inserted in the second intercostal space in the mid-​clavicular line or fourth or fifth inter- costal space anterior to mid-​axillary line. A purpose built aspiration kit, or a fluid giving set connected to a stopcock, is attached to the catheter and air is manually aspirated with a 60 ml syringe. If more than 4 litres of air is aspirated, an ongoing air leak is likely and an intercostal chest drain should be inserted. Similarly, in cases where aspiration has failed or is inappropriate, a chest tube is indicated. When a pneumothorax is loculated, imaging with CT or ultra- sound can help in localizing the safest site for aspiration or insertion of chest drain. Ambulatory management of pneumothorax with a Heimlich valve device (one way valve connected to the end of a chest drain) has been the subject of several publications in recent years. This is an attractive management strategy in that it allows the patient more freedom to mobilize and potentially be discharged from hospital, letting the lung re-​expand in its own time. However, there are no high quality studies to support this method over traditional manage- ment strategies, although a randomized controlled study examining this question is due to start soon in the United Kingdom. The role of thoracic suction in persistent air leaks is still widely debated. There is a paucity of evidence to suggest the use of thoracic suction accelerates lung re-​inflation, hence its routine use cannot be supported, although it may have a role in selected cases. VATS surgery with pleurectomy or talc poudrage appears a highly effective treatment for those with persistent air leaks, but optimum timing of surgery is still unknown. Prognosis and prevention of recurrence The risk of recurrence of pneumothorax where some form of pleurodesis has not been attempted is approximately 30%, range of 16–​52%, regardless of conservative management, aspiration, or chest tube insertion. Following one recurrence the risk of further re- currence is up to 50% per year therefore surgical management is in- dicated after a second event. Tall thin stature and continued smoking are other factors that influence pneumothorax. There is no relation- ship between the number of apical blebs on CT or the macroscopic appearance of lung at surgery, and the risk of recurrence. Surgery is indicated for professionals in high-​risk occupations such as divers and pilots, following a first pneumothorax. The surgical management of pneumothorax aims to reduce re- currence by resection of visible blebs or bullae and performing pleurodesis either by pleurectomy, pleural abrasion, and/​or instil- lation of a sclerosing agent. The surgical approach can be either through VATS or thoracotomy. Recurrence rates following surgery are less than 5% in most series. Instillation of pleurodesing agents via chest tube is less likely to be successful and is not advocated in patients who are fit enough to proceed with surgery. Iatrogenic pneumothorax Iatrogenic pneumothorax is the most common cause of a pneumo- thorax in the developed world, with an incidence increasing in par- allel to the increase in invasive procedures. Interventions such as Fig. 18.17.19  Chest radiographs showing a primary spontaneous pneumothorax before (a) and after (b) successful pleural aspiration.

section 18  Respiratory disorders 4324 thoracentesis, percutaneous and transbronchial biopsies, central venous catheter insertion, and assisted mechanical ventilation are all high-​risk procedures for pneumothorax. The incidence of iatro- genic pneumothorax with thoracentesis has been reported as high as 6.0%, with up to a third of these requiring chest tube drainage for management. Transthoracic needle biopsy of parenchymal lesions has a risk of up to 24%, with the rates being highest in patients with COPD and lesions deep within the lung. Risk of barotrauma in mechanically ventilated patients on ICU can range from 2.9–​4%. Rapid clinical deterioration in a mechan- ically ventilated patient should alert the clinicians to the possibility of a tension pneumothorax. Barotrauma and associated risk of pneumothorax is partly dependant on the underlying lung condi- tion, patients with acute respiratory distress syndrome, COPD, and Pneumocystis jirovecii pneumonia are at highest risk. Management The diagnosis is established by appropriate clinical suspicion in a high-​risk patient, combined with a chest radiograph. Treatment differs from spontaneous pneumothorax in that recurrence pre- vention is not needed as the underlying lung is normal, hence air evacuation is the sole aim of treatment. If the patient has few/​no symptoms, is not artificially ventilated, and the pneumothorax is small, simple observation with the administration of supplemental oxygen is appropriate. Simple aspiration or chest tube drainage is appropriate if the patient has significant symptoms or the pneumo- thorax is large. The patient with a pneumothorax secondary to assisted mechan- ical ventilation should always receive chest tube drainage to avoid the development of a tension pneumothorax due to the positive in- spiratory pressures generated by the ventilator driving air into the pleural space. Sometimes this mechanism produces an air leak so large that a high percentage of the total inspired volume exits via the chest tube. This usually still provides effective ventilation, as the drained gases have a similar CO2 content to exhaled air. Secondary spontaneous pneumothorax Secondary spontaneous pneumothorax is associated with underlying lung disease. Epidemiological data has shown a pneumothorax inci- dence rate for the over 55 age group in the order of 32.4/​100 000/​year for men and 10.9/​100 000/​year for women in the United Kingdom, with peak incidence of secondary spontaneous pneumothorax within the age range 60–​65 years. With poor pulmonary reserve and other comorbidities in this group of patients, a secondary pneumo- thorax tends to be symptomatic, require immediate treatment, and carries a high mortality rate. Aetiology COPD is by far the commonest cause of secondary pneumothorax, and risk of pneumothorax increases with increasing severity of the disease. Other diseases associated with secondary pneumothoraces are pulmonary fibrosis, tuberculosis, Pneumocystis jirovecii pneu- monia, cystic fibrosis, and other rare cystic lung diseases such as lymphangioleiomyomatosis and Langerhans cell histiocytosis. Clinical features Symptoms are more pronounced than with primary spontan- eous pneumothorax. Almost all patients will have dyspnoea. Any patient with COPD and with worsening dyspnoea, particularly in association with chest pain should be suspected of pneumothorax. Examination is unremarkable except for the finding of low oxygen saturations and low partial pressures of oxygen on arterial blood gas. A chest radiograph would help establishing the diagnosis but one must be cautious in distinguishing a large air containing bulla from a pneumothorax. The visceral pleural line in a pneumothorax is convex towards the lateral chest wall whereas the apparent pleural line in a bulla is concave towards the lateral chest wall. Where there is doubt between a pneumothorax and a large bulla a chest CT should be performed to help distinguish prior to any pleural intervention (Fig. 18.17.20). Attempted insertion of a chest tube into a bulla, with formation of a bronchopleural fistula, could have disastrous conse- quences for a patient who may already be compromised from their underlying disease. Management Secondary pneumothoraces are less likely than primary pneumo­ thoraces to be tolerated or resolve spontaneously. Prompt treatment and effective recurrence prevention are therefore higher priorities in secondary than in primary pneumothorax as patients are more symptomatic, have an appreciable mortality before treatment, and a higher recurrence rate (45% over 3–​5 years). Aspiration is less likely to be successful in this cohort of patients. Chest tube insertion often leads to a rapid improvement in symptoms. Those with ongoing air leak for more than 48 hours should be discussed with thoracic surgeons. The prognosis after tube drainage is worse than in primary pneumothorax. The median duration of drainage for a secondary pneumothorax due to COPD is 5 days, compared with 1 day for primary pneumothorax, and about 20% of patients with secondary pneumothorax have a prolonged air leak lasting for more than 7 days. Bronchoscopically placed endobronchial valves to manage prolonged air leaks, have shown promising results in small case series. Similarly, anecdotal evidence support the use Heimlich valves S P Fig. 18.17.20  CT showing a secondary pneumothorax (P) with subcutaneous air (S) (surgical emphysema). A chest tube is seen entering the chest cavity from in between the ribs.

18.17  Pleural diseases 4325 in an ambulatory setting to manage secondary pneumothoraces but large randomized controlled trials (RCTs) to support their use is yet to come. Prevention Surgical pleurodesis should be the treatment of choice where possible. Recurrence rate following surgery is generally low (1–​3%). For patients not fit for surgery chemical pleurodesis via chest tube using talc or doxycycline is appropriate but has a higher recurrence rate around 20%. Traumatic pneumothorax The incidence of a pneumothorax after blunt trauma depends on the severity of the injury, but is high and exceeds 35% in some series. With penetrating chest trauma the mechanism of pneumo- thorax is simply air entry through the wound or via the visceral pleura from injury to the lung. With nonpenetrating trauma a pneumothorax may develop if the visceral pleura is lacerated by a rib fracture or dislocation, but in most cases there are no associ- ated rib fractures and it is thought that sudden chest compression increases alveolar pressures and causes alveolar rupture. Air then enters the interstitial space and dissects towards either the visceral pleura or the mediastinum, with a pneumothorax developing when the visceral or mediastinal pleura ruptures and allows air to enter the pleural space. Diagnosis and management The diagnosis is made by chest radiograph or CT, with 40% of pneumothoraces demonstrated on the initial chest radiograph being clinically unexpected. Thoracic ultrasonography, performed at the bedside, is also a sensitive diagnostic technique, but is inaccurate in subjects with COPD. Most traumatic pneumothoraces are treated with chest tube drainage, although an occult or small pneumothorax can be man- aged conservatively if assisted ventilation is not needed. After chest tube drainage, the lung usually expands within 24 h. Traumatic pneumothorax is occasionally the presenting feature of rupture of the trachea or a major bronchus (usually after anterior or lateral fracture of some of the first three ribs). Most of these patients also have haemoptysis. Bronchoscopy should be performed when this diagnosis is suspected, with rapid surgical repair of any defect identified. Traumatic rupture of the oesophagus is another uncommon but important differential diagnosis presenting as pneumothorax (Boerhaave syndrome). Hydropneumothorax is usual in this situ- ation. The measurement of pleural fluid amylase (due to the entry of amylase rich saliva into the pleural space) reliably identifies this problem. Catamenial pneumothorax Catamenial pneumothorax is a rare condition, defined as spon- taneous, recurrent pneumothoraces occurring in women of child bearing age, in synchrony with menses. They are often right-​sided, but left-​sided and bilateral (not necessarily simultaneous) cases can occur. The aetiology of catamenial pneumothorax is obscure, but there are several hypotheses. Migration and deposition of endometrial tissue which undergoes cyclical necrosis and sloughing, leading to diaphragmatic and visceral pleural defects, is the most popular. Transvaginal air entry which travels into the thorax via diaphrag- matic pores is another theory. Diaphragmatic pores, nodules, or spots on the diaphragm and pleurae are characteristic intraoperative findings of catamenial pneumothorax. Medical treatment with hormonal therapy (GnRH analogue) for endometriosis is effective in approximately half the patients. VATS or open thoracic surgery allows inspection of the diaphragm and pleura, repair of diaphragmatic defects, and mechanical pleurodesis. This has a higher failure rate than when employed for primary spon- taneous pneumothorax, and postoperative use of hormonal control should be considered. Other issues Air travel after pneumothorax Air travel per se does not increase the risk of a pneumothorax, but the consequences of a pneumothorax during air travel maybe ser- ious. Air travel should be delayed until after definitive treatment of pneumothorax and complete lung expansion has been confirmed radiographically. Consensus on optimum time for travel after a pneumothorax varies, 2 weeks from complete radiographic reso- lution is generally the accepted rule, although there is no robust evi- dence to support this. Re-​expansion pulmonary oedema Unilateral pulmonary oedema (re-​expansion pulmonary oedema) occurs when the lung is rapidly reinflated after a period of collapse (usually at least several days) due to a pneumothorax or pleural effu- sion (Fig 18.17.21). The phenomenon is uncommon and only very rarely fatal, and its clinical frequency is far lower than the frequency with which it is discussed. There were three cases in the Veterans Administration cooperative study of more than 500 spontaneous pneumothoraces. Aetiology The alveolar oedema fluid has a high protein content, hence it is due to increased capillary leakiness rather than increased hydro- static pressure. Possible mechanisms include damage caused by mechanical stresses applied to the lung during re-​expansion, or ischaemia/​reperfusion injury due to oxygen free radicals. Oxygen-​ scavenging compounds such as dimethylthiourea, catalase, or superoxide dismutase partially inhibit neutrophilic infiltration of re-​expansion pulmonary oedema, but do not substantially de- crease the amount of oedema itself. In experimental animals, re-​ expansion oedema only occurs if the lung has been collapsed for several days and is re-​expanded rapidly: this fits the clinical picture where the pneumothorax or effusion has usually been present for more than 3 days. Clinical features Re-​expansion and oedema causes coughing and chest tightness during or immediately after lung re-​expansion. Symptoms may progress for 12–​24 h, with chest radiographs showing ipsilateral pulmonary oedema that may rarely progress to involved contralat- eral lung. If the patient survives the first 48 h, recovery is usually complete. Treatment is supportive, with administration of supple- mental oxygen, diuretics, intubation, and mechanical ventilation if needed.

section 18  Respiratory disorders 4326 Prevention The risk of re-​expansion oedema is probably reduced if lung in- flation is gentle, hence a chest tube for pneumothorax should be attached to an underwater seal drainage without suction to allow gradual lung re-​expansion. During drainage of a pleural effusion, the procedure should be terminated if the patient develops chest tightness or persistent coughing. Arbitrary maximal volumes for a single thoracentesis are often suggested to reduce the risk of re-​expansion oedema, but there is no direct evidence to substan- tiate this strategy. Acknowledgements We acknowledge Robert Davies, Fergus Gleeson, Fraser Brims, and Jose Porcel who produced earlier versions of the chapter in this book’s previous editions. Fig. 18.17.21  A chest X-​ray of a large right-​sided pleural effusion with a chest drain in situ is shown in figure (a). Second chest X-​ray following controlled drainage of 5 litres of fluid, showing air space shadowing (b). Coronal (c) and sagittal (d) CT images confirming pulmonary oedema. All changes resolved with conservative management.

18.17  Pleural diseases 4327 FURTHER READING The pleura Hooper C, Lee YCG, Maskell N (2010). Investigation of a unilateral pleural effusion in adults: British Thoracic Society pleural disease guideline 2010. Thorax, 65, ii4–​ii7. Leung AN, Muller NL, Miller RR (1990). CT in differential diagnosis of diffuse pleural disease. AJR Am J Roentgenol, 154, 3–​92. Light RW, Gary Lee YC (eds). (2016). Textbook of pleural diseases (3rd edn). CRC Press, Florida. Light RW, et al. (1972). Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med, 77, 507–​13. Maskell NA, Gleeson FV, Davies RJO (2003). Standard pleural biopsy versus CT-​guided cutting-​needle biopsy for diagnosis of malignant disease in pleural effusions: a randomised controlled trial. Lancet, 361, 1326–​30. Pleural effusion Arnold D, et al. (2015). Pleural fluid adenosine deaminase (Pfada) in the diagnosis of tuberculous effusions in a low incidence population. PloS One, DOI: 10.1371/​journal.pone.0113047. Heffner JE, Highland K, Brown LK (2003). A meta-​analysis derivation of continuous likelihood ratios for diagnosing pleural fluid exud- ates. Am J Respir Crit Care Med, 1679, 1591–​9. Matsuie S, et  al. (2012). Respiratory involvement in IgG4 related Mikulicz’s disease. Modern Rheumatology, 22, 31–​9. Menzies S, et al. (2011). Blood culture bottle culture of pleural fluid in pleural infection. Thorax, 66, 658–​62. Pyogenic pleural infection Colice GL, et  al. (2000). Medical and surgical treatment of parapneumonic effusions:  an evidence-​based guideline. Chest, 118, 4–​71. Davies H, Davies R, Davies C (2010). Management of pleural infection in adults: British Thoracic Society pleural disease guidelines. Thorax, 65, ii41–​ii53. Heffner JE, et  al. (1995). Pleural fluid chemical analysis in parapneumonic effusions. A meta-​analysis. Am J Respir Crit Care Med, 151, 1700–​8. Maskell NA, et al. (2005). UK controlled trial of intrapleural strepto- kinase for pleural infection. N Engl J Med, 352, 865–​74. Maskell NA, et  al. (2006). The bacteriology of pleural infection by genetic and standard methods and its mortality significance. Am J Respir Crit Care Med, 174, 817–​23. Rahman N, Kahan B, Miller R (2014). A clinical score (RAPID) to identify those at risk for poor outcome at presentation with pleural infection. Chest, 145, 848–​55. Rahman N, Maskell N, West A (2011). Intrapleural use of tissue plas- minogen activator and DNase in pleural infection. NEJM, 365, 518–​26. Tuberculous pleural effusion and empyema Cohen L, Light R (2015). Tuberculous pleural effusion. Turkish Thoracic Journal, 16, 1–​9. Diacon AH, et al. (2003). Diagnostic tools in tuberculous pleurisy: a direct comparative study. Eur Respir J, 22, 589–​91. Gopi A, et al. (2007). Diagnosis and treatment of tuberculous pleural effusion in 2006. Chest, 131, 880–​9. Chylothorax and pseudochylothorax Gruber-​Rouh T, Naguib N, Lehnert T (2014). Direct lymphangiog- raphy as treatment option of lymphatic leakage: indications, out- comes and role in patient’s management. Eur J Radiol, 83, 2167–​71. Light RW, Lee YCG (2005). Pneumothorax, chylothorax, hemothorax and fibrothorax. In: Murray J, et al. (eds) Textbook of respiratory dis- eases, 4th edition, pp. 1961–​88. W B Saunders, Philadelphia. Haemothorax Broderick SR, et  al. (2013). Hemothorax. Etiology, diagnosis, and management. Thorac Surg Clin, 23, 89–​96. Maxwell RA, et al. (2004). Use of presumptive antibiotics following tube thoracostomy for traumatic hemopneumothorax in the prevention of empyema and pneumonia—​a multi-​center trial. J Trauma, 57, 742–​8. Benign asbestos-​induced pleural disease King C, et al. (2011). Benign asbestos-​related pleural disease. Dis Month, 57, 27–​39. Pneumothorax Barker A, et al. (2006). Recurrence rates of video-​assisted thoracoscopic versus open surgery in the prevention of recurrent pneumothoraces: a systematic review of randomised and non-​randomised trials. Lancet, 370, 329–​35. Bintcliffe O, et al. (2015). Spontaneous pneumothorax: time to rethink management. Lancet Respir Med, 3, 578–​88. Gupta D, Hansell A, Nichols T (2010). Epidemiology of pneumothorax in England. Thorax, 55, 666–​71. MacDuff A, Arnold A, Harvey J (2010). Management of spontaneous pneumothorax: British Thoracic Society pleural disease guidelines 2010. Thorax, 65 supplement 2, ii8–​ii31. Noppen M, Baumann M (2003). Pathogenesis and treatment of primary spontaneous pneumothorax:  an overview. Respiration, 70, 431–​8. Noppen M, et  al. (2002). Manual aspiration versus chest tube drainage in first episodes of primary spontaneous pneumothorax: a multicenter, prospective, randomized pilot study. Am J Respir Crit Care Med, 165, 1240–​4. Tschopp JM, et  al. (2015). ERS taskforce statement:  diagnosis and treatment of primary spontaneous pneumothorax. Eur Respir J, 46, 321–​35. Visouli et al. Catamenial pneumothorax. J Thorac Dis, 4, 17–​31.

18.18 Disorders of the thoracic cage and diaphragm

18.18 Disorders of the thoracic cage and diaphragm 4328 John M. Shneerson and Michael I. Polkey

ESSENTIALS Disorders of the thoracic skeleton can lead to a severe restrictive ventilatory defect, the risk of respiratory failure being highest with (1) scoliosis—​particularly if the following characteristics are pre- sent: early onset, severe angulation, high in the thorax, respira- tory muscle weakness, low vital capacity; (2) kyphosis—​but only if of very sharp angulation (gibbus), most commonly seen fol- lowing tuberculous osteomyelitis; and (3)  after thoracoplasty—​ historically performed as treatment for pulmonary tuberculosis. While not a disorder of the skeleton, a similar pathophysiological pattern is seen in extreme obesity, and this is the fastest growing cause of referral to home ventilation centres Diaphragmatic weakness—unilateral paralysis rarely causes symptoms unless there is coexisting lung disease or weakness of other respiratory muscles. Bilateral paralysis usually presents as orthopnoea, which (by contrast to orthopnoea in cardiac failure) is relieved promptly by sitting up, and on examination the ab- domen moves paradoxically inwards as the diaphragm ascends during inspiration. Vital capacity in the sitting position is about 50% of that predicted and may fall by a further 50% when supine. Diaphragmatic screening or ultrasound examination may reveal paradoxical diaphragmatic movement during sniffing. Respiratory failure—this occurs initially during sleep, when the normal sleep related reduction in respiratory drive is insufficient to overcome the work of breathing, and then in wakefulness. Pulmonary hypertension and right heart failure often develop once the arterial Pco2 is elevated during the day. Arterial blood gases and quality of life can both be readily improved with noninvasive ventilation, usually using a nasal or face mask. Survival in most skeletal disorders after starting ventilation is around 80 to 90% at 1 year, 75% at 3 years and 50% at 5 to 10 years. Other clinical features—some conditions of the thoracic cage, particularly pectus excavatum and the straight back syndrome, can cause cardiac problems due primarily to distortion of the heart and major vessels. Ankylosing spondylitis leads to apical bullae, pleural thickening/effusions, and cricoarytenoid arth- ritis, but rarely causes respiratory failure in the absence of other comorbidities. Introduction Skeletal disorders of the thorax are an important group of conditions that frequently impair ventilation. They are often associated with re- spiratory muscle weakness due to neuromuscular disorders, which are described elsewhere. Most of these conditions restrict the devel- opment and/​or the expansion of the lungs so that alveolar ventila- tion rather than intrapulmonary gas exchange is primarily impaired. Disorders of the spine Scoliosis Scoliosis is defined as a lateral curvature of the spine, but it is in- variably also associated with rotation of the vertebral bodies (Fig. 18.18.1). This results in an unstable lordosis rather than a 18.18 Disorders of the thoracic cage
and diaphragm John M. Shneerson and Michael I. Polkey Fig. 18.18.1  Scoliosis following poliomyelitis.

18.18  Disorders of the thoracic cage and diaphragm 4329 kyphosis, and hence the frequently used term kyphoscoliosis is inaccurate. A mild degree of scoliosis is very common. Angles of curvature of 5° or 10° have been used to define when it becomes pathological, but these are arbitrary figures. Postural scoliosis can be distinguished from a structural scoliosis by its temporary nature and because it disappears on bending forward. The age of onset and natural history of scoliosis vary according to its cause (Box 18.18.1). When it is due to a neuromuscular dis- order (‘paralytic’ scoliosis) it usually arises during childhood or adolescence, or in poliomyelitis within about 2 years of the acute in- fection. Typically, the curve has a long C shape and may be severe. The scoliosis is due to asymmetrical weakness of the axial muscles causing the spine to rotate and move to one side. Weakness of chest wall muscles is almost invariable, occurs in a pattern which is char- acteristic of each disorder, and may have a profound influence on the clinical features. When the scoliosis is due to a congenital abnormality, such as a hemivertebra or a segmentation defect, it usually becomes apparent early in childhood. The scoliosis of neurofibromatosis and Marfan syndrome is probably due to an abnormality of connective tissue. Scoliosis due to pleural or pulmonary disease is less common than in the past, now that chronic infections are less frequent and more successfully treated. The commonest type is adolescent idiopathic scoliosis, where the spinal deformity develops at the time of the pubertal growth spurt. It is around four times as common in girls as in boys, and the convexity of the deformity is on the right in 80% of cases. The scoliosis may continue to worsen slightly even after growth of the spine stops. An infantile form of idiopathic scoliosis is less common and can progress to a severe deformity, although it may resolve spontaneously. Pathophysiology Scoliosis causes the compliance of the chest wall to be reduced, meaning that the generation of a specific amount of negative intrathoracic pressure results in less inspiratory airflow. This problem may be compounded by mechanical problems so that ten- sion generation in the respiratory muscles does not fully translate to negative intrathoracic pressure and by associated respiratory muscle weakness (Fig. 18.18.2). Reduced compliance becomes more marked in older people, possibly owing to degenerative changes in the costovertebral joints. The compliance of the lungs is also reduced, largely because they are at the lower end of the pres- sure volume curve. In addition, the distortion of the ribcage puts Box 18.18.1  Causes of scoliosis • Idiopathic -​ Infantile, adolescent • Osteopathic -​ Congenital (e.g. hemivertebrae) -​ Thoracoplasty • Neuromuscular (examples that follow are not an exhaustive list) -​ Syringomyelia -​ Friedreich’s ataxia -​ Poliomyelitis -​ Duchenne’s muscular dystrophy • Connective tissue disorders -​ Marfan’s syndrome -​ Neurofibromatosis -​ Osteogenesis imperfecta • Pleuropulmonary -​ Empyema -​ Pneumonectomy -​ Unilateral lung fibrosis • Complex surgery (e.g. cardiac) as an infant Respiratory failure more likely if Respiratory muscle weakness Respiratory muscles mechanically disadvantaged Load increased Drive reduced COPD: Hyperinflation Scoliosis Scoliosis Massive obesity Upper airway load (co-existent obstructive sleep apnoea) Sleep, worse in REM Sedative Medicines Respiratory system maintains homeostasis Respiratory failure occurs Fig. 18.18.2  Factors leading to respiratory failure in scoliosis and other disorders.

section 18  Respiratory disorders 4330 the inspiratory muscles at a mechanical disadvantage; those on the side of the convexity of the scoliosis are shortened and those on the side of the concavity lengthened. A restrictive defect and reduction of the maximum inspiratory and expiratory pressures develops even in the absence of any muscle weakness, but is more marked if this is present. In adults with severe scoliosis, exercise capacity is linked to the degree of reduction of the vital capacity and the forced expiratory volume in 1 s (FEV1). On exercise the tidal volume increases initially and then remains constant, while respiratory rate rises as exercise becomes more intense. Ventilation at any given oxygen uptake is greater than normal, and maximal exercise ventilation, which limits exercise capability, is often severely curtailed. The cardiac output may increase normally during exercise, but pulmonary artery pres- sure rises rapidly, and its rate of increase is linearly related to oxygen uptake and inversely related to the vital capacity. In mild scoliosis, the arterial blood gases are often normal, but the first abnormality is a fall in the partial pressure of oxygen (Po2). This is due to suboptimal ventilation and perfusion matching, particu- larly at the bases of the lungs. Even when the anatomical distortion of the two lungs is gross, there is usually rather less difference in function between the two lungs than might be expected. Effect of sleep Acute ventilatory failure may be precipitated by an intercurrent epi- sode (e.g. a chest infection or administration of an anaesthetic for other reasons), but chronic hypoventilation initially occurs during rapid eye movement sleep. Sleep is associated with loss of the vol- untary respiratory drive and a reduction in the reflex drive in re- sponse to hypoxia, hypercapnia, and other stimuli. Within each stage of nonrapid eye movement (NREM) sleep the respiratory pat- tern is regular, but it varies as NREM sleep moves from one stage to another. Central apnoeas may appear and the arterial Pco2 rises slightly despite a reduction in metabolic rate. However in rapid eye movement (REM) sleep particularly the respiratory drive to non-​ diaphragmatic muscles, and thus to the respiratory muscles overall, is less than during NREM sleep, and it is much more variable from moment to moment. Muscle activity is reduced, and whereas in NREM sleep this affects all the respiratory muscles to an equal ex- tent, in REM sleep diaphragmatic activity is selectively retained. Moreover, loss of activity in the upper airway dilator muscles in- creases the upper airway resistance and the work of the chest wall muscles. These changes during sleep are particularly important in scoliosis, where the diaphragm is attached to an asymmetrical ribcage and the respiratory pump often has little reserve. The effects of sleep are accentuated when the scoliosis is the result of neuromuscular dis- orders because the presence of muscle weakness in addition to the skeletal deformity reduces tidal volume and increases respiratory frequency, leading to alveolar hypoventilation. Arousals initially occur in REM sleep, which becomes fragmented, and at a later stage in NREM sleep, with loss particularly of slow wave sleep (stage 3). Sleep fragmentation itself reduces the respiratory drive promoting a vicious circle in which there are progressively more respiratory-​ induced arousals and deterioration in respiratory drive. Central apnoeas and hypopnoeas develop; hypercapnia then appears during wakefulness as well as in sleep. Risk factors for respiratory failure Chronic hypercapnia during the day is uncommon in childhood and is influenced in patients with scoliosis by the following: • Age of onset—​if the scoliosis appears before the age of about 8 years it may prevent normal alveolar multiplication so that the lungs fail to develop fully. The capillary surface area is reduced and there is an increased risk of developing respiratory and right heart failure later in life. The later onset of adolescent idiopathic scoli- osis is probably the main reason why these complications only rarely occur in this condition. • Level of the scoliosis—​in general, the higher the curve in the thor- acic spine, the more marked are the cardiac and respiratory prob- lems. Thoracolumbar or lumbar scoliosis has virtually no effect on respiration. • Severity of scoliosis—​the angle of scoliosis is closely related to the reduction in lung volume. This association is seen with all measures of lung volumes, including residual volume, total lung capacity, and functional residual capacity, as well as with vital cap- acity, except in patients with associated neuromuscular disorders where the changes in lung volumes are due also to the weakness of the respiratory muscles as well as the degree of deformity. The changes in lung volumes become significant when the angle of scoliosis is greater than about 100°. • Presence of muscle weakness—​the functioning of the respiratory muscles is impaired in scoliosis. Where the underlying aetiology is a neuromuscular disorder, this will precipitate respiratory failure at a lesser degree of angulation. Historically, maximum static mouth pressures have been used to assess respiratory muscle weakness, but it is now considered that the maximal sniff nasal inspiratory pressure is the most appropriate test. While the lower limit of normal is considered 60 cm H2O for women and 70 cm H2O for men, a serious contribution to re- spiratory failure may be expected when values of 40 cm H2O or less are observed • Small lung volumes—​respiratory failure usually occurs when lung volumes have been reduced to a degree such that vital capacity is less than 1.0 to 1.5 1. Consequences of respiratory failure Hypoxia causes pulmonary vasoconstriction, which increases the pulmonary vascular resistance and leads to pulmonary hyperten- sion, but the rate of rise of pulmonary artery pressure during ex- ercise correlates with the degree of restriction of lung volumes rather than arterial Po2. Right ventricular and atrial hypertrophy develop if hypoxia is prolonged. Significant pulmonary hyperten- sion is rarely seen unless the arterial Po2 is less than about 8 kPa, and pulmonary hypertension by itself rarely causes right heart failure, hence the exact mechanisms underlying these right-​sided cardiac changes are uncertain. The increase in sympathetic activity and circulating catecholamines associated with hypoxia cause renal vasoconstriction and a reduction in renal blood flow. This activates the renin–​angiotensin–​aldosterone system, leading to sodium and water retention. Hypercapnia is associated with an increase in renal tubular hydrogen ion excretion with sodium reabsorption in ex- change for hydrogen. This leads to fluid retention, which is accentu- ated by an increase in antidiuretic hormone secretion. Hypercapnia

18.18  Disorders of the thoracic cage and diaphragm 4331 probably also increases capillary permeability, which contributes to the appearance of oedema. Unlike patients with obstructive sleep apnoea, polycythaemia as a result of renal release of erythropoietin is seldom seen at presenta- tion in patients with scoliosis since NIV is usually offered either as a result of ongoing monitoring or symptoms related to hypercapnia. When present polycythaemia serves to increase oxygen carrying capacity of the blood, but also raises blood viscosity, increasing the work of the right and left ventricles and predisposing to arterial and venous thrombosis. Symptoms and physical signs The earliest symptom of scoliosis is usually a change in the appear- ance of the patient, such as asymmetry of the shoulders or promin- ence of the posterior rib hump. Backache is a late and uncommon presenting symptom, though it may cause patients with established scoliosis distress. With mild curvatures there may be no respiratory symptoms, but mild shortness of breath on exertion is common and a change in this often signifies the development of complications. Orthopnoea, or dyspnoea in water, suggests that diaphragmatic function is impaired. When respiratory failure develops, fatigue, ankle swelling, and even syncope may indicate that pulmonary hypertension and right heart failure are present. Frequent awaken- ings during sleep, associated with excessive daytime somnolence, indicate sleep fragmentation due to apnoeas and hypopnoeas, and are important symptoms that warn of impending respiratory failure. Physical examination may reveal the cause of the scoliosis, such as Marfan syndrome or neurofibromatosis, and other congenital abnor- malities. Any associated muscle weakness or congenital heart disease may be apparent. Ribcage expansion may be predominantly lateral or anterior, or achieved by extension of the spine. In some subjects, chest expansion is mainly oblique because of the rotation of the spine, and some areas of the chest wall may move paradoxically. Accessory muscle action is usually prominent. The presence of central cyanosis indicates that the arterial oxygen saturation is below around 80%. Signs of hypercapnia may also be present, including tachycardia, large volume pulse, peripheral venous dilatation, papilloedema, a flapping tremor, reduction in tendon reflexes, small pupils and—​if severe—​confusion and coma (‘CO2 narcosis’). Investigations The severity of scoliosis can be demonstrated radiologically, but chest radiography is often unhelpful in thoracic scoliosis because ro- tation of the spine obscures much of the lung fields. This can be over- come by obtaining an oblique view of the chest which, by aligning the spine behind the heart, simulates a posteroanterior view. Lung function testing reveals a restrictive defect with reduction in all lung volumes, although the change in residual volume is least marked such that the ratio of residual volume to total lung capacity is increased. TLCO is reduced but Kco is raised, as in other chest wall disorders that cause a restrictive defect and in which the lung tissue is normal. Maximum inspiratory and expiratory pressures, sniff nasal and transdiaphragmatic pressure may be reduced. Chest wall and lung compliance are less than normal, and exercise tolerance is impaired. Arterial blood gas analysis reveals a slightly low Pco2 in mildly af- fected subjects, but later in the course of disease a rise in Pco2 and a proportional fall in Po2 develop. Sleep studies show a variable degree of hypoxia and hypercapnia which are usually most marked in REM sleep. Electrocardiography and echocardiography may be required to establish if pulmonary hypertension or congenital heart disease is present and identify precise abnormalities. Prognosis The prognosis in adolescent idiopathic scoliosis is virtually normal, but life expectancy is reduced in many of the other forms of scoli- osis. This is particularly so in scoliosis of early onset, when it is both severe and high in the thorax and associated with respiratory muscle weakness, low vital capacity, and abnormal blood gases. In most patients the cause of death is either cardiac or respira- tory. Pneumonia and respiratory failure are particularly common in neuromuscular disorders, but hypoxic dysrhythmias during sleep are probably responsible for some deaths. Congenital heart defects, which have an increased prevalence in those with scoliosis, particu- larly when this is due to a congenital abnormality or of the idiopathic type, also contribute to mortality. Management Surgical Mild scoliosis does not need any specific treatment. The prognosis is normal and there is minimal respiratory deficit. However, as the scoliosis becomes more severe, spinal fusion or a costectomy, in which the parts of the ribs comprising the posterior hump are re- moved, may occasionally be of cosmetic value. Spinal fusion or rod insertion may also be required to prevent progression of the scoli- osis, to stabilize the spine, particularly in neuromuscular disorders, and in selected cases to try to improve cardiac or respiratory func- tion or to prevent its deterioration. The value of spinal fusion to prevent cardiorespiratory deterior- ation in adolescent idiopathic scoliosis is still under debate. Many studies of respiratory function before and after surgery have shown remarkably little change in lung volumes, blood gases, or exercise ability. However, in some patients with muscle weakness, particu- larly Duchenne’s muscular dystrophy, the rate of fall of the vital cap- acity can be slowed considerably, and it can even be improved in patients who have had poliomyelitis. However, despite these short-​ term improvements, there have been no properly conducted ran- domized controlled studies which indicate whether or not spinal fusion performed in childhood or adolescence prevents respiratory failure from appearing later in life. Respiratory failure If respiratory failure does develop, any acute illness—​most com- monly an infection or bronchial asthma—​that has precipitated it should be actively treated. Non​invasive ventilation or endotracheal intubation and ventilation may be required during the acute illness. A Cochrane systematic review in 2017 found no evidence to de- termine whether noninvasive or invasive mechanical ventilation should be preferred. If the latter is needed, the patient is then weaned from this either completely or on to a noninvasive method of long-​ term respiratory support. Chronic ventilatory failure usually responds to long-​term mech- anical respiratory support. Administration of oxygen at night and/​or during the day may be dangerous because of the risk of hypercapnia. Nasal or face mask positive-​pressure ventilation is the treatment of choice, although a negative-​pressure system, such as a cuirass or jacket, is a historical alternative, as is a rocking bed. Noninvasive

section 18  Respiratory disorders 4332 ventilation is usually only required during sleep, but some patients benefit from 1 or 2 h treatment during the day as well. A tracheos- tomy is rarely required to provide ventilatory support, but in com- plex neuromuscular disorders it may be indicated to bypass upper airway obstruction (e.g. due to vocal cord adduction, or to gain ac- cess to the tracheobronchial tree to aspirate secretions, or to protect the airway from aspiration of material from the pharynx). Noninvasive ventilatory support at night can improve the quality of sleep, breathlessness on exertion, daytime sleepiness, and early morning headaches. Activities of daily living may be carried out more easily and the number of visits required by general practi- tioners and the quantity of drugs prescribed can be reduced. Sleep architecture, daytime arterial blood gases and nocturnal oxygen sat- uration, and transcutaneous Pco2 can all be improved. Survival once treatment has been instituted is around 75–​85% at 5 years and 60% at 10 years (Fig. 18.18.3). Kyphosis Exaggeration of the normal thoracic kyphosis is most commonly due to osteoporosis and is not usually associated with any significant changes in respiratory function. The exception to this is when a very sharp kyphosis (gibbus) develops, usually caused by tuberculous osteomyelitis of the spine (Pott’s disease), although other conditions such as radiotherapy can cause a similar picture. The spine becomes rigid in the region of the gibbus, and when tuberculosis is the cause the costovertebral joints also become an- kylosed and limit the expansion of the ribcage. A restrictive defect in which the total lung capacity is reduced more than the residual volume is characteristic, but respiratory problems are uncommon unless the gibbus is high in the thoracic spine and develops in early childhood. This is probably because in this circumstance the thoracic deformity prevents the normal development of the lungs in a similar way to early-​onset scoliosis. Hypoxia and hypercapnia appear during sleep before they become apparent during wakefulness, but may be severe. Pulmonary hypertension and right heart failure frequently develop once chronic hypercapnia has become established. Slight breathlessness on exertion is common in the presence of a gibbus, but is rare in other types of kyphosis. Physical examination reveals the spinal deformity and limitation of ribcage expansion. The posteroanterior chest radiograph shows superimposition of the spinal deformity on the lung fields and heart, which makes it dif- ficult to interpret. The extent and severity of the kyphosis is usually well seen on a lateral projection. The typical changes in lung volumes have been described earlier. The arterial Po2 and Pco2 are usually as in scoliosis, the earliest abnormalities are revealed by sleep studies. Treatment of acute tuberculous infection with chemotherapy often prevents a gibbus from developing. Once it has been established and respiratory failure has developed, the only effective treatment is long-​ term respiratory support. This is best provided noninvasively by a nasal positive-​pressure ventilator, rather than a negative-​pressure system, because the sharp kyphosis makes it difficult to lie in the supine position required for negative-​pressure ventilation. Ankylosing spondylitis The initial manifestation of ankylosing spondylitis is usually painful inflammation of the sacroiliac joints, but this may spread to af- fect almost any joint including the intervertebral, costovertebral, manubriosternal, costochondral, and chondrosternal joints. When the inflammatory phase of the disease subsides, the joints become ankylosed and the spinal ligaments calcify. The effect of ankylosing spondylitis on the thorax is that the rib- cage becomes rigid. There is little spinal mobility, and a pronounced kyphosis often develops. The changes in lung volumes are character- istic in that, unlike all other skeletal disorders affecting the thorax, functional residual capacity increases. This is because the ribcage becomes fixed at its own relaxation volume, which is greater than the normal functional residual capacity that is influenced by the inward pull of the elastic recoil of the lungs. Total lung capacity and vital capacity are slightly reduced, and residual volume often increases. The immobility of the ribcage leads to atrophy of the intercostal muscles and both maximal inspiratory and expiratory pressures are reduced. However, there is no impairment of diaphragmatic or ab- dominal muscle function, and this largely compensates for the re- striction of ribcage expansion. The ventilatory responses to exercise are virtually normal and exercise is usually limited by musculoskel- etal and circulatory rather than respiratory factors. Respiratory failure is extremely uncommon in ankylosing spon- dylitis, probably as a result of the normal diaphragmatic function, unless another complication develops, which may be one of the following: • Airflow obstruction—​cricoarytenoid arthritis is a feature of an- kylosing spondylitis and may present with stridor, hoarseness of the voice, breathlessness, obstructive sleep apnoeas, or respiratory failure. • Pleural thickening and effusion—​these rare complications of an- kylosing spondylitis may precipitate respiratory failure. • Aspiration pneumonia—​oesophageal motility is often impaired in ankylosing spondylitis and aspiration pneumonia may develop. • Bullas—​apical fibrobullous lung disease is a feature of ankylosing spondylitis and may be complicated by opportunist infections such as Aspergillus fumigatus or saprophytic mycobacteria, and occasionally by pulmonary tuberculosis. • Abdominal surgery—​this restricts diaphragmatic function on which adequate respiration depends. Conversely, thoracic surgery has relatively little effect on respiration because of the small con- tribution that ribcage expansion plays. Percentage survival 100 50 Time (years) 1 2 3 4 5 6 7 8 9 18 Chronic air flow obstruction Sequelae of tuberculosis Scoliosis Other neurological disorders Poliomyelitis Fig. 18.18.3  Actuarial survival during treatment with ventilatory assistance for respiratory failure. Reproduced from Shneerson JM (1988). Disorders of ventilation, Blackwell, Oxford.

18.18  Disorders of the thoracic cage and diaphragm 4333 Chest pain during sudden movements such as coughing and laughing is common if the active phase of inflammation affects the thorax. These symptoms, which originate in either the joints or the muscles, become less prominent as the disease advances. Breathlessness and other respiratory symptoms are uncommon. Cricoarytenoid arthritis may occasionally present with hoarseness, stridor, or breathlessness, and extensive fibrobullous disease may also cause breathlessness. The most obvious physical sign related to the chest is restriction of ribcage movement associated with prominent accessory muscle activity and abdominal respiratory movements. Chest radiography may show calcification of the paraspinal liga- ments (bamboo spine) and reveal evidence of complications of ankylosing spondylitis such as pleural thickening, aspiration pneu- monia, and apical fibrobullous disease. The changes in lung volumes have been described earlier. Chest wall compliance is reduced but lung compliance is normal. The Kco is increased and arterial blood gases are normal during both rest and exertion. Physiotherapy and nonsteroidal anti-​inflammatory drugs may improve vital capacity and chest expansion, particularly in the early phase of the disease or during acute exacerbations. Disorders of the sternum and ribs Congenital abnormalities Congenital abnormalities of the ribs and sternum rarely cause any important respiratory problems. Multiple congenital rib abnormal- ities may occasionally lead to paradoxical movement of the chest wall or impair diaphragmatic function if they occur in the region of its insertion. Severe congenital defects of the sternum (e.g. agenesis or a bifid sternum) are rare, but may require surgery in the neonatal period in order to stabilize the anterior chest wall. Pectus excavatum Pectus excavatum is a depression deformity of the sternum that is often present at birth but may worsen during the adolescent growth spurt. It is occasionally familial and may be associated with other abnormalities such as the straight-​back syndrome or scoliosis. It ap- pears to result either from an increased inward pull on the sternum by the sternal diaphragmatic fibres or from an abnormally compliant chest wall. Transient paradoxical movement of the sternum during respir- ation is seen in neonates, particularly in the presence of upper airway obstruction or pneumonia. The sternal depression may become per- manent even if the cause, such as enlarged tonsils, resolves completely. In adults, pectus excavatum rarely causes any symptoms. Lung vol- umes are normal or only slightly diminished, and chest wall mobility appears to be normal. Arterial blood gases are normal both at rest and during exercise. Very occasionally, right ventricular filling can be impaired if the heart is compressed between the depressed sternum and the spine, and compression of the pulmonary outflow tract may cause a systolic murmur. These problems are most marked in the erect position and during exercise. Occasionally atrial dysrhythmias develop, and opening of a patent foramen ovale induced by hyper- ventilation may lead to a right-​to-​left shunt and arterial hypoxaemia. Surgery is sometimes performed for cosmetic reasons, although the result can be disappointing. It has little or no effect on the mild restrictive defect or exercise ability, except in the rare situation when right ventricular filling is impaired or atrial dysrhythmias have developed. Pectus carinatum Pectus carinatum is a protrusion deformity of the sternum in which the chest is often narrowed transversely. It becomes most marked during the pubertal growth spurt, although it may be present from birth and is occasionally associated with severe childhood asthma or ventricular septal defects. It is probably the result of excessive growth of the ribs or costal cartilages, and if this is asymmetrical the sternum becomes oblique. The respiratory consequences of pectus carinatum have hardly been investigated. Chest pain may arise at the insertions of the inter- costal muscles anteriorly, or in the costal cartilages and anterior ribs. Lung volumes appear to be normal. Surgery is indicated only for cosmetic reasons and not in order to improve respiratory function or exercise ability. Acquired abnormalities Flail chest A flail chest is one in which multiple rib fractures cause paradox- ical movement of the chest wall during respiration. It may be as- sociated with other injuries, such as rupture of the aortic arch or spleen, and with fractures of the skull and long bones. It is fre- quently associated with pulmonary contusion, pneumothorax, or haemothorax. Surgical stabilization of the chest wall is rarely required. Sufficient analgesia to enable the patient to cough adequately may be all that is needed in less severe cases, as long as the paradoxical movement does not impair alveolar ventilation. Positive-​pressure ventilation can achieve ‘pneumatic splinting’ of the flail segment if the problem is more severe. The effectiveness of this has not been definitely es- tablished, but it appears that positive end expiratory pressure or continuous positive airway pressure is beneficial by preventing any negative pressure swings within the pleura. Thoracoplasty The operation of thoracoplasty was developed for the treatment of pulmonary tuberculosis, when varying lengths of up to 11 ribs were removed to collapse the chest on the affected side (Fig. 18.18.4). This has been superseded by antituberculous chemotherapy, al- though thoracoplasty has recently been reported in multidrug re- sistant tuberculosis, and the procedure is occasionally required to treat chronic infections, particularly when there is a problem in obliterating the pleural space after pulmonary resection. It is estimated that as many as 30 000 operations were carried out in the United Kingdom between 1951 and 1960: some of these pa- tients still survive, and increasing numbers are being seen by chest physicians because of the late complications of the surgical pro- cedure. Other surgical approaches used at the time (phrenic nerve crush, recurrent therapeutic pneumothoraces and plombage) may also contribute to respiratory failure by reducing the capacity of the respiratory muscle pump or increasing the load. A similar pic- ture is increasingly being seen after patients have survived exten- sive surgery (e.g. pneumonectomy for cancer or decortication for empyema).

section 18  Respiratory disorders 4334 Consequences on respiratory function The consequences of thoracoplasty on respiratory function have been hard to elucidate because they are often combined with the ef- fects of the underlying lung disease for which the surgery was carried out, and those of other treatments such as lung resection. However, the removal of the ribs has the direct result of flattening the chest and reducing the volume of the thorax. The normal movements of the ribcage may be impaired and paradoxical movement at the site of the thoracoplasty is common. The compliance of the chest wall is re- duced, and it may fall further because the small range of movements of the costovertebral joints after surgery probably induces soft tissue changes which further limit the mobility of these joints. Chest wall compliance is also reduced by the almost invariable development of a thoracic scoliosis. This is convex to the side of the thoracoplasty and may progress for several years after the surgery. The severity of the scoliosis correlates with the number of ribs removed, but also depends on the details of the surgical technique. Respiratory muscle function is impaired by a thoracoplasty. The intercostal and shoulder girdle muscles are directly damaged by the surgery, and distortion of the ribcage and the development of a scoliosis put the inspiratory muscles at an additional mechanical disadvantage. Diaphragmatic excursion is reduced, particularly on the side of the thoracoplasty, but also occasionally contralaterally. The combination of reduced chest wall compliance and impaired respiratory muscle function accounts for the restrictive defect. All lung volumes are reduced, and in general the severity of the restrictive defect is proportional to the number of ribs that have been resected. A rapid respiratory rate with a small tidal volume is the characteristic respiratory pattern, particularly during exer- tion. Exercise is limited by ventilatory factors rather than by the cardiovascular system. Chronic airflow obstruction, which may be due to either tuberculous endobronchitis or the effects of tobacco smoking, may be significant in some patients, resulting in a pro- gressive fall in exercise ability and contributing to the development of respiratory failure. Ventilation and perfusion of the lung on the side of the thoracoplasty are usually reduced equally, hence the arterial Po2 often remains virtually normal. The function of the contralat- eral lung is much more important in determining the blood gases. Hypoxaemia usually first appears during sleep, as in scoliosis, and may be associated with hypercapnia. The presence of daytime hypercapnia correlates with the reduction in maximal inspiratory and transdiaphragmatic pressures. Clinical features and management The symptoms of patients with a thoracoplasty are similar to those with a scoliosis; recurrence of pulmonary tuberculosis is theor- etically possible, but extremely unusual in practice. Right heart failure often develops insidiously, either when respiratory failure appears or subsequently. It may be manifested by progressively worsening ankle swelling and fatigue. Physical examination re- veals a thoracotomy scar and a flattened area of chest in the region of the thoracoplasty which may move paradoxically. Accessory muscle activity, particularly on the side of the thoracoplasty, is often marked. The chest radiograph shows the extent of the thoracoplasty, other features which indicate the site and extent of previous tuber- culous infection, and the sequelae of treatment such as a previous phrenic nerve crush or an artificial pneumothorax, which often causes extensive, calcified pleural thickening. The characteristic physiological defect is restrictive, but airflow obstruction may also be significant. Maximum inspiratory and expiratory pressures and transdiaphragmatic pressures are reduced. Most patients are mildly hypoxic, but later in the clinical course the arterial Pco2 may rise, particularly during sleep. Life expectancy is reduced after a thoracoplasty for pulmonary tuberculosis, with death occurring particularly from respiratory but also from cardiac causes. These complications are related to the extent of the tuberculosis and to whether or not an artifi- cial pneumothorax was induced on the contralateral side to the thoracoplasty, since this often leads to pleural thickening and may indicate extensive tuberculous damage of the underlying lung. Respiratory failure can develop quite suddenly after a long period of stability, even when an acute illness such as a chest infection is not responsible. Conventional treatment of airflow obstruction with (for in- stance) bronchodilators may be effective, and right heart failure may respond to diuretics and angiotensin-​converting enzyme inhibitors. Chronic ventilatory failure usually responds well to nocturnal, noninvasive respiratory support. A few patients can be managed adequately with oxygen during the day and/​or at night as long as the Pco2 remains normal or only slightly raised. When respira- tory support is required, nasal positive-​pressure ventilation is usually effective. Some patients gradually require more intensive support, so that treatment is needed during the day as well as at night. This deterioration may be due to progressive worsening of small airway obstruction or respiratory muscle function, or to a fall in oxygen delivery to the tissues caused by a deteriorating cardiac output associated with advancing pulmonary hyperten- sion. Survival at 1 year is around 90%, at 3 years 75–​85%, and at 5 years 50–​65%. Fig. 18.18.4  Chest radiograph showing effects of thoracoplasty.

18.18  Disorders of the thoracic cage and diaphragm 4335 Disorders of the diaphragm Aetiology Diaphragmatic paralysis or paresis may be due to lesions affecting the diaphragm itself, or the phrenic nerve, its nucleus, or higher con- trol centres or pathways. The most common causes of diaphragmatic weakness are shown in Table 18.18.1. Often no cause is found in unilateral weakness, which is then presumed to be due to a crypto- genic phrenic neuropathy, either as part of a widespread peripheral neuropathy or isolated to the phrenic nerves. In clinical practice, patients without known neurological disease presenting to an outpatient service will most likely turn out to have diaphragm weakness associated with neuralgic amyotrophy, but clinicians should exclude adult onset Pompe disease since enzyme replacement therapy is now available. Follow up is recommended since a more sinister neurological disease may emerge: respiratory muscle weakness is a presenting feature in approximately 3% of pa- tients with motor neuron disease. Pathophysiology Unilateral weakness of the diaphragm causes it to move upwards (paradoxically) into the thorax during inspiration, instead of descending. This decreases the tidal volume and the mechanical ef- ficiency of breathing. It is worse in the supine position (or in water), when the weight of the abdominal contents pushes the paralysed diaphragm further into the thorax and decreases the functional re- sidual capacity. The diaphragm is splinted in an expiratory position so that it moves relatively little, even though it is paralysed. When the subject lies on one side, the lower half of the diaphragm behaves in this way if it is paralysed, but if the upper half is paralysed it moves paradoxically. Patients with unilateral diaphragm weakness tend to be more comfortable sleeping with the affected side downward (so the contralateral side can move freely), in contrast to other condi- tions (e.g. pleural effusion) where patients are more comfortable with the diseased side up to preserve ventilation/​perfusion (VQ) matching in the unaffected lung. The loss of inspiratory muscle strength is partially compensated by recruitment of intercostal and accessory muscles, but the max- imum inspiratory and transdiaphragmatic pressures are reduced. The vital capacity in the upright position is approximately 20 to 25% less than normal, and a further fall of about 15% occurs when lying supine. There are similar changes in the total lung capacity and func- tional residual capacity; residual volume is unchanged and expira- tory muscle strength is largely preserved. The distribution of ventilation and perfusion is affected by uni- lateral diaphragm weakness. Ventilation is slightly diminished, par- ticularly at the base on the side of the diaphragmatic paralysis in the sitting position, but this is more marked when supine. Similar changes occur with perfusion on a regional basis, but ventilation–​ perfusion matching is impaired and hypoxia results. Hypercapnia does not occur during wakefulness or sleep. The physiological abnormalities seen with bilateral diaphragmatic weakness in adults are much more marked than in unilateral dia- phragmatic disorders. The diaphragm moves paradoxically during inspiration and expiration, and intrapleural pressure changes are transmitted across it so that abdominal pressure falls during inspir- ation and the anterior abdominal wall moves paradoxically. The max- imum transdiaphragmatic pressure falls in proportion to the degree of diaphragm weakness, and since the diaphragm is the main inspira- tory muscle, the maximum inspiratory pressure is correspondingly reduced. The vital capacity in the sitting position is about 50% of that predicted and may fall by a further 50% when supine, the influence of the supine position being greater than with unilateral diaphrag- matic weakness because the weight of the abdominal contents pushes both halves of the diaphragm into the thorax. Ventilation is particu- larly reduced at the bases in the supine position, with less change in perfusion so that the arterial Po2 falls. This postural change is partly responsible for the hypoxia that has been observed during sleep, but the rapid respiratory rate, small tidal volume, and short inspiratory time contribute to this and to hypercapnia. Symptoms and physical signs Unilateral diaphragmatic paralysis in adults rarely causes symptoms unless there is coexisting pulmonary disease or weakness of other respiratory muscles. In contrast, bilateral weakness can cause se- vere breathlessness. This may occur during exertion, but a specific feature is orthopnoea: this occurs within a few seconds of lying flat and is relieved promptly by sitting up, in contrast to left ventricular failure and nocturnal asthma with which it is frequently confused. Breathlessness may also occur when standing in water, since the passive inspiratory descent of the diaphragm due to gravity is pre- vented by the externally applied hydrostatic pressure. Patients will complain of dyspnoea on picking things from the floor, tying their shoelaces and getting out of a car: these are all manoeuvres which increase intra-​abdominal pressure. The physical signs of unilateral diaphragm weakness can be subtle. Dullness to percussion over the lower part of the thorax may be pre- sent. The normal inspiratory outward movement of the abdomen may be reduced or absent on the side of diaphragmatic paralysis, and expansion of the lower chest may lag behind the normal expansion of the other side. The physical signs of bilateral diaphragmatic paralysis are much more obvious. Orthopnoea is usually readily apparent, and the ab- domen moves paradoxically inwards as the diaphragm ascends during inspiration. A  maximum transdiaphragmatic pressure of less than 30 cmH2O is necessary for this sign to be detected. The accessory muscles are active, particularly in the supine position. The quality of sleep is often poor and as a result excessive daytime Table 18.18.1  Main causes of diaphragmatic weakness Unilateral Bilateral Neuralgic amyotrophy Neurological disease (motor neurone disease, muscular dystrophies, adult onset Pompe disease, myopathies) Congenital (e.g. agenesis, eventration) Trauma Surgery (cardiac, thyroid) High cervical cord lesions Trauma, causing phrenic nerve avulsion Poliomyelitis Adjacent mass (e.g. neoplasm, aneurysm) Peripheral neuropathy, including Guillain Barre Herpes zoster ICU acquired diaphragm weakness Mononeuritis

section 18  Respiratory disorders 4336 somnolence may be a problem. Bilateral, basal dullness due to the high diaphragms is characteristic, but can be mimicked by bilateral pleural effusions. Investigations In unilateral diaphragmatic paralysis the chest radiograph may show elevation of the affected diaphragm, and usually reveals any adja- cent mass that may be responsible. Both the diaphragms are raised if there is bilateral paralysis, and there is often some basal linear shadowing due to subsegmental lung collapse. Overall, however, the chest radiograph cannot be considered a reliable tool to confirm or refute diaphragm paralysis Diaphragmatic screening or ultrasound examination reveals that the diaphragm moves paradoxically, particularly during sniffing, a test which should be carried out in the supine position with a weight on the abdomen. These precautions reduce the likelihood of ab- dominal muscle contraction during expiration from mimicking dia- phragmatic activity by reducing the end expiratory volume below functional residual capacity, so that inspiration then occurs through the elastic recoil of the lungs and chest wall. Nevertheless, this type of imaging carries a false positive rate of approximately 6%. A low vital capacity, which falls further in the supine position, is the hallmark of diaphragmatic weakness, particularly when this is severe and bilateral. All lung volumes are reduced except for the re- sidual volume since expiratory muscle strength is largely preserved. Maximum inspiratory mouth and the maximum sniff nasal pressures are also reduced, but diaphragmatic weakness can be more specif- ically diagnosed by estimating the transdiaphragmatic pressure (the arithmetic difference between oesophageal and gastric pressure). This can be carried out by asking the patient to sniff or to take a max- imum inspiratory effort. Where accurate quantification is required, or to investigate hemidiaphragm disease, magnetic stimulation of the phrenic nerve in the neck in conjunction with measurement of the transdiaphragmatic pressure is required. Care is required to carry out these investigations using a standardized method in order to obtain repeatable results. The function of the phrenic nerve can also be estimated by measuring its conduction time: this is normally less than about 9.5 ms, but is prolonged in some neurological diseases, although importantly not in axonal neuropathies. The arterial Po2 is characteristically slightly reduced, with a normal Pco2 during the daytime and in sleep as long as pulmonary function is normal and there is no other muscle weakness. If either of these is present, however, bilateral diaphragmatic weakness can cause hypercapnia with profound hypoxia during sleep. Treatment Plication for hemidiaphragmatic paralysis is rarely required in adults and the procedure is best reserved for those in whom spon- taneous recovery does not occur, where there is evidence of reduced lung function, and where frequent chest infections with radiological evidence of atelectasis are a problem. Bilateral plication is not effective if there is bilateral weakness. Treatment with nasal positive-​pressure ventilation is usually re- quired. Ventilatory support is typically needed only at night and until the function of the diaphragm or phrenic nerve improves. However, the converse is true in progressive neurological conditions where diaphragm weakness is a feature: the patient will likely progress to daytime use of noninvasive ventilation (NIV), and the clinician will often need to have a discussion with the patient about the option of progressing to continuous tracheostomy ventilation at some point. Phrenic nerve pacemakers are only worth considering when bi- lateral diaphragmatic weakness is due to lesions above the phrenic nerve nucleus in C3 to C5 or C6. Few centres offer this therapy, the commonest indication for which is a high cervical spinal cord injury due to trauma. FURTHER READING Benditt JO (2019). Respiratory care of patients with neuromuscular disease. Respir Care, 64, 679–88. Bredin CP (1989). Pulmonary function in long-​term survivors of thoracoplasty. Chest, 95, 18–​20. Budweiser S, et al. (2006). Impact of ventilation parameters and dur- ation of ventilator use on non-​invasive home ventilation in re- strictive thoracic disorders. Respiration, 73, 488–​94. Dolmage TE, Avendano MA, Goldstein RS (1992). Respiratory func- tion during wakefulness and sleep among survivors of respiratory and non-​respiratory poliomyelitis. Eur Resp J, 5, 864–​70. Franssen MJAM, et al. (1986). Lung function in patients with anky- losing spondylitis. A study of the influence of disease activity and treatment with non-​steroidal antiinflammatory drugs. J Rheumatol, 13, 936–​40. Gibson GJ (1989). Diaphragmatic paresis: pathophysiology, clinical features, and investigations. Thorax, 44, 960–​70. Haller JA Jr, et al. (1996). Chest wall constriction after too extensive and too early operations for pectus excavatum. Ann Thorac Surg, 61, 1618–​25. Hart N (2002). The effect of severe isolated unilateral and bilateral dia- phragm weakness on exercise performance. Am J Respir Crit Care Med, 165, 1265–​70. Kafer ER (1975). Idiopathic scoliosis. Mechanical properties of the respiratory system and the ventilatory response to carbon dioxide. J Clin Invest, 55, 1153–​63. Kinnear WJM, et al. (1988). The effects of one year of nocturnal cuirass-​ assisted ventilation in chest wall disease. Eur Resp J, 1, 204–​6. Lindahl T (1954). Spirometric and bronchospirometric studies in five-​ rib thoracoplasties. Thorax, 9, 285–​90. Luo F, et al. (2017). Invasive versus non-invasive ventilation for acute respiratory failure in neuromuscular disease and chest wall disorders. Cochrane Database Syst Rev, 12:CD008380. doi: 10.1002/14651858. CD008380.pub2. Man WDC, et al. (2004). Magnetic stimulation for the measurement of respiratory and skeletal muscle function. Eur Resp J, 24, 846–​60. Midgren B, et al. (1988). Nocturnal hypoxaemia in severe scoliosis. Br J Dis Chest, 82, 226–​36. Newsom-​Davis J, et al. (1976). Diaphragm function and alveolar hypo- ventilation. Q J Med, 145, 87–​100. Nickol AH, et al. (2005). Mechanisms of improvement of respiratory failure in patients with restrictive thoracic disease treated with non-​ invasive ventilation. Thorax, 60, 754–​60. Pehrsson K, Bake B, Larsson S, Nachemson A (1991). Lung function in adult idiopathic scoliosis: a 20 year follow up. Thorax, 46, 474–​8. Phillips MS, et al. (1989). Exercise responses in patients treated for pul- monary tuberculosis by thoracoplasty. Thorax, 44, 268–​74. Polkey MI, et al. (1995). Measurement of respiratory muscle strength. Thorax, 50, 1131–​5. Polkey MI, et al. (1999). Respiratory aspects of neurological disease. J Neurol Neurosurg Psych, 66, 5–​15.

18.18  Disorders of the thoracic cage and diaphragm 4337 Shneerson JM (1978). The cardiorespiratory response to exercise in thoracic scoliosis. Thorax, 33, 457–​63. Shneerson J (1998). Sleep in neuromuscular thoracic cage disorders. Eur Resp Monogr, 10, 324–​44. Shneerson JM (2004). Respiratory failure in tuberculosis: a modern perspective. Clin Med, 4, 72–​6. Shneerson JM, Simonds AK (2002). Noninvasive ventilation for chest wall and neuromuscular disorders. Eur Respir J, 20, 480–​7. Simonds AK, Elliott MW (1995). Outcome of domiciliary nasal inter- mittent positive pressure ventilation in restrictive and obstructive disorders. Thorax, 50, 604–​9. Smith IE, et al. (1996). Kyphosis secondary to tuberculous osteomye- litis as a cause of ventilatory failure: clinical features, mechanisms and management. Chest, 110, 1105–​10. Tzelepis GE, McCool FD, Hoppin FG Jr (1989). Chest wall distortion in patients with flail chest. Am Rev Resp Dis, 140, 31–​7.

18.19 Malignant diseases 4338 18.19.1 Lung cancer

18.19 Malignant diseases 4338 18.19.1 Lung cancer 4338 S.G. Spiro and N. Navani

CONTENTS 18.19.1 Lung cancer  4338 S.G. Spiro and N. Navani 18.19.2 Pulmonary metastases  4360 S.G. Spiro 18.19.3 Pleural tumours  4361 Y.C. Gary Lee 18.19.4 Mediastinal tumours and cysts  4368 Y.C. Gary Lee and Helen E. Davies 18.19.1  Lung cancer S.G. Spiro and N. Navani ESSENTIALS Lung cancer remains the commonest killing cancer in both men and women in the developed world, and is increasingly common in developing countries, although as a result of decreased tobacco consumption in Western countries there has been a considerable reduction in the incidence among men over the last 20 years, and a slowing down in incidence in women over the last few years. Nevertheless, lung cancer is a greater cause of mortality in women than breast cancer in Western countries. There are several important industrial associations with lung cancer, in particular asbestos, but tobacco remains by far the most important cause. Pathology—​there are four main cell types of lung cancer, of which adeno-​, squamous, and large-​cell varieties comprise non-​small cell lung cancer, with the more aggressive type—​small cell—​being regarded as a separate entity from the point of view of treatment and prognosis. Clinical features—​there are no particular presenting features that strongly suggest a new lung cancer, hence it is a disease that often presents late and with metastatic disease. Symptoms and signs can be subdivided into (1) intrapulmonary symptoms—​cough (most com- monly), haemoptysis (most dramatically), wheeze, chest discomfort, and breathlessness (rare as a presenting feature); (2) extrapulmonary, intrathoracic symptoms and signs—​Horner’s syndrome, vocal cord paralysis, superior vena caval obstruction, dysphagia, cardiac tam- ponade, arrhythmias; (3) extrathoracic, metastatic manifestations—​ 30% of patients present with symptoms due to distant metastases, the most common sites being bones, liver, adrenal glands, brain and spinal cord, lymph nodes, and skin; and (4)  paramalignant syndromes—​syndrome of inappropriate secretion of antidiuretic hor- mone, ectopic ACTH syndrome, hypercalcaemia, neuromyopathies, finger clubbing, and hypertrophic pulmonary osteoarthropathy. Incidental findings and screening—​about 5% of lung cancers are found by chance on a chest radiograph or CT scan performed for reasons other than suspicion of cancer, and these tend to have a better prognosis. Screening of high-​risk groups for lung cancer with low-​dose CT scanning of the thorax is being implemented and ran- domized trials are beginning to be reported. The very large National Lung Screening Trial of 53 000 individuals in the United States has shown a 20% reduction in mortality from lung cancer with three an- nual CT screens compared to a control group, and a 6.7% reduction in all-​cause mortality. Clinical staging—​accurate clinical staging is paramount for treat- ment decisions, especially for non-​small cell lung cancer, which may be resectable. Following a chest radiograph, a CT of the neck, thorax, and upper abdomen should be performed. Biopsy of the primary tumour (via a bronchoscope for centrally situated lesions or by per- cutaneous image-​guided needle, depending on best access) or of a metastasis (often mediastinal lymph nodes by endobronchial ultra- sound systems) is required. The latter provides a diagnosis and in- formation on disease stage at the same time. PET scanning, which depends on the uptake of a glucose analogue (fluorodeoxyglucose, FDG) by active tumour and its metastases, is recommended as a sta- ging test in those patients where resection or another curative treat- ment is contemplated. Integrated PET-​CT changes the clinical stage in about 20% of apparently resectable cases, but has low resolution for detecting brain metastases, hence further imaging of the brain by MRI or CT may be required before embarking on surgical resection. Prognosis and management—​(1) non-​small cell lung cancer—​ ‘cura- tive’ treatment by surgical resection can be applied to 15–​20% of all cases, of whom about 60% survive at 5 years. Radical radiotherapy cures very few with locally advanced disease, although better re- sults are obtained with the addition of concurrent chemotherapy. Newer techniques such as stereotactic radiotherapy, with tighter focus on the tumour, may increase the cure rate. In patients with advanced non-​small cell lung cancer and good performance status, survival at 1 year is 15–​20% with supportive care alone, and 50% with 18.19 Malignant diseases

18.19.1  Lung cancer 4339 chemotherapy tailored to the non-​small cell lung cancer phenotype. Emerging evidence of mutations within tumours has led to better identification of those who may respond to targeted therapy (e.g. with tyrosine kinase inhibitors, rather than cytotoxic chemotherapy in patients whose tumour harbours an epidermal growth factor re- ceptor mutation). Immunotherapy has been an importance advance in treatment of advanced disease and is likely to play an increasing role in the future. (2) Small-​cell tumours—​life expectancy of those with untreated disease is about 3.5 months for limited disease and 6 weeks for extensive disease. Chemotherapy remains the cornerstone of treatment: modern regimens would be expected to achieve a com- plete response rate (i.e. disappearance of all measurable disease) in 40 to 50% of cases and a partial response rate (>50% reduction in tu- mour bulk) in a further 40%. Patients achieving a complete response after chemotherapy should have prophylactic cranial irradiation, and consolidation thoracic radiotherapy in some cases. Median survival is around 18 months for limited disease and 9 months for extensive stage disease. Management of complications—​some complications of lung cancer require specific measures to alleviate symptoms: (1) vocal cord par- alysis may be helped by injection of Teflon into the affected cord; (2) obstruction of the upper airway causing stridor, or of the lower major airways, is usually treated initially with radiotherapy; (3) ma- lignant pleural effusion is treated with talc pleurodesis or indwelling pleural catheter; (4) dexamethasone may control the symptoms of brain metastasis and, if so, this may be consolidated with whole brain radiotherapy, and (5) intravenous stenting can cause dramatic relief from superior vena caval obstruction. The multidisciplinary team—​the importance of the combined support to the patient and the family given by the lung cancer nurse specialist family doctor, palliative care medical and nursing staff, and hospice or- ganizations, and the hospital team cannot be overemphasized. Epidemiology Lung cancer is the most common cause of death with malignant dis- ease in the Western world. It has shown the greatest relative and absolute rise in mortality of any tumour this century in England and Wales, and particularly in Scotland. It causes 35 000 deaths per year in England and Wales, with 70% of these occurring in men. In the European Union there are 1.35 million deaths per year in men (the highest death rate from any tumour), and in women in 1995 it accounted for 24% of all female cancer deaths. In the United States of America it has been increasing in incidence by up to 10% per year since the 1930s, but over the last decade this trend has levelled off, particularly in men. Nevertheless, about 120 000 American men die of lung cancer each year, the figure for women being 34 000, similar to that for breast cancer. However, whereas the age-​adjusted incidence in women increased by 4.1% per year between 1973 and 1994, between 1990 and 1994 the annual incidence rose by only 0.2%. The increasing incidence in women means that lung cancer is now the fourth commonest cancer in women worldwide and the second commonest cause of cancer death. Age-​standardized mortality rates for cancer show that in Europe lung cancer in men was by far the commonest cause of death. Hungary has the highest mortality (109.5 deaths per 100 000 population) with Poland (104.5) second, and Estonia third with 91.5 deaths per 100 000. For women, Denmark has the highest incidence (49.5), with Hungary (39.8) second and the United Kingdom (38.7) third. Within the United Kingdom there are much higher rates in Scotland and the North of England, reflecting smoking patterns. Perhaps the worst epidemic is in China, where 0.8 million men died in the year 2000 from smoking-​related diseases. Of all deaths attrib- uted to tobacco in China, 15% were due to lung cancer. Aetiological factors Tobacco In every country, the increase in mortality from lung cancer has ap- peared to coincide with an increase in tobacco usage, particularly cigarette smoking, after what seemed to be an appropriate latent interval. Prospective studies, among which the long-​term study of British doctors was particularly informative, confirmed the in- creased risk of death from lung cancer from any tobacco use, but most specifically that of cigarettes. There was a strong dose–​response relationship with the number of cigarettes smoked, illustrated in Table 18.19.1.1. The most important variable in smoking inten- sity is the number of cigarettes smoked, but other variables include the depth of inhalation, number of puffs, butt length, use of a filter, and the type of tobacco smoked. Further evidence that the relation- ship was causal came from a study which documented reduction in mortality after stopping smoking: 15 years after cessation the risk of death fell from 15.8 times to twice that in nonsmokers, equiva- lent to 11% of that pertaining in those who continued to smoke. Stopping smoking before the age of 40 years greatly reduces the risk of developing smoking-​related diseases. Globally, there has been a huge change in cigarette consumption. Between 1970 and 1985 the overall world consumption rose by 7% while there was a drop of 25% and 9% in consumption in the United Kingdom and the United States of America, respectively. This is due to huge increases in Asia (22%), Latin America (24%), and Africa (42%). The current epidemic of smoking in China lags be- hind Western society by 20 years. Thus, in China in 1996 the average Table 18.19.1.1  Death rate from lung cancer in males by smoking habits when last asked (British doctors’ study) Tobacco use category Death rate (age-​standardized
per 100 000) Nonsmokers 10 Ex-​smokers 43 Continuing smokers   Any tobacco 104   Pipe and/​or cigar only 58   Mixed 82   Cigarette smokers only 140 Number smoked per day   1–​14 78   15–​24 127   25 or more 251

section 18  Respiratory disorders 4340 number of cigarettes smoked per adult male was 11 per day, a figure that that peaked in the West at 10 a day in 1980. Nearly one-​third of the world’s smokers reside in China, who reported 1.3 million new cases of lung cancer in 2003. Another disturbing trend is the increasing incidence among women. More women in developed nations will die of lung cancer than breast cancer. Due to historical smoking patterns the incidence rates of lung cancer in women are not declining, because smoking rates have not yet started to decline, as they have in men. Currently far more men than women are dying of this disease, but the gap is re- lentlessly closing. With regard to socioeconomic status, lung cancer is likelier to occur in the poor and less educated, which is a wide- spread pattern around the world. Primary prevention and smoking cessation must be directed at these groups. Passive smoking Evidence that passive smoking predisposes to lung cancer is far from certain. Approximately 15% of lung cancers occur in nonsmokers, and 5% of these have been attributed to passive smoking. However, the perceived risk to those working in smoke-​filled environments has led to a ban on smoking in public places in an increasing number of countries. Occupation People who develop lung cancer as a result of their occupation are a small but important group. The association with asbestos is now firmly established, various studies having identified that those ex- posed are at 4.9 to 7.3 times greater risk than those who are not. This risk is much enhanced if the asbestos industry worker smokes cigarettes; one study estimating this at 93 times higher than for nonsmokers not exposed to asbestos. Exposure to radioactive isotopes, mainly radon daughters, is as- sociated with a higher risk of lung cancer and occurs among various groups of miners, particularly those involved in extraction of pitch- blende and uranium. Polycyclic aromatic hydrocarbons are believed to be responsible for the increased risk in workers in gas and coke ovens and in foundry workers. Workers in nickel refining, chromate manufacture, and the arsenical industry are also exposed to a higher risk of lung cancer. Diesel engine exhaust is a major cause of lung cancer in truck drivers and railway workers (See http://​www.iarc.fr/​ en/​media-​centre/​pr/​2012/​pdfs/​pr213_​E.pdf). The amount of lung cancer caused by occupational exposure may well have been underestimated in the past, and a summary of the important industrial products and processes involved is shown in Box 18.19.1.1. Air pollution The decline in male mortality is occurring earlier than would be ex- pected from changes in smoking habits. The high mortality figures in the United Kingdom and Germany compared with France and Italy, for example, seem likely to be due in part to heavy industry and coal burning. Analysis by county in the United States of America shows an association between lung cancer deaths and counties with chem- ical, petroleum, ship-​building, and paper industries. Legislation for cleaner air has caused both environmental and occupational pollu- tion to fall dramatically in the past 30 years, and this has preceded changes in smoking habits. Pathology A detailed understanding of the natural history, pathology, and pathogenesis of lung cancer is becoming increasingly important as the assessment, management, and prognosis of the disease depends largely upon the tumour phenotype, genotype, and the presence or absence of metastases at the time of presentation. It has been esti- mated that about seven-​eighths of a tumour’s life will have passed when it is diagnosed, and that the vast majority will have dissemin- ated at the time of diagnosis, even though most metastases may be too small to detect. Squamous cell carcinomas seem to arise most commonly in seg- mental and subsegmental bronchi in response to repetitive carcino- genic stimuli or inflammation and irritation. The mucosal lining is most susceptible to injury at the bifurcation of bronchial structures. Dysplasia progresses to carcinoma in situ, when the entire thick- ness of the mucosa may be replaced by proliferating neoplastic cells. These changes may be strictly localized or multicentric, and are thought to be a field cancerization effect, sometimes causing syn- chronous primary tumours. Tumour infiltration follows loss of the basal membrane. The precise origins of small-​cell carcinomas re- main an enigma, while evidence is emerging that adenocarcinomas arise in areas of alveolar adenomatous hyperplasia. A  significant number of lung tumours arise in the periphery of the lung, perhaps three-​quarters of adenocarcinomas and large-​cell anaplastic malig- nancies, one-​third of squamous (or epidermoid) carcinomas, and one-​fifth of small-​cell carcinomas. Adenocarcinoma has become the commonest cell type; it is more prevalent in eastern Asia and the United States of America where approximately 50% of new lung cancers are adenocarcinomas. Squamous cell lung cancer still accounts for up to one-​half of new cases in Europe, although this is changing as adenocarcinomas seem to be becoming commoner throughout the world. There has been a slow decline in the prevalence of small-​cell lung cancers to 15–​20% of new diagnoses, with 10–​15% of the less easily differentiable large-​ cell tumours comprising the rest. Adeno-​, squamous-​, and large-​cell tumours are grouped as nonsmall-​cell lung cancers (NSCLC) as their staging and treatment is similar. From studies of growth rates of radiologically measurable primary tumours, adenocarcinomas have Box 18.19.1.1  Industrial products and processes known to cause or suspected of causing lung cancer • Fibre exposure (asbestos) • Nickel refining • Aluminium industry • Arsenic and arsenic compounds • Benzoyl chloride • Beryllium • Cadmium • Chloromethyl ether • Chromates • The electronics industry • Irradiation • Soots, tar, oils • Mustard gas • Diesel engine exhaust

18.19.1  Lung cancer 4341 a volume-​doubling time of 90–​120 days, squamous cell 60 days, and small-​cell 30 days, making this last cell type extremely aggressive. Squamous (epidermoid) carcinoma These tumours are composed predominantly of flattened to polyg- onal neoplastic cells that tend to stratify, form intercellular bridges, and elaborate keratin. About 60% present as obstructive lesions in lobar and main-​stem bronchi. The tumours tend to be bulky and produce intraluminar granular or polypoid masses, hence distal pneumonia and abscess formation are common, and cavitation is seen in about 10%. The cells are usually well differentiated, but in some cases differentiation is poor and the appearances are those of predominantly anaplastic cells, frequently arranged in the classical pattern of stratifying sheets. Small-​cell anaplastic carcinoma This is now recognized as a pathologically and clinically distinct form of lung cancer. The tumour is composed of neoplastic cells with dark oval to round spindled nuclei and scanty, indistinct cytoplasm arranged in ribbons, nests, and sheets. The cells tend to crush easily on biopsy, and extensive areas may be necrotic. This type of tumour presents as a proximal lesion in 75% of cases and may arise anywhere in the tracheobronchial tree and rapidly in- vade vessels and lymph nodes, disseminating widely even before symptoms arise from the primary tumour. It is invariably associ- ated with smoking, and over 50% of patients have extensive, ad- vanced disease at presentation. The cells secrete peptides which cause clinical syndromes in 10% of cases. Adenocarcinoma This tumour forms acinar or glandular structures, having prom- inent papillary processes, and may be mucin-​provoking. About 70% ­appear to originate peripherally in the lung and they are frequently fairly circumscribed. The initial presentation is a pleural effusion in about 10% of cases. If related to bronchi, they tend to cuff and stenose the lumen. Adenocarcinomas occasionally arise in old tuberculous scars and are the predominant tumour type in patients with lung cancer related to asbestos, or in patients who have never smoked. Approximately 80% of lung adenocarcinomas express thyroid tran- scription factor-​1 (TTF-​1), which is a helpful diagnostic tool. Several subtypes of adenocarcinoma are recognized (http://​ www.ncbi.nlm.nih.gov/​pubmed/​21252716). The confusing term bronchoalveolar carcinoma has been replaced with the morpho- logically more accurate term adenocarcinoma in situ to describe lung cancer arising in distal bronchioles or alveoli with a lepidic growth check lepidic pattern. Invasive adenocarcinoma is divided into acinar, papillary, micropapillary, solid, and mucinous subtypes. Mutation in the epidermal growth factor receptor (which sensitizes the patient’s tumour to tyrosine kinase inhibitors) rarely occurs in the mucinous adenocarcinoma subtype, but is present in 10–​15% of all lung adenocarcinomas. Large-​cell carcinoma These tumours, which have been described as an unclassified category, include all tumours that show no evidence of maturation or differentiation. They are composed of pleomorphic cells with variable enlarged nuclei, prominent nucleoli and nuclear inclu- sions, and abundant cytoplasm, and they are mucin-​producing in many instances. The tumours tend to be bulky and are often nec- rotic. They are frequently peripheral, invade locally, and disseminate widely, with about one-​half of patients having disseminated disease on presentation. Although these tumours are highly malignant and undifferentiated, the cure rate after surgery is surprisingly high, but radiotherapy is ineffective in controlling the disease. Large-​cell car- cinoma is a smoking-​related disease in more than 90% of patients. Tumour heterogeneity It is increasingly apparent that lung cancer subtypes do not exist in a single patient in isolation. Resected small cell lung cancers com- monly contain areas of NSCLC differentiation. Adenosquamous carcinomas are also well recognized. Larger biopsy specimens and sampling from different metastatic sites have demonstrated tumour heterogeneity to be an important clinical issue. Carcinoid tumours Carcinoid tumours are described in Chapter 15.9.2. Genetics and biology Genetic influences may play a role in the development of lung can- cers, particularly in patients under 50. In one study, lung cancers were attributable to a mendelian dominant inheritance pattern in 27% of patients under 50, but only 9% of those over 70. Oncogenes and tumour suppressor genes The ras family of oncogenes (H, K, and N) was the first to be de- scribed in association with lung cancer. Mutations of ras genes occur in 20–​40% of NSCLC, especially adenocarcinomas, and the presence of K-​ras mutations is linked with significantly shortened survival and resistance to tyrosine kinase inhibitors. Lung cancer cells not only show mutations that activate dominant cellular proto-​oncogenes, but also genetic mechanisms that inacti- vate recessive tumour suppressors. The commonest abnormality is a deletion in the short arm of chromosome 3, which is found in over 90% of small-​cell lung cancer and 50% of NSCLC patients. Other sites of loss of heterozygosity include 11p, 13q, and 17p. Tumour suppressor genes have been identified in inherited cancers, mainly in studies of familial retinoblastoma. Mutations in TP53 occur in 75% of small-​cell lung cancer and 50% of NSCLC. The gene is lo- cated on the short arm of chromosome 13q14, and it is thought that it may normally protect cells against accumulation of mutations. Depletions and mutations of TP53 are linked with metastatic dis- ease. Alterations of p53 protein have been found in early bronchial neoplasia, and may be a useful marker for the early detection of lung cancer. Other markers, including heterogenous nuclear ribonuclear protein A2/​B1 overexpression in sputum, may allow earlier detec- tion of tumours. Lung-​cancer-​associated antigens Several monoclonal antibodies have been generated against lung-​ cancer-​associated antigens. Thirty-​six monoclonal antibodies raised against small-​cell lung cancer have been grouped into eight clus- ters. No antigen is specific for small-​cell lung cancer. Antibodies belonging to the major cluster (cluster 1) are directed against the neural-​cell adhesion molecule (NCAM), but the nature of the other

section 18  Respiratory disorders 4342 antigens remains unclear. Studies of both small-​cell and NSCLC cell lines show that NCAM secretion is associated with a neuroendo- crine phenotype irrespective of the histological type of lung cancer. Monoclonal antibodies may have a therapeutic value when coupled with a radionuclide or a toxin. Radiolabelled antibodies can be used to detect minimal disease in bone marrow aspirates or biopsy specimens. Epidermal growth factor receptor tyrosine kinase The expression of epidermal growth factor receptor (EGFR) tyro- sine kinase is up-​regulated in 70% of squamous cell cancers and 50% of adenocarcinomas, and the discovery of a mutation in the EGFR receptor in some patients with lung cancer was a significant break- through. This led to highly successful trials with the small-​molecule tyrosine kinase inhibitors gefitinib, erlotinib, and Afatanib. The re- sponses to these targeted treatments in those with the EGFR muta- tion is striking, and has led to pathologists examining all diagnostic biopsies for their presence. Targeted therapy is now the first-​line treatment for EGFR positive individuals, who commonly are Asian, women, and nonsmokers with an adenocarcinoma. Other molecular aberrations NSCLC harbours other ‘driver’ mutations, which if ‘turned off’ can be a highly effective antitumour therapy. These are found in mul- tiple genes, particularly adenocarcinomas, including (in addition to EGFR) HER2, KRAS, BRAF, PIK3CA, ATK1, MEK1, ROS1 and, ALK. Mutations within individual genes can be associated with pri- mary drug resistance, primary drug sensitivity, or secondary drug resistance. The distinct tumour mutation profile of many Asian women has become a target for treatment (see next) as 90% of them may contain one of EGFR, HER2, ALK, ROS1, and KRAS, of which EGFR, HER2, ROS1, and ALK are treatable with kinase inhibitors. It is estimated that 70% of adenocarcinomas have a currently iden- tifiable oncogenic driver, which may be the tumour’s Achilles heel. The roll out of next generation genetic sequencing technologies has meant that it is now possible to genotype a patient’s lung cancer to provide the most appropriate treatment. Clinical features Lung cancers present late in their natural history. In general, death will occur when a tumour load reaches 1 kg, which is equivalent to 40 volume-​doubling times, yet halfway through the lifespan of a lung cancer—​20 volume doublings—​it is only 1 mm in diameter (Fig. 18.19.1.1). It becomes visible on a chest radiograph at about 1 cm and the typical size at presentation with symptoms or signs is 3–​4 cm. CT and PET-​CT will identify lesions as nodules when they are considerably smaller, but up to 98% of incidentally discovered nodules are benign, making radiological investigations problematic. The clinical features of lung cancer are very variable: they can be respiratory, but all too often they are constitutional and attrib- utable to metastatic disease. In one series of 678 consecutive pa- tients only 27% presented with symptoms related to the primary tumour. Most had either nonspecific symptoms, including anorexia, weight loss, and fatigue (27%), or specific symptoms of metastatic disease (32%). However, in about 5% of patients the presentation is a radiographic abnormality found by chance on routine examin- ation (Fig. 18.19.1.2). These patients tend to have a better prognosis (20–​70% 5-​year survival) than those with symptoms related to the primary tumour (12–​35% 5-​year survival). There is usually a considerable time delay between the patient noticing a symptom and presenting to a primary care physician, which varies in different studies from 4 months to 2 years, with the specific exception of haemoptysis, when the mean delay from first symptom to first visit is much shorter at about 43 days (range 0–​256 days). There may also be a delay between first presentation to a physician and the realization that there may be a lung cancer present. One study identified a delay of 56 days (range 0–​477 days). This is understandable in the context that an average primary care physician (in the United Kingdom) sees a new lung cancer only every 102 104 106 108 1010 1012 Tumour size Number of tumour cells Number of doublings 40 10 30 20 1mm 5mm 1cm 3cm 10cm 1014 CT/PET Chest radiograph Average size at presentation Fig. 18.19.1.1  The lung cancer growth curve and ability to detect a tumour during its natural history. Fig. 18.19.1.2  Chest radiograph showing a chance finding of a right upper lobe mass (arrow) with a bulky right hilum.

18.19.1  Lung cancer 4343 12 months or so, and in a Dutch study of patients presenting with cough (11 092 separate patient encounters), lung cancer was not listed as a specific entity among the 20 most common eventual causes. Clinical symptoms and signs of lung cancer can be subdivided into those arising from the lung itself; from the extrapulmonary intrathoracic structures; extrathoracic metastases; and from endo- crine, metabolic, and neurological (paramalignant) syndromes (Table 18.19.1.2). Intrapulmonary symptoms Cough is the most common initial presenting symptom, but be- cause it is a symptom of so many respiratory disorders, the possi- bility of tumour may be overlooked and cough may be attributed to some other cause, particularly in smokers who have had chronic bronchitis for many years. Patients with a persistent cough should have a chest radiograph, particularly if they are smokers over 40 years of age (Figs. 18.19.1.3–​18.19.1.7). A change in the cough habit, or a cough lasting more than 3 weeks, is significant and also requires investigation. If the trachea or main bronchi are involved, the cough may be harsh in character and may be accompanied by wheezing or stridor. If cough is manifestly ineffective, with its explosive ability lost, in- volvement of the recurrent laryngeal nerve should be suspected, especially if there is accompanying hoarseness. A recent awareness campaign which for three months in summer 2013 asked those in a UK region with a cough lasting more than three weeks to see their GP, resulted in 700 more primary lung cancers being found than in the corresponding period two years earlier. Expectoration of sputum may be due to irritation of the tumour in a major airway or to infection occurring distal to partial bronchial obstruction, although this is more common in chronic obstructive pulmonary disease (COPD). The value of sputum cytology in diag- nosis is described next. Haemoptysis, which is the sole presenting symptom in about 5% of cases and occurs at some stage in the disease in 50% of patients, is a symptom not easily ignored by patient or physician. The degree varies from streaking of the sputum with blood to larger amounts, but massive haemoptysis (>200 ml) is rare, except as a terminal event when the tumour may erode a large pulmonary blood vessel. The Table 18.19.1.2  The presentation of lung cancer (frequency (%) of commoner symptoms/​signs indicated) Chest symptoms Mediastinal involvement Chest radiographic abnormalities Paramalignant syndromes Extrathoracic metastases Haemoptysis (6–​35) Superior vena caval obstruction (0–​4) Peripheral nodule Hypercalcaemia (0–​10) Bone pain (6–​25) Cough (8–​75) Left recurrent laryngeal nerve palsy (0–​10) Lobar/​lung collapse SIADH (0–​50) Neurological Wheeze (0–​10) Diaphragmatic palsy (0–​5) Cavitating mass SIACTH (0–​5) Jaundice Stridor (0–​2) Pericardial effusion Abnormal hilum HPOA/​clubbing (0–​20) Skin nodules Pain (20–​50) Dysphagia Pleural effusion Lambert–​Eaton syndrome (0–​3) Lymphadenopathy Dyspnoea (3–​60) Lymphangitis Cerebellar dysfunction Weight loss (0–​68) Bone lesion Neuropathies Lethargy (0–​10) Wide mediastinum SIACTH, syndrome of inappropriate ACTH; SIADH, syndrome of inappropriate antidiuretic hormone; HPOA, hypertrophic pulmonary osteoarthropathy. Fig. 18.19.1.3  Cavitating squamous cell lung cancer. Fig. 18.19.1.4  Chest radiograph showing a tumour in the right lower lobe behind the heart causing a double shadow for right heart border.

section 18  Respiratory disorders 4344 most significant description given by patients is that of coughing up blood, or with streaks in their sputum, every morning for several days in succession. Wheeze may be observed in a few patients. Localized persistent wheeze, often volunteered to come from one side of the chest, even after coughing, is a significant observation indicating obstruction of a larger or central airway (Fig. 18.19.1.7). Stridor is a feature that is poorly recognized and often confused with wheeze. It is due to narrowing of the glottis, trachea, or major bronchi, and is best heard after the patient coughs and then breathes in deeply with the mouth open. Dyspnoea is a presenting symptom in only a few patients. As the disease progresses dyspnoea is inevitable, being proportional to the amount of lung involved, either directly by tumour replace- ment or indirectly by endobronchial disease causing airway nar- rowing or obstruction. Progressive breathlessness is also a feature of malignant pleural and, rarely, pericardial effusion, superior vena caval obstruction, and lymphangitis carcinomatosis. Chest discomfort is a common symptom, occurring in up to 40% of patients at diagnosis. The discomfort is often of an ill-​ defined nature and may be described in terms of intermittent aching somewhere in the chest. Definite pleural pain may occur in the presence of infection, but invasion of the pleura by tumour may be painless. However, invasion of the ribs or vertebrae causes continuous, gnawing, localized pain (Fig. 18.19.1.8). A tumour in the superior pulmonary sulcus (Pancoast tumour) can cause progressive constant pain in the shoulder, upper anterior chest, or interscapular region, soon spreading to the arm once the bra- chial plexus is invaded. Other symptoms of this type of tumour in- clude weakness and atrophy of the muscles of the hand, Horner’s syndrome, hoarseness, and spinal cord compression at levels D1 and D2. Fever, chills, and night sweats may occur due to chest infection, but fever may very rarely be present in rapidly progressive tumours without evidence of infection, particularly if there are hepatic metastases. Extrapulmonary, intrathoracic symptoms Invasion of adjacent, mainly mediastinal, structures can give rise to certain specific clinical features. Involvement of the last cervical and first thoracic segment of the sympathetic trunk by cancer produces Horner’s syndrome. Malignant infiltration of the recurrent laryngeal nerve—​almost always the left branch because of its course adjacent to the left hilum—​gives rise to vocal cord paralysis. The right recur- rent laryngeal nerve is occasionally affected in the base of the neck. Recurrent aspiration pneumonias may follow vocal cord paralysis. Extension of the tumour with invasion or compression of the superior vena cava or by paratracheal lymphadenopathy results Fig. 18.19.1.5  Chest radiograph showing a collapsed left upper lobe due to proximal tumour. Fig. 18.19.1.6  (a) Chest radiograph showing an ill-​defined parenchymal mass (arrow) in the left upper lobe; (b): CT scan of the chest of the same patient as in (a), confirming a large central mass (arrow) encasing the left upper lobe bronchus.

18.19.1  Lung cancer 4345 in the characteristic features of superior vena caval obstruction—​ awareness of tightness of the collar, fullness of the head, and suf- fusion of the face (particularly after bending down), blackouts, breathlessness, and engorgement of veins with a downward venous flow in the neck, the upper half of the thorax, and arms, often accom- panied by oedema of the face. Dysphagia is due to compression of the mid-​oesophagus from without by tumour metastases in subcarinal lymph nodes and only rarely to direct invasion. Cardiac and pericardial metastases usually occur late in the disease and are manifested clinically by tachycardia, arrhythmias, pericardial effusion, and breathlessness. Invasion of the phrenic nerve results in elevation and paralysis of a hemidiaphragm, with increased dyspnoea in those with pre-​existing lung disease (e.g. COPD). Involvement of the ribs, spine, and pleura are extrathoracic manifestations. Very rarely bronchogenic carcinoma causes spon- taneous pneumothorax. It must not be forgotten that spread of tu- mour to the other lung may occur, or that synchronous primaries may coexist. Extrathoracic metastatic symptoms About 30% of patients present with symptoms due to distant metas- tases, the most common sites being bones, liver, adrenal glands, brain Fig. 18.19.1.7  (a) Chest radiograph showing a right upper lobe tumour causing wheeze with bulky right paratracheal nodes (arrow); (b) CT scan of the chest of the same patient as in (a), showing grossly enlarged mediastinal pretracheal lymph nodes (arrow); (c) chest radiograph of the same patient as in (a), showing complete response after two courses of chemotherapy.

section 18  Respiratory disorders 4346 and spinal cord, lymph nodes, and skin (Figs. 18.19.1.8–​18.19.1.11). Metastases to nodes are frequent and should be sought with great care, particularly those in the scalene area, which are usually the first to be involved. The best position for examination for these is from behind with the patient seated relaxed in a chair. The side affected usually corresponds to the side of the lung lesion, the exception being that tumours from the left lower lobe may metastasize to the nodes in the right scalene area. Involvement of the nodes in the floor of the supraclavicular fossa is equally common. Bony metastases are common, particularly in small-​cell tumours, and occur predominantly in the skull, ribs, vertebrae, humeri, and femora. They cause pain as a presenting symptom in up to 25% of patients. Early involvement may be detected by a rise in al- kaline phosphatase of bony origin, isotope scanning, or biopsy. Conventional skeletal surveys are often unhelpful and misleading. Bone lesions are usually confirmed when a PET-​CT scan is done for staging purposes, and isotope scans are now rarely performed. Liver secondaries are common and may be silent, although a rise in liver enzymes, particularly alkaline phosphatase of liver origin, may be an early sign. CT scans and ultrasonography may detect involvement in a liver which is not clinically enlarged, but as the metastases develop the liver may become grossly enlarged with an irregular margin. Metastases to the brain may be the presenting symptom in lung cancer in 4% of patients and may be encountered at some time in the illness in 30% (Fig. 18.19.1.10). The symptoms simulate those of any expanding brain tumour. The adrenal glands are involved in 15 to 20% of patients, rarely producing symptoms and found on a staging CT. The skin should be examined for the presence of the typical, slightly bluish, umbilicated lesions of tumour spread. Subcutaneous metastases may be found at almost any site (Fig. 18.19.1.11). Organ-​specific scans are rarely required with the use of PET-​CT, and these are only conducted in patients with organ-​specific symp- toms, or with general symptoms such as weight loss or malaise. Lack of energy and, more particularly, loss of interest in normal pursuits are symptoms of great importance; a sense of vague ill health com- monly occurs. Paramalignant syndromes Endocrine and metabolic manifestations Many of the unusual manifestations of malignant disease are the result of endocrine and metabolic manifestations of the cancer itself. Cancer cells appear to be able to synthesize polypeptides that mimic virtually all the hormones produced by conventional endocrine organs—​hence the term ‘ectopic hormones’. From time to time the clinical features resulting from ectopic hormone se- cretion precede those of the pulmonary tumour, emphasizing the importance of a high index of suspicion in such circumstances. Fig. 18.19.1.8  Chest radiograph showing a large left upper lobe mass with a right rib metastasis (arrow) causing pain, which was the reason for presentation in this case. Fig. 18.19.1.9  CT scan of the upper abdomen revealing a large necrotic liver metastasis (arrow). Fig. 18.19.1.10  CT scan of the brain in patient presenting with vagueness. Note marked cerebral oedema around metastases (arrows), and midline shift.

18.19.1  Lung cancer 4347 Ectopic hormone measurement cannot, however, be used for screening purposes. These syndromes can occur in up to 10% of patients with lung cancer. Syndrome of inappropriate secretion of antidiuretic
hormone (SIADH) The continued secretion of vasopressin (ADH) in excess of the body’s needs for control of blood tonicity leads to retention of water in both the intracellular and extracellular compartments. The cerebral oedema resulting from water intoxication can cause drowsiness, lethargy, irritability, mental confusion, and disorientation, with fits and coma being the most profound fea- tures. The patient is usually asymptomatic until the sodium falls below 120 mmol/​litre, when the hyponatraemia is dilutional in type with a low serum osmolality. Urine osmolality usually ex- ceeds 300 mosmol/​kg. The commonest cancer causing this syn- drome is small-​cell lung cancer, where it is clinically obvious in 1 to 5% of cases, with subclinical involvement detectable by a water-​loading test in more than 50%. Restriction of fluid to a daily intake of 700–​1000 ml may redress the hyponatraemia, and demethylchlortetracycline (demeclocycline) 600–​1200 mg daily is often highly effective, making water restriction unnecessary. Tolvaptan, a selective competitive vasopressin receptor antagonist, has also been shown to be effective in this scenario. The syndrome resolves promptly (within 3 weeks) with combination cytotoxic chemotherapy in most patients with small-​cell lung cancer, but commonly recurs at, or predicts, relapse. Ectopic ACTH syndrome Secretion of an adrenocorticotrophic substance by a small-​cell car- cinoma or bronchial carcinoid leads to bilateral adrenal hyperplasia and to secretion of large amounts of cortisol. The onset of symptoms may be so acute that death may occur within a few weeks, when the typical features of Cushing’s syndrome do not have time to develop. However, it is a common paramalignant syndrome and increased levels of adrenocorticotropic hormone (ACTH) may be detectable in up to 50% of patients with small-​cell lung cancer, with Cushing’s it- self described in 1 to 5% of these patients. The chief clinical features are thirst and polyuria, oedema, pigmentation, and hypokalaemia. Hypertension and profound myopathy may also be present. Serum cortisol is often grossly elevated, with loss of the normal diurnal rhythm; the level is not suppressed by dexamethasone; and hypo- kalaemic alkalosis can be severe, with plasma potassium less than 3.0 mmol/​litre and bicarbonate more than 30 mmol/​litre. Drugs which block adrenocortical steroid biosynthesis may produce partial and re- versible medical adrenalectomy, and metyrapone in doses from 250 mg three times daily to 1 g four times daily may cause temporary relief of symptoms. Removal of the tumour, if practicable, will cause remission, particularly if the cause is a carcinoid tumour. Small-​cell lung cancers with this syndrome seem to respond poorly to chemotherapy. Hypercalcaemia Hypercalcaemia may be associated with ectopic secretion of para- thormone by squamous cell cancers but is more commonly due directly to the presence of multiple bone metastases. The primary tumour may also produce a cAMP-​stimulating factor or a prosta- glandin causing hypercalcaemia. A  protein with parathormone-​ like activity has been purified from lung cancer cell lines. Increased bone resorption as the explanation for hypercalcaemia has been attributed to the parathormone-​like protein released from cancer cells. The incidence in patients with lung cancer ranges from 2 to 6% at presentation, to 8 to 12% during the course of the disease. Hypercalcaemia is unlikely to cause symptoms unless the serum cal- cium exceeds 2.8 mmol/​litre, and levels much higher than this are sometimes encountered. Endogenous serum parathyroid hormone levels are usually completely supressed. The main clinical features are nausea, vomiting, abdominal pain, and constipation, polyuria, thirst, and dehydration, muscular weakness, psychosis, drowsiness, and eventually coma. Immediate treatment is to relieve fluid deple- tion, and large volumes of intravenous 0.9% saline (up to 5 litres in 24 h) may be required. Intravenous bisphosphonates followed by oral maintenance therapy is now the treatment of choice. Gynaecomastia Swelling of the breasts, which may be painful, occurs mainly in the subareolar area, and there may be atrophy of the testes. The associ- ation is chiefly with large-​cell carcinomas. Increased gonadotropin production is the cause. Fig. 18.19.1.11  CT (A) and PET (B) scan of the abdomen showing a solitary mass in the right anterior abdominal wall (arrows) in a patient with a lung tumour. The mass is PET positive.

section 18  Respiratory disorders 4348 Other endocrine manifestations Hyperthyroidism is a rare feature, but neither goitre nor eye signs are prominent. Spontaneous hypoglycaemia, the masculinizing syndrome in young women, and hyperglycaemia are very rarely encountered. Pigmentation associated with α-​ and β-​melanocyte-​ stimulating hormone may occur. Neuromyopathies A variety of poorly understood neurological syndromes can occur with lung cancer. The diagnosis of a paramalignant neurological syn- drome should only be made once other causes including electrolyte imbalance, metastatic disease, cerebral and spinal vascular disease, infection, and toxicity from associated treatment have been elimin- ated. The main neurological syndromes include the Lambert–​Eaton myasthenic syndrome (LEMS), limbic encephalopathy, polyneur- opathy, cerebellar degeneration, retinopathy, and autonomic neur- opathy. LEMS is the most widely recognized of these disorders and presents with gradual onset of proximal limb weakness, more notice- able in the legs than the arms. Difficulty in swallowing and dryness of the mouth are common, although diplopia is rare. The symptoms may be worse in the mornings and improve as the day progresses. Physical examination will confirm weakness and loss of tendon jerks, but the latter can be restored for a few minutes by performing tasks of repetitive forced contractions (post-​tetanic potentiation). Neurological paramalignancies are associated almost exclusively with small-​cell lung cancers, affecting up to 4% of cases. Recent studies of consecutive new patients with small-​cell lung cancer re- ported LEMS in 1.6%, polyneuropathy in less than 1%, subacute cerebellar degeneration in less than 1%, and limbic encephalitis in less than 1%. The severity of the syndromes is not related to tumour bulk and seems to occur more frequently in patients with limited disease; in some a primary tumour is not detected before death, despite disabling symptoms. Nearly all the neurological paramalignant syndromes are asso- ciated with the presence of type 1 antineuronal nuclear antibodies (ANNA-​1), also known as anti-​Hu antibodies. Small-​cell lung can- cers express Hu antigen and up to 20% of these patients have detect- able circulating levels of anti-​Hu antibodies, although not all will develop paramalignant disorders. The response of these syndromes to effective chemotherapy of the underlying tumour is variable. Improvement is uncommon with motor or sensory neuropathies, or with cerebellar degeneration. However, LEMS can be associated with a better overall prognosis, and the condition responds to specific therapy with 4-​aminopyridine which appears to potentiate the release of acetylcholine at the nerve receptor end plate. Finger clubbing and hypertrophic pulmonary osteoarthropathy Finger clubbing accompanies a variety of intrathoracic disorders. Gross clubbing is readily recognizable; its early presence may best be demonstrated by the ability to rock the nail on its abnormally spongy bed; the nail fold angle will become obliterated as increased transverse curvature of the nail develops. Clubbing of the toes can be present but is less pronounced. Hypertrophic pulmonary osteoarthropathy (HPOA), which is a systemic disorder, may be preceded by finger clubbing alone. It con- sists of a painful symmetrical arthropathy, usually of the ankles, knees, and wrists, and periosteal new bone formation in the distal limb long bones. Associated finger clubbing can be gross. Clubbing and HPOA can be associated with any cell type of lung cancer, but mostly with squamous and adenocarcinoma, and very rarely with small cell types. The typical radiographic appearances are shown in Fig. 18.19.1.12. The affected areas are hot and painful and sometimes oedematous, making walking difficult. Removal of the tumour is followed by im- mediate regression, but symptoms recur if the tumour recurs. Clubbing is much more common than HPOA, occurring in up to 25% of patients presenting with lung cancer. It seems to be com- moner in women than men, and in NSCLC compared to small-​cell, while HPOA is seen in less than 5% of patients with NSCLC. Miscellaneous The haematological effects of lung cancer are normally nonspecific. Normocytic normochromic anaemia is the most common finding. Leucoerythroblastic anaemia denotes bone marrow infiltration and is particularly likely in small-​cell lung cancer. Venous thrombosis and thrombophlebitis due to hypercoagulability are common complica- tions of malignancy and may precede the detection of the underlying cancer; recurrent migratory phlebitis resistant to anticoagulation is an ominous feature. Marantic endocarditis is extremely rare, as are skin rashes such as acanthosis nigricans, dermatomyositis, hypertrichosis languinosa, and erythema gyratum repens. Rarely, the nephrotic syn- drome due to membranous glomerulonephritis is encountered. Investigations The investigations used to make the diagnosis and assess the stage of lung cancer will vary according to the presentation, the cell type, the age, and general condition of the patient. The rapid doubling time of small-​cell lung cancer causes it to dis- seminate widely, and at diagnosis it is very rarely considered oper- able. However, the slower doubling times for squamous cell cancers and adenocarcinomas, together with the relatively lesser tendency for Fig. 18.19.1.12  Radiograph of the ankle showing new periosteal growth due to hypertrophic pulmonary osteopathy.

18.19.1  Lung cancer 4349 the former to disseminate, makes surgery the best option whenever possible for the NSCLCs. A precise anatomical staging classification was first applied to lung cancer in 1973 and immediately demon- strated that the prognosis of NSCLC depended strongly on the extent (or stage) of the disease, and the introduction of the TNM staging system (T describing the primary tumour, N the extent of regional lymph node involvement, and M the absence or presence of metas- tases) encouraged an ordered assessment of investigations and selec- tion of cases for surgery. Based on this experience, the system was modified in 1997 and again in 2009 using a much more extensive data set from centres around the world, and survival data is now based on more than 100 000 cases (Table 18.19.1.3 and Table 18.19.1.4). The following investigations form the basis for the diagnosis and staging of patients with lung cancer. Chest radiography The value of the chest radiograph in the diagnosis and management of pulmonary neoplasm needs no emphasis Table 18.19.1.3  International Association for the Study of Lung Cancer staging project: TNM classification T: Primary tumour Tx Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy T0 No evidence of primary tumour Tis Carcinoma in situ T1 Tumour ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the main bronchus)a T1a(mi) Minimally invasive adenocarcinomab T1a Tumour ≤1 cm in greatest dimensiona T1b Tumour >1 cm but ≤2 cm in greatest dimensiona T1c Tumour >2 cm but ≤3 cm in greatest dimensiona T2 Tumour >3 cm but ≤5 cm or tumour with any of the following featuresc: –  Involves main bronchus regardless of distance from the carina but without involvement of the carina –  Invades visceral pleura –  Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung T2a Tumour >3 cm but ≤4 cm in greatest dimension T2b Tumour >4 cm but ≤5 cm in greatest dimension T3 Tumour >5 cm but ≤7 cm in greatest dimension or associated with separate tumour nodule(s) in the same lobe as the primary tumour or directly invades any of the following structures: chest wall (including the parietal pleura and superior sulcus tumours), phrenic nerve, parietal pericardium T4 Tumour >7 cm in greatest dimension or associated with separate tumour nodule(s) in a different ipsilateral lobe than that of the primary tumour or invades any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina N: Regional lymph node involvement Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in ipsilateral peribronchial and/​or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2 Metastasis in ipsilateral mediastinal and/​or subcarinal lymph node(s) N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral, or contralateral scalene, or supraclavicular lymph node(s) M: Distant metastasis M0 No distant metastasis M1 Distant metastasis present M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural (or pericardial) effusiond M1b Single extrathoracic metastasise M1c Multiple extrathoracic metastases in one or more organs a The uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximal to the main bronchus, is also classified as T1a. b Solitary adenocarcinoma, ≤3 cm with a predominately lepidic pattern and ≤5 mm invasion in any one focus. c T2 tumours with these features are classified as T2a if ≤4 cm in greatest dimension or if size cannot be determined, and T2b if >4 cm but ≤5 cm in greatest dimension. d Most pleural (pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple microscopic examinations of pleural (pericardial) fluid are negative for tumour and the fluid is nonbloody and not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging descriptor. e This includes involvement of a single distant (nonregional) lymph node. Goldstraw P., Chansky K., Crowley J., et al, The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer, Journal of Thoracic Oncology, Vol 11. No 1 (January 2016) reproduced with permission from Elsevier.

section 18  Respiratory disorders 4350 (see Figs. 18.19.1.2–​18.19.1.8). Anything suspicious should lead to the radiologist suggesting a CT scan of the neck, thorax, and upper abdomen (including particularly the liver and adrenals) when faced with the likelihood of a new lung cancer. The finding of a normal radiograph of the chest does not exclude lung cancer, as patients presenting with haemoptysis and a normal chest radiograph are sometimes found to have a central tumour on bronchoscopy. The rounded or ovoid shadow of a peripheral tumour is described in greater detail as follows; these are sometimes cavitated. The common appearance of a tumour arising from the main central airways (70% of all cases) is enlargement of one or other hilum. Even experienced observers sometimes have difficulty in deciding whether or not a hilar shadow is enlarged, and if there is any suspicion, investi- gation by CT and/​or bronchoscopy—​ideally with endobronchial ultra- sound to examine the lymph nodes—​should be pursued. Consolidation and collapse distal to the tumour may have occurred by the time that the patient presents, with the tumour itself often being obscured in the process. Collapse of the left lower lobe is often hard to identify, as is a tumour situated behind the heart (see Fig. 18.19.1.4). Apically lo- cated masses or superior sulcus tumours (Pancoast tumours) may be misdiagnosed as pleural caps, and often have a history of several months of pain in the distribution of the brachial nerve roots. Loss of the head of the first, second, or third rib is not unusual. The mediastinum may be widened by enlarged nodes. Involve­ ment of the phrenic nerve may lead to paralysis and elevation of the hemidiaphragm, which then moves paradoxically on sniffing. Tumour spreading to the pleura causes effusion, but such an abnormality may also be secondary to infection beyond obstruction caused by a central tumour. The ribs and spine should be carefully examined for the pres- ence of metastasis (see Fig. 18.19.1.8). Spread of tumour from medi- astinal nodes peripherally along the lymphatics gives the appearance characteristic of lymphangitis carcinomatosa—​bilateral hilar enlarge- ment with streaky shadows fanning out into the lung fields on either side. Rarely, localized obstructive emphysema may be observed. Sputum cytology Cytological examination of sputum is a noninvasive test for the diag- nosis of malignant pulmonary disease. The positive incidence on a single sample is 40% with tumours less than 2 cm in diameter and 60% with larger masses. Central tumours yield more positive results than peripheral lesions. The yield increases according to the number of spe- cimens examined, and three consecutive morning specimens should be submitted in the first instance. The yield rose to 85% with four samples in a study of those in whom a diagnosis of lung cancer was eventually made. However, given current emphasis on detailing tumour phenotype and genotype, sputum cytology is no longer recommended for patients who are well enough and agree to minimally invasive tissue sampling. CT scanning Although it is recommended that patients suspected of having lung cancer should be referred for a chest X-​ray, we know from screening studies that CT is about four times better at identifying new lung can- cers than the conventional chest radiograph. CT imaging is extremely important in the staging of lung cancer. It can identify the site, size, and extension of the primary tumour far more clearly than a conventional chest radiograph. CT imaging is extremely important in the staging of lung cancer. It can identify the site, size, and extension of the primary tu- mour far more clearly than a conventional chest radiograph. It also fre- quently identifies mediastinal lymphadenopathy when posteroanterior and lateral chest radiographs fail to show any abnormality. It will also identify silent metastatic disease in the supraclavicular lymph nodes, liver, adrenal glands, and in abdominal lymph nodes. It is recommended that a CT is performed prior to considering bronchoscopy as the primary lesion may be shown to be poorly ac- cessible to the bronchoscope and may be easier to sample by CT guided transthoracic biopsy. The CT scan may also identify medias- tinal involvement which can be directly sampled by bronchoscopic or ultrasound-​guided techniques, or direct sampling towards an ab- dominal metastasis. These would both provide a diagnosis and also help stage the disease from a single procedure. Mediastinal lymphadenopathy on CT is arbitrarily taken to be pathological if a gland is more than 10 mm in short axis. However, pre- vious infective conditions such as tuberculosis or an associated distal pneumonia can cause appearances indistinguishable from malignant enlargement. Positive CT scans of the mediastinum must therefore be confirmed by mediastinal lymph node biopsy to confirm tumour involvement. This is important because nearly 40% of lymph nodes deemed enlarged on CT criteria are found not to contain cancer when they are sampled, either by biopsy or at the time of surgery. PET-​CT Table 18.19.1.4  International Association for the Study of Lung Cancer staging project: stage grouping Occult carcinoma TX N0 M0 Stage 0 Tis N0 M0 Stage IA1 T1a(mi) N0 M0 T1a N0 M0 Stage IA2 T1b N0 M0 Stage IA3 T1c N0 M0 Stage IB T2a N0 M0 Stage IIA T2b N0 M0 Stage IIB T1a-c N1 M0 T2a N0 M0 T2b N0 M0 T3 N0 M0 Stage IIIA T1a–c N2 M0 T2a-b N2 M0 T3 N1 M0 T4 N0 M0 T4 N1 M0 Stage IIIB T1a–c N3 M0 T2a–b N3 M0 T3 N2 M0 T4 N2 M0 Stage IIIC T3 N3 M0 T4 N3 M0 Stage IVA Any T Any N M1a Any T Any N M1b Stage IVB Any T Any N M1c TNM, tumour, node, metastasis; Tis, carcinoma in situ; T1a(mi), minimally invasive adenocarcinoma. Goldstraw P., Chansky K., Crowley J., et al, The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer, Journal of Thoracic Oncology, Vol 11. No 1 (January 2016) reproduced with permission from Elsevier.

18.19.1  Lung cancer 4351 scanning (see next section) is often performed before a lymph node is biopsied: this will confirm abnormality by an increased uptake (SUV) and/​or it may identify an occult metastasis that might be more access- ible to biopsy and upstage the patient, thus changing management. Another advantage of CT is its ability to detect tumour invasion of the surrounding pleura and chest wall, although its ability to assess invasion of the mediastinum itself is poor and should not be used as a criterion of unresectability. Bronchoscopy Bronchoscopy, which is described in detail in Chapter 18.3.3, is a common diagnostic method in lung cancer. About 50% of all lung cancers arise in a main bronchus, lobar, first-​, or second-​generation airways, and will be visible and within biopsy or cytological brush range. Histological confirmation is now obtainable in 85–​90% of bronchoscopically visible lesions, and with five or more biopsies of a visible endobronchial lesion should approach 95% sensitivity. Bronchoscopy allows blind mediastinal lymph node sampling using dedicated transbronchial aspiration needles, which can pro- vide critical staging information, but this technique has been super- seded by endobronchial ultrasound-​guided transbronchial needle aspiration (see next section). In addition to diagnostic information, bronchoscopy also yields valuable information regarding suitability for surgical resection. Attempts to resect are ill advised if the main carina is obviously in- volved, or where there is involvement of the trachea, unless confined to the right lateral wall. Endobronchial ultrasound-​guided transbronchial
needle aspiration (EBUS-​TBNA) and endoscopic ultrasound needle aspiration biopsy (EUS-​FNA) Historically the mediastinum has been staged and malignant involve- ment of mediastinal nodes has been confirmed by surgical sampling by mediastinoscopy (for right paratracheal and subcarinal nodes) and/​or anterior mediastinotomy for left-​sided nodes. These tech- niques are being increasingly replaced by minimally invasive tech- niques including endobronchial ultrasound-​guided transbronchial needle aspiration (EBUS-​TBNA), where fine needle aspiration is per- formed with a needle placed within the working channel of a bron- choscope which harbours an ultrasound probe integrated into the tip. Endoscopic ultrasound needle aspiration or core-​biopsy (EUS-​FNA) allows access to posterior and left-​sided mediastinal lymph nodes via a similar needle placed within an echoendoscope in the oesophagus. EBUS-​TBNA and EUS-​FNA are reported to be highly sensitive and specific in diagnosing metastases to mediastinal and hilar lymph nodes. EBUS-​TBNA allows minimally invasive sampling of paratracheal, subcarinal and hilar lymph nodes, and meta-​analyses of diagnostic accuracy have demonstrated a sensitivity of 90% in accessible lymph nodes. Sampling mediastinal lymph nodes via EBUS-​TBNA provides diagnostic tissue suitable for sequencing, as well as an accurate nodal staging, in a single investigation. A recent trial has shown that routine use of EBUS-​TBNA can speed up the diagnostic pathway and provide more accurate staging, which resulted in a survival benefit for patients (http://​www.ncbi.nlm.nih.gov/​pubmed/​25660225). Percutaneous transthoracic needle biopsy Percutaneous needle biopsy of an intrapulmonary mass may be carried out using a variety of cutting needles to obtain a core of tissue for histo- logical analysis. The procedure can be performed under fluoroscopic, CT, or ultrasound control, but is best avoided in patients with poor respiratory function, bullae adjacent to the tumour or with bleeding di- atheses. Positive yields as high as 90% have been reported, with biopsy samples having a higher and more specific yield than cytological aspir- ates. It is a useful diagnostic method in patients for whom exploratory thoracotomy may be hazardous, or in attempts to determine whether a solid mass is a primary, secondary, or benign tumour. Pneumothorax occurs following about 25% of procedures, with some 2–​4% requiring a chest drain. Small haemoptyses are a common complication. Thoracoscopy Visualization of the parietal and visceral pleura plays an important part in the diagnosis of effusions and pleural tumours. Biopsy of le- sions can be carried out under direct vision, and absence of pleural tumour is important in decisions about resectability of a lung tu- mour. Thoracoscopy is inadvisable in the absence of effusion or pneumothorax, and is unsatisfactory in the presence of empyema or gross haemothorax. However, in otherwise operable tumours with a pleural effusion that is not bloodstained and without positive cy- tology or pleural biopsy, thoracoscopy may be a useful next step in determining operability. Video-​assisted thoracoscopy (VATS) has extended this technique and will also permit inspection and sam- pling of suspicious intrathoracic lymph nodes. Positron emission tomography (PET) scanning Integrated PET-​CT scanning, which depends on the uptake of a glucose analogue (fluorodeoxyglucose, FDG) by active tumour and its metas- tases, has gained wide acceptance as a test with much better character- istics than CT, especially for systemic staging. It is now recommended in those where resection or another curative treatment is contemplated. Because uptake of the PET isotope in malignant structures is based on tumour activity and not (as with CT) just lesion size, its routine use as a preoperative staging tool has been shown to save about 20% of all thoracotomies, which (if proceeded with) would have been futile and noncurative. However, PET scanning has a 40% false-​positive rate, due to coexisting infection or inflammation, and a positive area of uptake should always be confirmed by sampling if that abnormal area would directly affect a management decision. A new generation of combined MRI/​PET scanners are currently under evaluation. Lung function testing The ability to climb one flight of stairs without breathlessness has been claimed to be a very good indication of fitness for resection, but formal evaluation of lung function is essential in all patients being considered for treatment with curative intent. Spirometry, lung volumes and transfer factor are required prior to offering sur- gery or radiotherapy with curative intent. This allows assessment of peri-operative risk but also physiological reserve after treatment. Differential lung function needs assessing using a ventilation perfu- sion scan to calculate the quality of performance of the lung tissues likely to remain after a planned resection. Simple formulae are avail- able to predict the postoperative lung function from these scans with reasonable accuracy. However, if the predictions are borderline for the resection intended, then an exercise test should be performed to calculate the maximum oxygen uptake and surgery only performed if this is more than 15 ml/​kg per min. In general, the risks are greater for a pneumonectomy and worse for a right-​sided operation, and much greater than for a lobectomy. The surgeon needs to be given clear advice as to how extensive a resection an individual patient can tolerate safely, without significant respiratory compromise as a result of a curative pulmonary resection.

section 18  Respiratory disorders 4352 Other investigations In general, the ability to identify small metastatic deposits is as unsatisfac- tory for lung carcinomas as for other solid tumours. The available tech- niques are relatively crude, and this partially explains the high extrathoracic relapse rate following so-​called ‘curative’ resections for NSCLC. In patients with no symptoms other than those caused by their pri- mary tumour, imaging scans of brain, liver, and bones are unhelpful if there is no clinical evidence of neurological, hepatic, or bony disease, and normal biochemistry. Such scans have been superseded by PET-​CT. CT scan of the upper abdomen identifies abnormalities of one or both adrenal glands in up to 10% of patients considered for surgery, and fine needle aspiration of the adrenal gland should be performed if this remains the only contraindication to pulmonary resection. Bone scans have a high false-​positive rate due to Paget’s disease, active arth- ritis, healing fractures, renal disease, and hyperparathyroidism. PET-​ CT scans have a similar sensitivity to bone scans but a significantly higher specificity, only rarely being positive in nonmalignant bone conditions. Recent data suggest that MRI scans of the brain may de- tect asymptomatic brain metastases in 5% of patients undergoing lung surgery, with higher rates in upper lobe adenocarcinomas, tumours more than 3 cm, and when there is nodal involvement, MRI brain with contrast is now routinely recommended by NICE for patients with stage III being considered for treatment with curative intent. Biopsy or cytological aspiration of enlarged lymph nodes and skin metastases should be carried out whenever indicated. If an iso- lated hepatic or bony lesion identified with PET-​CT or CT scanning appears to be the only contraindication to surgery, then this should be biopsied under radiological control. Staging The staging algorithm investigations for NSCLC are summarized in Fig. 18.19.1.13. The final procedure before thoracotomy, or other lo- calized treatment such as radical radiotherapy, is assessment of the mediastinum, since this may be involved in up to 50% of patients with a peripheral, poorly differentiated tumour, and in a much greater per- centage of those with central lesions. If CT shows no other obvious site of disease and a PET scan only confirms uptake in the primary tumour and at no other distant site, then the surgeon can proceed directly to thoracotomy. If the CT and/​or PET scan is abnormal at a distant site, this should be assessed and biopsied. If a CT is abnormal in the medias- tinum and PET is not available, then mediastinal exploration should be performed by whatever technique is applicable. Increasingly this is by EBUS-​TBNA or EUS, proceeding to mediastinoscopy only if biopsies of suspicious areas are not confirmed by these techniques. Similarly, isolated suspicious lesions in the liver, adrenal glands, and other organs should be biopsied as they both stage as inoperable and provide the pathological diagnosis. However, most patients with extrathoracic me- tastases will have abnormal nodes within their mediastinum. Treatment and prognosis of NSCLC Surgery Surgery remains the single modality most likely to be curative in NSCLC. Before surgery, the patient should have been carefully staged (Fig. 18.19.1.13), and the chances of long-​term survival will be greatly influenced by this. All patients with stage IIIB disease (Table 18.19.1.4) should not undergo thoracotomy, but those with stage I, II, and some with IIIA disease can be considered for resection. In general, patients with squamous cell carcinomas have higher 5-​ and 10-​year survival rates than those with adenocarcinoma and large-​ cell carcinomas, and the more differentiated the tumour the better is the prognosis. Clearly, small peripheral lesions with no nodal disease (stage IA) fare best (up to 70% survival at 5 years), but the survival rate decreases with both size of tumour and increasing involvement of hilar and mediastinal nodes. The 5-​year survival curves for a series of 3 211 patients from Norway, operated upon between 1993 and 2002, are shown in Fig. 18.19.1.14 for survival by pathological stage and for extent of resection. Essentially the survival data is similar to that for a decade previously, as used by Mountain in the setting of the updated TNM classification, although this may change with the 2009. About 20% of all patients who present with NSCLC eventually come to surgery. Most of the others are excluded almost immedi- ately because of clinically evident metastatic disease, radiological or bronchoscopic evidence of inoperability, general frailty and/​or sig- nificant associated other illnesses, or inadequate lung function. Of those having a ‘curative’ resection, the overall survival rate at 5 years is approximately 50% and at 10 years it is 16–​18%. Death from local or distant recurrence of the tumour is equally probable, highlighting the inadequacies of current staging techniques. However, the careful application of the TNM system and the advent of more sophisticated scanning equipment such as PET-​CT may lead to improvement. NEW PRESENTATION Chest radiograph, CT Scan Bronchoscopy and Biopsy (TBNA/EUS) Guided Biopsy Stage/Cell Type Small Cell (usually chemotherapy) Metastatic NSCLC Nonsurgical Management NSCLC- potentially resectable Assess Patient (age, co-morbidity, lung function) PET scan Primary Only Avid Distant Sites Avid Biopsy Resect Negative Unfit Fit Positive Fig. 18.19.1.13  Staging algorithm for non-​small-​cell lung cancer.

18.19.1  Lung cancer 4353 Advanced age is not a contraindication to surgery. About 45% of new patients with lung cancer are over 70 years of age and these in- dividuals appear to tolerate lobectomy as well as younger patients, although the mortality for pneumonectomy (8–​10%) is double that of those under 70. There is no evidence that tumours grow more slowly in elderly people, hence the disease is as likely to be the ter- minal event in older as in younger patients and resection should be encouraged in patients who are fit. Smokers should be persuaded to stop smoking before thoracotomy because continued smoking increases perioperative complications. Video-​assisted thoracoscopic resection of peripheral masses was ini- tially reserved for those with inadequate lung function for lobectomy, as hilar and mediastinal node evaluation and dissection is not always possible. However, as experience has developed, it is being used more and more for lobectomy, as well as exploration of the draining hilar and mediastinal nodes. Advantages may include less postoperative pain and shorter inpatient stays. The survival data shows no differ- ences between a VATS lobectomy and a lobectomy by thoracotomy and clinical trials are ongoing. However, a wedge resection may confer a worse 5-​year survival than anatomical segmentectomy. These lung sparing procedures may be more suitable for elderly subjects. Radiotherapy Patients who are excluded from surgery because of adverse prognostic factors, advanced stage of tumour, or other coincidental disease con- stitute the largest group treated with radiotherapy. Although the usual aim of radiotherapy will be palliative, there will be a small group of patients in whom more aggressive therapy will be used in the hope of cure, or at least long-​term survival, particularly in those who have refused surgery. Radiotherapy for lung cancer is limited by the com- parative radiosensitivity of three critical normal tissues likely to be in- cluded in the radiation beam: normal lung, spinal cord, and the heart, each of which has a specific tolerance dose. Increased radiation dose leads to greater killing of tumour cells but may produce unwanted damage to normal cells. Radiation dose must be expressed not only in terms of total dose but also numbers of fractions and overall time. Standard of care is to use stereotactic ablative radiotherapy (SABR) to allow accurate radiation delivery. If conventionally fractionated rad- ical radiotherapy is used the typical regimen are 55 Gy in 20 fractions over four weeks, or 60-66 Gy in 30-33 fractions over 6-6 1/2 weeks. Alternative to surgery In some patients with a technically resectable tumour there may be medical contraindications for resection or the patient may refuse sur- gery. In general, the results of radical radiotherapy in these patients are inferior to the 5-​year survival following surgery. The best result for radiotherapy was a 5-​year survival rate of 22% for peripheral squa- mous cell cancers, but other series record a 5-​year survival rate of 6%. Stereotactic ablative body radiotherapy (SABR) is a new treat- ment which is seen as a meaningful alternative to surgery for per- ipheral stage 1 (<3 cm) lung cancers. It allows very high (ablative) doses of radiotherapy to be given to precise areas of the lung and therefore minimizes damage to uninvolved lung parenchyma. This means that patients with poor lung function who would not tolerate 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Years 0 1 2 3 4 5 6 7 8 9 10 Pneumonectomy Bilobectomy Lobectomy 11 Survival probability Sublobar resection 0 24 48 72 Months 0% 20% 40% 60% 80% 100% Proposed Events/N MST 24 Month 60 Month IA1 IA2 IA3 IB IIA IIB IIIA 2052/3200 IIIB 1551/2140 68/781 NR 97% 92% 505/3105 NR 94% 83% 546/2417 NR 90% 77% 560/1928 NR 87% 68% 215/585 NR 79% 60% 605/1453 66.0 72% 53% 29.3 55% 36% 19.0 44% 26% IIIC 831/986 12.6 24% 13% IVA 336/484 11.5 23% 10% IVB 328/398 6.0 10% 0% Fig. 18.19.1.14  Left panel: Kaplan–​Meier survival curves according to surgical procedure for patients resected for lung cancer diagnosed between 1993 and 2002 in Norway. Right panel: same population showing survival by stage. Goldstraw P., Chansky K., Crowley J., et al, The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer, Journal of Thoracic Oncology, Vol 11. No 1 (January 2016) reproduced with permission from Elsevier.

section 18  Respiratory disorders 4354 thoracic surgical resection, can have SABR with similar 5 year lung cancer specific survival rates. Preoperative and/​or postoperative radiotherapy Preoperative radiotherapy has been given in a few uncontrolled studies, but there is no evidence that this approach improves survival in patients who have a complete resection. Two recent meta-​analyses have shown no benefit from postoperative radiotherapy for stage I and II disease, and it is not clear whether or not it has any value in stage IIIA disease with nodal involvement, but benefit is likely to be small and it is not currently recommended. Where a surgical resec- tion is not complete (e.g. there is microscopic pleural or bronchial margin involvement of tumour), many centres employ postoperative radiotherapy to the involved margin. Radical radiotherapy for locally advanced, inoperable disease In otherwise fit patients with small-​volume intrathoracic disease which is not resectable, usually because of mediastinal involvement, it is common practice to attempt to cure with radiotherapy. Results with daily single fractions are disappointing, even with doses of up to 60 Gy, with 5-​year survival rates ranging from 5 to 17%. In 1997 continuous hyperfractionated accelerated radiotherapy (CHART), with a fraction every 8 h for 12 consecutive days to a total of 54 Gy, was compared to conventional daily radiotherapy in NSCLC. CHART gave an absolute improvement in 2-​year survival from 20% to 29%, with the greatest benefit (14% absolute improve- ment) in squamous cell cancers. This appears a real advance in the provision of radiotherapy for locally advanced, inoperable tumours, but it has not proved to be a feasible technique for busy radiotherapy departments. A similar approach with no treatment at week-​ends (CHARTWELL) may be as useful and seems to be effective. Studies of combining radiotherapy with concurrent or sequential courses of chemotherapy have been compared to radiotherapy alone and shown a survival benefit. It also appears that concurrent chemo- therapy may be better than the two treatment modalities given con- secutively, although the toxicity for the concurrent approach is higher. Concurrent chemoradiotherapy is now regarded as the approach of choice for locally advanced, inoperable NSCLC. Very recent data have also demonstrated the benefit of adding immunotherapy with Durvalumab to concurrent chemo-radiotherapy to inoperable stage III disease (https://www.nejm.org/doi/full/10.1056/NEJMoa1809697). Palliation Radiotherapy can provide excellent palliation for many symptoms, with two of the most distressing, haemoptysis and cough, controlled in up to 80% of cases. Administration of two fractions (each of 8.5 Gy, 1 week apart) appears adequate. Dyspnoea from bronchial obstruction and dysphagia are relieved in most cases. The syndrome of superior vena caval obstruction is relieved in about 80% of suf- ferers, but usually requires a more conventional course of five to ten fractions of radiotherapy. Pain from bone secondaries can be re- lieved in more than 50% by a single fraction of 8 Gy, often given at the same time as a clinic visit. Brain metastases generally respond poorly to radiotherapy. A 48-​ h trial of dexamethasone, 4 mg orally four times daily or 8 mg twice daily, is recommended as initial management. If a worthwhile re- sponse follows the resolution of the oedema surrounding the metas- tases, then radiotherapy will consolidate this gain, after which steroids should be rapidly withdrawn. A UK randomized trial has called into question the role of whole brain radiotherapy for patients with brain metastases from lung cancer. Selected patients may benefit from stereotatic radiosurgery to the brain when there are a limited number of metastases. Spinal cord compression is a relatively common occurrence as- sociated with vertebral body metastatic disease. Pain and bony ten- derness often precede it and may be helpful in localizing the lesion. Responses to radiotherapy are usually incomplete and disappointing, often because of interruption of the vascular supply to the spinal cord by the tumour. Systemic anti-cancer therapy Conventional chemotherapy Several cytotoxic agents show activity against NSCLC, but much less frequently or dramatically than with small-​cell tumours. However, combination chemotherapy can achieve impressive response rates; par- tial responses in 50% of patients with locally advanced disease and in 35% of those with advanced extrathoracic disease have been reported. Chemotherapy became a routine treatment for inoperable NSCLC about 20 years ago after a meta-​analysis of 53 randomized controlled studies in which patients did or did not receive chemotherapy in add- ition to surgery, radiotherapy, or to best supportive care. This sug- gested a 5% advantage for the addition of chemotherapy to surgery (confidence intervals—​1 to 7%), a smaller nonsignificant advantage for the addition of chemotherapy to radiotherapy, and—​in those with advanced disease—​a 10% improvement in survival at 1 year for the addition of chemotherapy to best supportive care. The agents used in these early trials were more toxic than the newer, currently available agents, and the associated deleterious effects on quality of life have dramatically improved. Also it has emerged that different combin- ations of drugs are more effective for different cell types of NSCLC. The optimal initial chemotherapy for squamous cell NSCLC is carboplatin or cisplatin, plus gemcitabine. A large study of these agents compared to cisplatin and pemetrexed, showing superior survival for the latter doublet for adenocarcinomas and large-​cell carcinomas, and this had become the initial treatment of choice. However, the routine assessment for EGFR mutation and other genetic changes as well as bio- markers for response to immunotherapy has changed this (see next). In patients with adenocarcinoma and stable disease after first-​ line chemotherapy, maintenance chemotherapy with pemetrexed is often considered. In the United Kingdom, only 20% of patients receive second line chemotherapy after progression of disease with initial treatment. The use of chemotherapy as an adjuvant following successful sur- gery has shown a 5.2% increase in the 5-​year post-​surgery survival for patients with at least Stage IIA disease, and this should be offered to those who have recovered well and within 60 days of their surgery. In advanced disease, which will include up to 75% of all cases of NSCLC, chemotherapy confers an important survival advantage compared to best supportive care alone. In general, studies of pal- liative chemotherapy have shown a quality of life benefit, at least over the first few months after treatment is complete. There is no particular regimen that stands out, but chemotherapy in advanced disease, chosen on their cell type, for patients with a good perform- ance status will increase the median survival by 4 to 6 months and the 1-​year survival from 18% untreated to 35 to 50%. More recent clinical trials have shown a differential effect of chemotherapy in that adenocarcinomas have a higher response rate and survival with

18.19.1  Lung cancer 4355 pemetrexed plus a second agent, while squamous cell tumours re- spond better to platinum containing doublets. Hence the import- ance of establishing the cell type in NSCLC prior to planning therapy. Targeted therapies The rapid evolution of molecular biology and the ability to identify the presence of mutations in small biopsy tissue samples has led to a drive for targeted therapy based on inhibition of the ‘driver’ mutant gene. The first important mutation discovered—​and now routinely sought for—​ was EGFR, and mutation of EGFR in NSCLC has made it a target for treatment. Several oral inhibitors of EGFR, including gefitinib, erlotinib, afatinib and osimertinib are in current use. Patients who harbour EGFR mutations have approximately a 70% better response rate and pro- longed progression-​free survival and improved quality of life on an EGFR tyrosine kinase inhibitor (TKI) than with conventional chemo- therapy. Conversely, patients whose tumours are wild-​type for EGFR display minimal responses to EGFR TKI, and may do better with first-​ line chemotherapy. With this approach the overall survival of patients with EGFR mutant tumours treated first line with TKIs is about 27–​ 30 months. By comparison, the overall survival of patients with meta- static unselected NSCLC on first-​line chemotherapy is 10–​12 months. Similar observations have been made for patients with tumours harbouring ALK fusions, which can now be treated with the ALK TKI crizotinib, which is also used for non-squamous NSCLC that has rearrangements in the receptor tyrosine kinase, ROS1. Other targeted therapies are in preparation, and this approach is likely to become of increasing importance in the future. Immunotherapy Immune checkpoint inhibition has emerged as a key advance in the management of advanced lung cancer. Immunotherapy has demon- strated significant clinical utility in patients with advanced NSCLC, and several anti PD-1 and anti PD-L1 monoclonal antibodies have been approved as first or second-line therapies. These agents interfere with both costimulatory and co-inhibitory pathways regulating the antigen specific T-cell response. PD-1 is a cell-receptor involved in pro- grammed cell death. The PD-1 receptor binds to the ligands PD-L1 and PD-L2 and results in downregulation of anti-tumour cytolytic T-cell activity, inducing T cell exhaustion and immune tolerance. Immune checkpoint inhibitors therefore allow the host’s immune system to rec- ognise tumour cells and exert anti-tumour activity. This group of medi- cations are genereally well tolerated but due to their mechanism of action may result in autoimmune disorders. Pembroluzimab together with chemotherapy is currently approved for the first line treatment of advanced NSCLC and has been shown to be superior to chemotherapy alone (https://www.ncbi.nlm.nih.gov/pubmed/29658856). It has been approved by NICE as the first line systemic therapy for advanced NSCLC. In patients who have high levels of expression of PD-L1 (>50% of cells) pembroluzimab alone is licensed for use (https://www. ncbi.nlm.nih.gov/pubmed/27718847). Immunotherapy is commonly also used a second line treatment and is currently being investigated in the adjuvant and neo-adjuvant settings for earlier stage disease. Treatment and prognosis of small-​cell lung cancer Small-​cell lung cancer is separated from the other types of lung cancer because of its very different biological and clinical features. It has an ex- plosive growth pattern, and careful staging puts most patients into the inoperable category. However, simple staging has some prognostic im- pact and those with limited disease (tumour confined to one hemithorax and the ipsilateral supraclavicular fossa) fare better than those with ex- tensive disease (involvement of any site outside the hemithorax). The life expectancy of those with untreated small-​cell lung cancer is about 3.5 months for limited disease and 6 weeks for extensive disease. Prognostic factors Multivariate analyses of large patient populations show that routine biochemical values such as serum sodium, albumin, and alkaline phosphatase allow separation of prognostic subgroups. In addition, performance status and extent of disease are important influences. For instance, a good performance status and normal biochemical values (i.e. a good prognostic category) has a 2-​year survival rate of 20%, yet a correspondingly low performance status with one or more abnormal biochemical parameters (poor prognosis) has virtually no 2-​year sur- vivors (Fig. 18.19.1.15). Women tend to do better than men and those under 60, better than those over 60 years of age. These factors are helpful both for stratification within clinical studies and for identifying those patients likely to do well with chemotherapy and those for whom intensive potentially toxic chemotherapy would appear inappropriate. Survival beyond 5 years (cure) is achieved in 4 to 12% of patients with limited disease and in hardly anyone with extensive disease at diag- nosis. Most studies of long-​term survival report late deaths due to other cancers, including NSCLCs in up to 30% of these long-​term survivors. Surgery Very occasionally patient with small-​cell lung cancer can be surgi- cally cured, usually those presenting with a peripheral tumour and no evidence of local spread or metastasis despite extensive staging investigations. These patients are rare, but nevertheless have a 5-​year survival rate in the region of 30 to 40% when surgery is combined with adjuvant chemotherapy. Radiotherapy Radiotherapy has an important role in palliation of symptoms that may develop after relapse following chemotherapy. Chest irradiation also significantly decreases the rate of recurrence at the primary tumour site 100 90 80 70 60 50 40 Cumulative % surviving 30 20 10 9 18 27 36 45 Months P I G E L Fig. 18.19.1.15  Survival in small-​cell lung cancer by prognostic factors (G, good; Im, intermediate; P, poor) compared to full staging (L, limited; E, extensive disease).

section 18  Respiratory disorders 4356 and in the mediastinum. A total dose of 40 to 50 Gy is usually given. Two meta-​analyses on the value of adding radiotherapy to chemotherapy have shown a 5% advantage at 3 years for the addition of radiotherapy. The optimal timing of radiotherapy in relation to chemotherapy has been the subject of much debate. The 2019 NICE guidelines recom- mend offering twice-daily radiotherapy concurrently with the first or second cycle of chemotherapy to patients with limited-stage disease and good performance status, if their disease can be encompassed within a radical thoracic radiotherapy volume. If patients are not well enough for concurrent chemoradiotherapy but respond well to chemotherapy, then radiotherapy can be offered after chemotherapy is completed. Cranial irradiation Cranial metastases are common, with 10% of patients in remission developing them as their first site of relapse. Prophylactic cranial ir- radiation given at the end of chemotherapy will delay the presenta- tion of cerebral metastases and also reduce their overall incidence. This is important, as the development of cerebral disease is associ- ated with severe morbidity, often making it difficult for the sufferer to live at home. A meta-​analysis looking at the effects of prophylactic cranial irradiation on survival showed that the cumulative incidence of brain relapse was halved and the risk of death reduced by 16%, with this survival benefit being maintained after 6 years, hence it is now recommended that patients achieving a complete response after chemotherapy should have prophylactic cranial irradiation. Chemotherapy Small-​cell lung cancer is much more sensitive to cytotoxic chemo- therapy than the NSCLC tumours, with a much higher response rate for several cytotoxic drugs. In the late 1970s there was a very rapid improvement in median survival, and subsequent studies using combinations of three and four drugs brought longer re- sponse times, but responses have subsequently reached a plateau. Nevertheless, with modern combination cytotoxic treatment, which is usually given as an outpatient procedure every 3 weeks, the median survival has been extended to 14 to 18  months for limited disease and to 9–​12 months for extensive disease. There is no outstanding regimen, although etoposide and carboplatin is favoured by most. Modern regimens would be expected to achieve a complete response rate (i.e. disappearance of all measurable disease) in 40–​50% of cases and a partial response rate (>50% reduction in tumour bulk) in a further 40%, giving a total response rate of 80–​ 85%. All these regimens have side effects: most patients will experi- ence some nausea and vomiting, and life-​threatening septicaemia occurs in 1 to 4%, but treatment-​related deaths are uncommon. There is no established second line treatment at relapse, although if remission has been achieved for a year or longer, restarting the same chemotherapy regimen can be effective in some cases. Much effort has been applied during the last 25 years to improve the median and long-​term survival of patients with small-​cell lung cancer. Recently, the addition of immunotherapy has been shown to improve survival in patients with extensive small cell lung cancer (https://www. ncbi.nlm.nih.gov/pubmed/30280641). In general, those patients likely to do better are those who present with limited disease and a good performance status. Patients with extensive disease tend to have a uni- versally bad prognosis and very few survive beyond 2 years. However, some metastatic sites (bone and bone marrow) are not as sinister as others (brain or liver), and the occasional patient with extensive dis- ease does well with chemotherapy, but in general treatment is offered in this circumstance for palliation and not in the hope of cure. Studies assessing the quality of life in patients presenting with small-​cell lung cancer have shown that over 70% have important symptoms such as weight loss, malaise, bone pain, dyspnoea, and haemoptysis. Most of these patients have extensive disease, but after 3 months of chemotherapy symptoms can be relieved in 60 to 70% of sufferers, making chemotherapy worthwhile, with symptomatic benefits far outweighing the potential side effects. Ten per cent of small-​cell lung cancer patients present with superior vena caval obstruction: this re- sponds as well as any presentation to chemotherapy. Intensity of treatment Intensifying the dosage or the frequency of administration of cyto- toxic agents has been thoroughly explored without real benefit on median survival. Small advantages are occasionally seen, but these have to be balanced by the increased toxicity resulting from a more aggressive approach. Attempts to overcome or delay the emergence of cell resistance to chemotherapy have involved alternating com- binations of drugs, but these more complicated regimens have not been rewarding either. Similarly, the use of colony growth stimula- tion factors to allow higher or more frequent doses of drugs has not added to survival. Other studies with very high dose schedules and bone marrow harvesting and reinfusion have been unsuccessful. Duration of treatment Toxicity of chemotherapy increases with the number of courses given. It is now apparent that most of the tumour response to chemotherapy occurs within the first two or three cycles. Studies attempting to minimize the duration of chemotherapy without ad- versely affecting survival have shown that six courses of combin- ation chemotherapy is optimal (with a course every 3 weeks), with no benefit from maintenance regimens in this setting. General management of patients with lung cancer There is increasing emphasis on pre-habilitation, optimsing co-morbidities prior to anti-cancer treatment, improving nutrition and treating nicotine addiction in patients with lung cancer. There are also certain complications which require specific measures to al- leviate symptoms. Vocal cord paralysis Patients who seem likely to survive for 6 months or more and who have vocal cord paralysis are considerably helped by an injection of PTFE (Teflon) into the affected cord, which restores voice produc- tion in a high percentage of cases and reduces the risk of aspiration. Airway obstruction Obstruction of the upper airway causing stridor, or of the lower major airways, is usually treated initially with radiotherapy. Should this complication recur or be unsuitable for radiotherapy, then endobronchial tumour can be debulked using laser photocoagulation or cryoextraction, administered either via a video bronchoscope or under general anaesthetic via a rigid instrument. This is most suit- able as a palliative treatment in central tumours occluding large air- ways: removal of considerable quantities of tumour can be achieved in a single treatment session with the rigid instrument. Trials are in pro- gress assessing the additional benefits of endobronchial radiotherapy

18.19.1  Lung cancer 4357 (brachytherapy) using iridium or caesium wires delivered via the video bronchoscope. This procedure irradiates endobronchial tu- mour to a circumferential depth of about 1 cm, and will often produce a further remission. It is used where further external-​beam radio- therapy cannot be given because of the risk of exceeding normal tissue tolerance. Infection distal to tumour requires antibiotic therapy and, where appropriate, oxygen therapy and bronchodilators. Severe, re- current haemoptysis may be controlled by radiotherapy or laser. Pleural effusion Malignant pleural effusion recurs after aspiration unless the pleural space is obliterated. Chemical pleurodesis can be induced by intrapleural instillation of several agents, or by the more invasive procedure of talc pleurodesis. However, the increasing availability of VATS makes a talc pleurodesis preferable in all reasonably fit pa- tients who can undergo a general anaesthetic (see Chapter 18.17). In general a pleurodesis is recommended early in management, before embarking on chemotherapy in NSCLC. Indwelling pleural catheters are an important option for patients with malignant pleural effusions. In small-​cell lung cancer it is worthwhile to give chemotherapy first as it is likely to gain control. Other issues Dexamethasone, 4 to 16 mg orally daily, may control the symptoms of brain metastasis and, if so, this should be consolidated with radio- therapy to prevent severe steroid-​induced myopathy, especially in pa- tients who show a good symptomatic response to the steroids. Prednisolone, 20 mg orally daily, is often used to improve the sense of well-​being, as are blood transfusion or hyperalimentation. Steroids are often helpful for the control of pain from liver metas- tases involving the liver capsule. Pain and hypercalcaemia from bone metastases can be particu- larly challenging to control. Bisphosphonates are commonly used for palliation in this setting. Denosumab, a human monoclonal anti- body that targets bone remodelling, has also been approved by NICE for use in patients with lung cancer and bone metastases. Early evi- dence may suggest that it may have anticancer effects and offer some survival benefit over bisphosphonates in this setting (http://​www. ncbi.nlm.nih.gov/​pubmed/​23154554). Palliative care is described in Section 7, but the importance of the combined support to the patient and the family given by the family doctor, palliative care medical and nursing staff, hospice or- ganizations, and the hospital team cannot be overemphasized. Prevention and screening Smoking cessation Lung cancer is a preventable disease which in 80% of cases is due to smoking, particularly of cigarettes. Strenuous efforts must be made to persuade people not to start smoking, to establish more effective methods of enabling people to stop, and to promote further research into effective health education. The promotion of cigarettes with low tar, nicotine, and carbon monoxide contents may have made a small contribution to prevention, but low-​tar cigarettes are not a substitute for giving up smoking. Penal taxation by governments may help, as will smoke-​free public places. The use of electronic nicotine delivery systems is booming, with US$3bn spent on these globally in 2013 and sales forecast to increase by a factor of 17 by 2030 (http://​apps.who.int/​gb/​fctc/​PDF/​ cop6/​FCTC_​COP6_​10-​en.pdf?ua = 1). While such systems may be a pathway to the reduction of tobacco smoking, they may also be viewed as products that could undermine efforts to denormalize to- bacco use and encourage uptake in younger people. The role of elec- tronic nicotine delivery systems in tobacco control is currently the subject of intense debate. Occupational measures The identification of occupational hazards and implementation of appropriate measures to safeguard the health of employees are clearly important preventive measures, even although the number at risk is very small. Population screening Screening of normal but high-​risk populations with chest radiog- raphy and/​or sputum cytology has been shown to have no effect on the mortality from lung cancer, even though more cancers are discovered. However, new studies of various populations using low-​ dose spiral CT have identified lung cancers in 1.4–​2.7% of subjects in prevalence screens, the great majority having stage I disease, which is about four to six times what one would pick up by chest radi- ography. The older the subjects screened, the greater the smoking history and the presence of airways obstruction, the higher the inci- dence of occult lung cancers. A large study of 53 454 individuals has been published. The National Lung Screening Trial (NLST) randomized current and ex-​smokers to three annual low-​dose CT scans in the screened group, whereas the control group had a chest radiograph. The trial has shown a 20% re- duction in mortality for the CT-​screened arm, with 247 deaths from lung cancer per 100 000 person-​years in the screened arm versus 309 in the controls. This represents an overall reduction in all-​cause death rate of 6.7%. A study of this magnitude is unlikely to ever be repeated and its impact will seriously affect thinking regarding screening for lung cancer, although there is data to suggest that the high-​risk in- dividual for lung cancer is elderly, poorly educated and risk averse, and unlikely to participate in a screening trial. However, other ran- domized trials, smaller than NLST, are in progress and will report soon, and although low-​dose CT may become an important method of identifying lung cancers early, it has its problems and limitations. Small-​cell cancers grow too rapidly to be found by screening and will present with symptoms. Depending on where in the world the study is performed, many subjects will be found to have benign nodules that require follow-​up according to radiological algorithms which may re- quire repeated scans. The incidence of nodules varies from 15 to 40%, which is a potentially huge burden for imaging departments. Despite these caveats, CT screening for lung cancer began in the United States in 2014. Cost-​effectiveness data from the NLST is now available and suggests a cost per QALY of $81 000, but with wide con- fidence intervals (http://​www.ncbi.nlm.nih.gov/​pubmed/​25372087). Refining the population that undergoes CT screening for lung cancer may improve cost-​effectiveness and is of key importance if imple- mentation of CT screening is to take place universally. Various tools can be used to select individuals according to their lung cancer risk in a more nuanced approach than simply smoking history (http://​www. ncbi.nlm.nih.gov/​pubmed/​23863051). Application of these risk pre- diction tools to individuals, combined with smoking cessation, may make CT screening more palatable to healthcare systems if they can maximize cost-​effectiveness.

section 18  Respiratory disorders 4358 Other primary lung tumours The slow-​growing intrabronchial lesions previously grouped under the heading of bronchial adenoma have now been re- classified into bronchial carcinoids, adenoid cystic tumours, and mucoepidermoid tumours. They are not related to cigarette smoking, and tend to be diagnosed at a younger age than car- cinoma of the bronchus. Bronchial adenomas True bronchial adenomas derived from bronchial glands are rare. These tumours were once thought to be benign, but they are po- tentially and often frankly malignant, being capable not only of destructive local growth but also of metastasis to regional lymph nodes in about one-​third of patients, and to distant organs, par- ticularly liver and brain, in about 10%. They are occasionally lo- cated in the trachea. Bronchial carcinoids The most common symptoms of bronchial carcinoids are cough, haemoptysis, and recurrent pneumonia, although not infrequently the lesion is discovered on routine radiographic examination be- fore symptoms develop. In the few cases that have extensive liver secondaries, there may be the classical symptom pattern of inter- mittent cyanotic flushings, intestinal cramps and diarrhoea, bronchoconstriction, and cardiovascular lesions. The radiographic appearances are those of a solitary nodule, pulmonary collapse, or obstructive hyperinflation. As most of the tumours occur in main stem or proximal portions of lobar bronchi, bronchoscopy is usually the definitive diagnostic measure. The tumour appears as a white or pink polypoid or lobulated mass, with the bronchial mucosa ap- pearing to be intact. Biopsy should be carried out with caution as it may be followed by brisk haemoptysis. Surgical resection is the treatment of choice. In the absence of regional spread or distant metastases 5-​year survival prospects are excellent, but if there is involvement of regional nodes, survival rates fall to 70%. Some aggressive carcinoid tumours carry a much worse prognosis. The mechanism and management of the general symptoms of the carcinoid syndrome are described in Chapter 15.9.2. FURTHER READING Ahrendt SA, et  al. (1999). Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer. J Natl Cancer Inst, 91, 332–​9. Albain KS, et  al. (2009). Radiotherapy plus chemotherapy with or without surgical resection for stage III non-​small-​cell lung cancer: a phase III randomised controlled trial. Lancet, 374, 379–​86. American Thoracic Society and European Respiratory Society (1997). Pretreatment evaluation of non-​small-​cell lung cancer. Am J Respir Crit Care Med, 156, 320–​32. Annema JT, et al. (2010). Mediastinoscopy vs endosonography for me- diastinal nodal staging of lung cancer: a randomized trial. JAMA, 304, 2245–​52. Arbour KC, Riely GJ (2019). Systemic Therapy for Locally Advanced and Metastatic Non-Small Cell Lung Cancer: A Review. JAMA, 322, 764–74. Auperin A, et al. (1999). Prophylactic cranial irradiation for patients with small cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med, 341, 476–​84. Beckles MA, et al. (2003). The physiological evaluation of patients with lung cancer being considered for surgery. Chest, 123, 105–​14S. British Thoracic Society, Society of Cardiothoracic Surgeons of GB, Ireland Working Party (2001). Guidelines on the selection of pa- tients with lung cancer for surgery. Thorax, 56, 89–​106. Brown JS, et al. (1996). Age and the treatment of lung cancer. Thorax, 51, 564–​8. Bruske-​Hohlfeld I, et  al. (2000). Occupational lung cancer risk for men in Germany: results from a proband case-​control study. Am J Epidemiol, 151, 384–​95. Carney DN (1992). Biology of small-​cell lung cancer. Lancet, 339, 843–​6. Chang JY, et al. (2015). Stereotactic ablative radiotherapy versus lobec- tomy for operable stage I non-​small-​cell lung cancer: a pooled ana- lysis of two randomised trials. Lancet Oncol, 16, 630–​7. Chansky K, et al. (2017). The IASLC Lung Cancer Staging Project: External Validation of the Revision of the TNM Stage Groupings in the Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol, 12, 1109–21. Depierre A, et  al. (2002). Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (ex- cept T1N0), II and IIIa non-​small-​cell lung cancer. J Clin Oncol, 20, 247–​53. Doll R, Peto R (1976). Mortality in relation to smoking: 20 years’ ob- servations on male British doctors. Br Med J, ii, 1525–​36. Duma N, Santana-Davila R, Molina JR (2019). Non-small cell lung cancer: epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc, 94, 1623–40. Du Rand IA, et al. (2013). Summary of the British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults. Thorax, 68, 786–​7. Fischer B, et al. (2009). Preoperative staging of lung cancer with com- bined PET-​CT. N Engl J Med, 361, 32–​9. Fountana RS, et al. (1984). Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic Study. Am Rev Respir Dis, 130, 561–​5. Fritscher-​Ravens A, et  al. (2000). Role of transesophageal endosonography-​guided fine-​needle aspiration in the diagnosis of lung cancer. Chest, 117, 339–​45. Furuse K, et al. (1999). Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable Stage III non-​small-​cell lung cancer. J Clin Oncol, 17, 2692–​9. Garon EB, et  al. (2015). Pembrolizumab for the treatment of non-​ small-​cell lung cancer. N Engl J Med, 372, 2018–​28. Goldstraw P, Crowley J, Chansky K et  al. (2007). The IASLC Lung Cancer Staging Project:  proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol, 2, 706–​14. Goya T, et al. (2005). Prognosis of 6644 resected non-​small cell lung cancers in Japan; a Japanese lung cancer registry study. Lung Cancer, 50, 227–​34. Grant D, Edwards D, Goldstraw P (1988). Computed tomography of the brain, chest, and abdomen in the preoperative assessment of non-​small-​cell lung cancer. Thorax, 43, 883–​6. Henschke CI, et al. (1999). Early lung cancer detection project: overall design and baseline screening. Lancet, 354, 99–​105.

18.19.1  Lung cancer 4359 Holty JE, Kuschner WG, Gould MK (2005). Accuracy of transbronchial needle aspiration for mediastinal staging of non-​small-​cell lung cancer: a meta-​analysis. Thorax, 60, 949–​55. International Agency for Research on Cancer (2014). Diesel and Gasoline Engine Exhausts and Some Nitroarenes. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 150. Izbicki JR, et  al. (1992). Accuracy of computed tomographic scan and surgical assessment for staging of bronchial carcinoma. A pro- spective study. J Thorac Cardiovasc Surg, 104, 413–​20. Kaneko M, et al. (1996). Peripheral lung cancer: screening and detec- tion with low-​dose spiral CT versus radiography. Radiology, 201, 798–​802. Landreneau RJ, et al. (1992). Thoracoscopic resection of 85 pulmonary lesions. Ann Thorac Surg, 54, 415–​19. Laroche C, et al. (2000). Role of computed tomographic scanning of the thorax prior to bronchoscopy in the investigation of suspected lung cancer. Thorax, 55, 359–​63. Mok T, et al. (2009). Gefitinib or carboplatin-​paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 361, 947–​57. Mountain CF (1997). Revisions in the international system for staging lung cancer. Chest, 111, 1710–​17. Muers MF, Round CE (1993). Palliation of symptoms in non-​small-​cell lung cancer. Thorax, 48, 339–​43. Naruke T, et al. (2001). Prognosis and survival after resection for bron- chogenic carcinoma based on the 1997 TNM-​staging classifica- tion: the Japanese experience. Ann Thorac Surg, 71, 1759–​64. National Lung Screening Trial Research Team (2011). Reduced lung cancer mortality with low dose computed tomographic screening. New Engl J Med, 365, 395–​409. Navani N, et  al. (2015). Lung cancer diagnosis and staging with endobronchial ultrasound-​guided transbronchial needle aspiration compared with conventional approaches: an open-​label, pragmatic, randomised controlled trial. Lancet Respir Med, 3, 282–​9. NICE (2019). Lung cancer: diagnosis and treatment. Available from: http://​www.nice.org.uk/​guidance/​ng122 Non-​Small-​Cell Lung Cancer Collaborative Group (1995). Chemotherapy in non-​small-​cell lung cancer: a meta-​analysis using updated data on individual patients from 52 randomised clinical trials. BMJ, 311, 899–​909. Pandey M, Mathew A, Nair MK (1999). Global perspective of tobacco habits and lung cancer. A lesson for third world countries. Eur J Cancer Prev, 8, 271–​9. Pfannschmidt J, et al. (2007). Prognostic assessment after surgical re- section for non-​small cell lung cancer: experience in 2083 patients. Lung Cancer, 55, 371–​7. Pignon JP, et al. (1992). A meta-​analysis of thoracic radiotherapy for small cell lung cancer. N Engl J Med, 327, 1618–​24. Pless-​Mulloli T, et  al. (1998). Lung cancer, proximity to industry, and poverty in northeast England. Environ Health Perspect, 106, 189–​96. PORT Meta-​analysis Trialists Group (1998). Postoperative radio- therapy in non-​small-​cell lung cancer: systematic review and meta-​ analysis of individual patient data from nine randomised controlled trials. Lancet, 352, 257–​63. Potton E, Spiro SG (2009). The surgical treatment of lung cancer. In:  Spiro SG, Huber RM, Janes SM (eds) Thoracic malignancies. European Respiratory Society Monograph, 44. Reed CE, et al. (2003). Results of the American College of Surgeons Oncology Group Z0050 trial: the utility of positron emission tom- ography in staging potentially operable non-​small-​cell lung cancer. J Thorac Cardiovasc Surg, 126, 1943–​51. Ries LAG, et  al. (1995). Cancer statistics review:  1973–​1993. US Government Printing Office, Bethesda, MD. Saunders M, et al. on behalf of the CHART Steering Committee (1997). Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-​small-​cell lung cancer: a randomised multicentre trial. Lancet, 350, 161–​5. Scagliotti GV (1995). Symptoms and signs and staging of lung cancer. In:  Spiro SG (ed.) Carcinoma of the lung, European Respiratory Monograph, Vol. 1, No. 1, pp. 91–​137. European Respiratory Society Journals, Sheffield. Schiller JS, et al. (2002). Comparison of four chemotherapy regi- mens for advanced non-​small-​cell lung cancer. N Engl J Med, 346, 92–​8. Shepherd RA, et al. (2005). Erlotinib in previously treated non-​small-​ cell lung cancer. N Engl J Med, 353, 123–​32. Shigematsu H, Gazdar AF (2006). Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer, 118, 257–​62. Silvestri G, Pritchard R, Welch HG (1998). Preferences for chemotherapy in patients with advanced non-​small-​cell lung cancer:  descriptive study based on scripted interviews. BMJ, 317, 771–​5. Silvestri GA, et al. (2003). The noninvasive staging of non-​small-​cell lung cancer: the guidelines. Chest, 123, 147–​56. Sobue T, et al. (2002). Screening for lung cancer with low-​dose helical computed tomography: anti-​lung cancer association project. J Clin Oncol, 20, 911–​20. Souhami RL, et  al. (1985). Prognostic significance of laboratory parameters measured at diagnosis in small cell carcinoma of the lung. Cancer Res, 45, 2878–​82. Spiro SG, Goldstraw P (1984). The staging of lung cancer. Thorax, 39, 401–​7. Spiro SG, et al. (2004). Chemotherapy versus supportive care in ad- vanced non-​small-​cell lung cancer: improved survival without det- riment to quality of life. Thorax, 59, 828–​36. Spiro SG, et  al. (2006). Early compared with late radiotherapy in combined modality treatment for limited-​disease small-​cell lung cancer: a London Lung Cancer Group multicenter randomized clin- ical trial and meta-​analysis. J Clin Oncol, 24, 3823–​30. Strand T-​E, et  al. (2006). Survival after resection for primary lung cancer: a population based study of 3211 resected patients. Thorax, 61, 710–​15. Tammemägi MC, et  al. (2013). Selection criteria for lung-​cancer screening. N Engl J Med, 368, 728–​36. Tammemägi MS, et al. (2014). Impact of lung cancer screening results on smoking cessation. J Natl Cancer Inst, 106, dju084. Temel JS, et al. (2010). Early palliative care for patients with metastatic non-​small-​cell lung cancer. N Engl J Med, 363, 733–​42. Thatcher N, et al. (1995). Chemotherapy in non-​small-​cell lung cancer. Ann Oncol, 6 (Suppl. 1), S83–​95. Thatcher N, et al. (2005). Gefitinib plus best supportive care in previ- ously treated patients with refractory advanced non-​small-​cell lung cancer: results from a randomised, placebo-​controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet, 366, 1527–​37. Travis WD, Brambilla E, Riely GJ (2013). New pathologic classifica- tion of lung cancer: relevance for clinical practice and clinical trials.
J Clin Oncol, 31, 992–​1001. Wallace MD, et al. (2001). Endoscopic ultrasound-​guided fine needle aspiration for staging patients with carcinoma of the lung. Ann Thorac Surg, 72, 1861–​7.

18.19.2 Pulmonary metastases 4360 S.G. Spiro

18.19.2 Pulmonary metastases 4360 S.G. Spiro

section 18  Respiratory disorders 4360 18.19.2  Pulmonary metastases S.G. Spiro ESSENTIALS Malignant metastasis to the lung is common. It may present as a soli- tary enlarging nodule, as multiple nodules ranging enormously in size and number, and/​or with diffuse lymphatic involvement. Diagnosis can usually be secured by percutaneous CT-​guided biopsy and most suspicious lesions will be PET positive. Surgical excision may prolong survival or result in cure in some cases. Introduction Malignant metastasis to the lung is common because of the lung’s rich blood supply, and may present as a solitary enlarging nodule, as multiple nodules, or with diffuse lymphatic involvement. Surgical metastasectomy In all patients, before resection is attempted, the patient needs to be assessed as fit for lung resection, the primary tumour site should be controlled, and all metastatic disease must be considered removable. More than one attempt at excision is possible. Solitary metastases About 10% of all round pulmonary lesions are metastases, but some 70% of round lesions occur in patients with a known malignancy. Colorectal cancer is reported to be the commonest tumour of origin. Diagnosis can usually be secured by percutaneous CT-​guided bi- opsy, often preceded by a staging PET scan, where the lesion is most likely to be positive. In many cases, surgical excision may prolong survival and result in cure in some, depending on the state of the pri- mary tumour and the likelihood of other occult metastases. Surgery is sometimes recommended after successful control of the disease with chemotherapy, or if any residual tissues become PET negative. Routine follow-​up with CT scanning has revealed an increasing number of clinically well patients deemed clear of disease at their primary site, but with distant pulmonary metastases. Usually such disease is caught at an early stage of recurrence, is of low volume, and can be resected relatively easily, usually thoracoscopically. However, if the new lesion appears solitary, the possibility of a second primary (i.e. a lung cancer), needs to be considered before resection. Multiple metastases Multiple metastases may range considerably in size and number, from cannon balls to multiple lesions of varying size, down to mil- iary shadowing, which may be accompanied by hilar lymphaden- opathy or pleural effusion. Breast, colon, renal cancers, melanoma, and lung primaries are the commonest underlying tumours, but other tumours amenable to chemotherapy occur, such as testicular cancer, choriocarcinoma, and also sarcomas. Diagnosis may be achieved by cytology or histology on various samples from the pleura or lung and can occasionally be made from cytology of expectorated or induced sputum. Tumours that are suitable for chemotherapy (e.g. choriocarcinoma) or endocrine manipulation (e.g. breast) need to be recognized. Solitary or multiple Kaposi’s sar- coma is a feature of AIDS and can involve the bronchi and pleura as well as lung tissue. Resection remains the treatment of choice, and good prognostic factors include the time from treatment of the primary tumour to the development of lung metastases, the fewer the number, the absence of extrapulmonary metastases, and the longer the tumour doubling time. The most favourable group are younger patients with a good performance status, with sarcomas who present with lesions a year or more after successful treatment of the primary disease. Factors including older age, male sex, and more lung metastases predict poorer survival after resection of any initial pulmonary metastases. The number of lung metastases present at a first metastasectomy and the preoperative interval predict recurrence in the lung. Survival following surgical excision is summarized in Table 18.19.2.1. In a study of recurrent lung metastases after excision of colorectal cancer, which is the commonest type of cancer in clin- ical reports of surgical metastasectomy, the overall median survival from second lung metastasectomy was 70 months. Other techniques Other techniques to remove pulmonary metastases include radio-​ or microwave ablation. This can achieve high ablation rates (>70%) and is usually most effective in lesions of 3 cm diameter or less. Two year survival rates of about 75% are common. The commonest com- plication is pneumothorax (<10%), with a very occasional need for an intercostal drain. Pulmonary haemorrhage is also a significant risk at about 5%. FURTHER READING Patrini D, et al. (2017). Surgical management of lung metastases. Br J Hosp Med, 78, 192–8. Phillips JD, Hasson RM (2019). Surgical management of colorectal lung metastases. J Surg Oncol, 119, 629–35. Regal AM, et al. (1985). Median sternotomy for metastatic lung lesions in 131 patients. Cancer, 55, 1334–​9. Stewart JR, et al. (1992). Twenty years’ experience with pulmonary metastasectomy. Am Surg, 58, 100–​3. Table 18.19.2.1  Five-​year survival following resection of pulmonary metastases according to primary tumour type Tumour type 5-​year survival (%) Soft tissue sarcoma 25 Osteogenic sarcoma 20–​40 Colon/​rectal carcinoma 8–​37 Renal cell carcinoma 13–​50 Breast carcinoma 14–​49 Head/​neck carcinoma 40–​50 Melanoma 25

18.19.3 Pleural tumours 4361 Y.C. Gary Lee

18.19.3 Pleural tumours 4361 Y.C. Gary Lee

18.19.3  Pleural tumours 4361 Suzuki H, et al. (2015). Long-term outcomes after surgical resection of pulmonary metastases from colorectal cancer. Ann Thorac Surg, 99, 435–40. Van Geel AN, et al. (1996). Surgical treatment of lung metastases: the European Organization for Research and Treatment of Cancer—​ Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer, 77, 675–​82. Vogl TJ, et al. (2011). Microwave ablation therapy: clinical utility in treatment of pulmonary metastases. Radiol, 261, 643–​51. 18.19.3  Pleural tumours Y.C. Gary Lee ESSENTIALS Benign tumours are rare in the pleural cavity, with solitary fibrous tumour of the pleura the most frequent of these rarities. Malignant pleural tumours are common and can arise from the pleura (most commonly mesothelioma) or as metastases from extrapleural malignancies (especially lung and breast cancer). They typically present with breathlessness, chest pain, and a pleural effusion. Diagnosis requires histocytological con- firmation of malignant cells from pleural fluid and/​or pleural biopsies. Mesothelioma—​most cases are due to asbestos exposure, char- acteristically after a latent period of more than 20 years, with risk related to the duration and intensity of asbestos exposure and the fibre type (worst with needle-​like amphiboles). The condi- tion is incurable, with overall median survival of about 9 months.
Care involves control of pain and pleural effusion, chemotherapy with pemetrexed, cisplatin and bevacizumab, and radiotherapy
for symptom palliation. Recent randomized trials did not show benefits of radical resection. Metastatic pleural malignancy—​most tumours that have spread to the pleura are incurable. For tumours that are highly responsive to chemotherapy (e.g. lymphoma or small cell car- cinoma) treatment may control pleural fluid re-​accumulation. Definitive treatment for fluid control (e.g. talc pleurodesis) should be performed in patients with symptomatic recurrence of malignant pleural effusions. Randomized trials did not find significant differences in efficacy whether talc is delivered by thoracoscopic poudrage or as a slurry. Indwelling pleural catheters provide an effective alternative to pleurodesis or when the latter fails. Surgical pleurodesis may be considered in selected patients. Introduction Pleural malignancies can arise as primary tumours from the pleura (mostly mesotheliomas) or as metastases from extrapleural cancers (especially lung, breast, and ovarian carcinomas). Malignant pleural effusion affects about 660 patients per million population annually, and account for up to 50% of exudative ef- fusions. Relatively little research has been performed on the best management for malignant effusions, and a recent worldwide survey of 859 respiratory specialists identified marked differ- ences in clinical practice. Benign pleural tumours Benign tumours are relatively rare in the pleural cavity, with solitary fibrous tumour of the pleura the most frequent of these rarities. Asbestos pleural thickening (e.g. plaques and round atel- ectasis) are discussed elsewhere (see Chapter 18.17). Extrapleural fat can occasionally mimic malignant pleural thickening, espe- cially in obese patients. Pleural lipoma is a rare entity of little clin- ical significance. Solitary fibrous tumour of the pleura Solitary fibrous tumour of the pleura (SFTP) accounts for less than 5% of all pleural tumours. It has also been called ‘localized fibrous mesothelioma’, ‘benign mesothelioma’ or ‘pleural fibroma’. The aeti- ology is unknown: there is no established relationship with asbestos or tobacco exposure. It affects both sexes equally and can affect pa- tients of all ages. The tumour arises from mesenchymal cells, usually from the visceral pleura. Symptoms and effusions are uncommon. Cough, chest pain, or dyspnoea is relatively mild, even if present. Hypertrophic pul- monary osteoarthropathy affects around 20% of patients, and inter- mittent hypoglycaemia due to tumour secreted insulin-​like growth factor is reported. SFTPs are often huge when discovered (>10 cm in 50% of cases in one series—​Fig. 18.19.3.1) and can be pedunculated (more common) or sessile. CT scanning usually reveals a well-​ encapsulated, lobulated mass showing heterogeneous attenuation, but there are no pathognomonic findings on imaging. The condition is usually amendable to surgery. Most SFTPs (c.80%) are benign with good long-​term prognosis after resection. Malignant SFTPs do occur, the diagnosis usually being based on histological findings (hypercellular clusters, high mitotic activity, and infiltrations) but not on clinical or radiological findings. Recurrence after resection occurs at a rate of 2–​8% in benign SFTPs, but up to 63% in malignant variants, and patients with malignant sessile SFTPs have a 30% mortality at 2 years. The role of neoadjuvant or postoperative chemotherapy has not been established. Mesothelioma Malignant pleural mesothelioma kills up to 3000 patients in the United Kingdom a year. An estimated 250 000 deaths from meso- thelioma are expected in western Europe alone over these three decades. Asbestos mining and its global uses are still increasing, especially in developing countries where regulation is poor. A sig- nificant rise of the global incidence of mesothelioma in the coming decades has been predicted.

section 18  Respiratory disorders 4362 Aetiology Asbestos exposure Most mesotheliomas are due to asbestos exposure, characteristic- ally after a long latent period (>20 years in 96% of patients). Most (>90%) mesothelioma arises from the pleura, occasionally from the peritoneum, and rarely from the pericardium and tunica vaginalis of the testis. The risk of mesothelioma is related to the duration and intensity of asbestos exposure and the fibre type. Workers involved in the mining and processing of asbestos, and those using end-​products of asbestos for insulation (e.g. plumbers and builders), are at obvious risk of developing mesothelioma, but family members of asbestos workers are also at increased risk from asbestos fibres brought home on work clothes. Home renovation that disrupts asbestos material used in old buildings are now increasingly recognized as a common source of exposure. The risk of developing mesothelioma depends on the physical characteristics of the inhaled asbestos fibres. Needle-​like amphibole fibres—​for example, crocidolite (blue asbestos), amosite (brown asbestos), anthophyllite, tremolite, and actinolite—​are eliminated slowly from the lungs (half-​life >7 years) and carry the highest risks. Serpentine fibres—​ for example, chrysotile (white asbestos)—​are cleared more rapidly as they are curly, more soluble, prone to frag- ment, and are less oncogenic than amphiboles. The oncogenic mechanism(s) of asbestos is poorly understood, but involves DNA damage, alteration of cell-​cycle check points, chromosomal rearrangement/​loss, altered expression of cytokine mediators, and dysregulation of apoptosis pathways. There are currently no means to identify which people exposed to asbestos are likely to develop mesothelioma. Recent research efforts have concentrated on identifying screening tests for early mesothelioma, but serum levels of soluble mesothelin, the most studied biomarker for this purpose, still have inadequate sensitivity to be used as clinically as a screening tool for the asbestos-​exposed population. Other causes Erionite, a naturally occurring mineral found mainly in Turkey, induces pleuropulmonary diseases similar to asbestos and includ­ing mesothelioma. Mesothelioma is not linked with prior thoracic irradiation (e.g. for Hodgkin’s lymphoma), or with smoking. Simian virus 40 (SV40) can induce pleural, peritoneal, and pericardial mesotheliomas in experimental animals, but epi- demiological studies do not support a causal link in humans. There is increasing preclinical evidence that carbon nanotubes can induce significant damage to the mesothelium and pre- dispose to mesothelioma, although this has yet to be proven in humans. No definite cause can be identified in up to 20% of patients with mesothelioma. Pathology Mesothelioma typically spreads in a diffuse sheet-​like manner, beginning in the parietal pleura followed by visceral pleural in- volvement. The latter often results in encasement of the underlying lung (Figs. 18.19.3.2 and 18.19.3.3). As mesothelioma progresses it can infiltrate surrounding structures including the ipsilateral lung, chest wall, mediastinum, and later the contralateral pleural cavity and peritoneum. The gross appearance is often indistin- guishable from pleural metastatic carcinoma. Spread to regional lymph nodes is common, but clinically significant distant me- tastases are infrequent, although at autopsy 60% of patients have extrathoracic metastases. The common histological subtypes of malignant mesothelioma are epithelioid (60% of cases), sarcomatoid (10%), and biphasic with components of both (30%). Median survival is worse in patients with the sarcomatoid variant (<6 months) than in the epithelioid Fig. 18.19.3.1  Solitary fibrous tumour. The chest radiograph (a) of a 56-​year-​old man with a persistent cough shows a large lobulated opacity in the left hemithorax. Computed tomography (CT) and positron emission tomography (b) showed a 10.8 cm solid pleural-​based mass (arrow) with heterogeneous low-​grade fluorine-​18 fluorodeoxyglucose (FDG) uptake, involving the left lower lobe and invading across the oblique fissure to involve the left upper lobe. CT-​guided core biopsy of the mass (c) showed features consistent with a solitary fibrous tumour, which was subsequently resected.

18.19.3  Pleural tumours 4363 type (12  months). Desmoplastic mesothelioma is a rare (<1%) variant that histologically mimics benign fibrous tissue. Clinical features and diagnosis Pleural effusion and the associated dyspnoea and/​or chest pain are the commonest presentations. Most (95%) patients have a pleural effusion at least sometime during their disease course. Constitutional symptoms, especially weight loss and lethargy, are common (c. 30%) at presentation and increasingly so as the cancer advances. Tumour fever can occur and is difficult to distinguish from infection. Involvement of other (mainly intrathoracic) struc- tures may result in pericardial effusion/​arrhythmia, dysphagia, Horner’s syndrome, spinal cord compression (Fig. 18.19.3.4) or su- perior vena cava obstruction. Distant metastases (e.g. cerebral in- volvement) are late events. The diagnosis of pleural mesothelioma usually arises from the in- vestigation of undiagnosed pleural effusion (see Chapter 18.17). Biomarkers for mesothelioma Much recent research has focused on discovering biomarkers for mesothelioma. Patients with mesothelioma have an ele- vated mesothelin level in their serum and pleural fluid when compared with patients with other pleural cancers or benign pleuritis. However, the sensitivity and specificity of mesothelin are insufficient to allow it as a standalone diagnostic test. In pa- tients with equivocal histocytologic results or who are unsuit- able for diagnostic interventions, an elevated mesothelin level may contribute to the clinical-​radiologic-​histologic diagnosis in a multidisciplinary tumour board setting. Elevated serum mesothelin can occur in occasional carcinomas, and in patients with renal failure. Conversely, sarcomatoid mesotheliomas rarely overexpress mesothelin. Other biomarkers (fibulin-​3, osteopontin, megakaryocyte potentiating factor, and so on) have shown promise but their roles as biomarkers have not been as thoroughly scrutinized as mesothelin. Prognosis The overall median survival for malignant pleural mesothelioma is about 9 months. Good performance status and epithelioid hist- ology are associated with better survival. Rarely isolated cases of long survivors (e.g. over 10 years) have been reported. There are several staging systems (e.g. International Mesothelioma Interest Group classification), and early-​stage disease (e.g. limited to parietal pleura) carries better prognosis. Disease response in research settings are usually monitored by the modified RECIST criteria. Total glycolytic volume measurements on PET and mesothelin levels before and after chemotherapy also have pre- dictive values on survival. Management Mesothelioma is incurable despite the use of surgery, chemotherapy, radiotherapy, or their combinations. Specific antifolate/​cisplatin chemotherapies are the only treatment to have shown survival bene- fits, albeit for about 12 weeks. Management should therefore aim to improve quality of life. The use of a multidisciplinary palliative care team experienced in mesothelioma is recommended, as the clinical course of mesothelioma differs from other solitary tumours. Patients often pursue legal claims for compensation, which can create additional stress. Pain control Most patients eventually experience pain and dyspnoea, and early use of opioids is required. Radiotherapy is effective for localized pain (e.g. from bone erosion) and needle tract metastases. Invasive pain control techniques with indwelling epidural catheters and spinal cordotomy are sometimes needed. Fig. 18.19.3.2  A patient with advanced right pleural mesothelioma: CT scan showed a thick rind of tumour encasing the lung (arrows), with resultant shrinking of the ipsilateral hemithorax. Fig. 18.19.3.3  Thoracoscopic view of pleural mesothelioma on the parietal pleural surface.

section 18  Respiratory disorders 4364 Pleural fluid control Recurrent effusions (and dyspnoea) are a key problem for most pa- tients with mesothelioma. In a series of 390 patients, 42% required further treatment to control fluid re-​accumulation. Pleurodesis (either as surgical approach or talc slurry) was effective in two-​ third of patients and avoid further pleural intervention. However, pleurodesis is not useful when tumour has encased the visceral pleura, preventing lung expansion (‘trapped lung’, Fig. 18.19.3.5) and prohibiting apposition of the pleural surfaces. An indwelling pleural catheter is an increasingly used alternative and allows domiciliary pleural fluid drainage (Fig. 18.19.3.6)—​see also under ‘Metastatic pleural malignancy’. Fig. 18.19.3.4  Spinal cord compression in mesothelioma. This 80-​year-​old patient with known malignant pleural mesothelioma presented with back pain, paraplegia, and urinary retention. (a) Magnetic resonance imaging of the spine shows tumour (short arrow) encasing the upper thoracic spinal cord resulting in severe canal stenosis and cord compression. (b) Malignant pleural disease is demonstrated by high signal intensity on the T2-​weighted image. Fig. 18.19.3.5  Trapped lung. This 60-​year-​old man with mesothelioma underwent insertion of an indwelling pleural catheter for management of his large symptomatic malignant pleural effusion (left panel). Trapped lung was suspected prior to effusion drainage because of the absence of mediastinal shift away from the side of the large effusion. The lung failed to fully expand after fluid evacuation (right panel). The presence of visceral pleural thickening further supports the diagnosis of a trapped lung.

18.19.3  Pleural tumours 4365 Chemotherapy Mesothelioma is relatively resistant to common chemotherapeutic agents and drug penetration to the pleura and underlying tissues is variable. Palliative chemotherapy using cisplatin with either pemetrexed or raltitrexed (antifolate agents) can im- prove symptoms and prolong median survival by 2.8 months in mesothelioma. Radiotherapy Radiotherapy has been tried with curative intent, but the disease area to be covered is too large and the resulting radiation toxicity (to the underlying heart, liver, and so on) unacceptable. Intensity-​ modulated radiotherapy is under investigation. Radiotherapy however has an established role in symptom palli- ation, with about 60 to 80% of patients experiencing improvement in specific tumour-​related complications, although it does not pro- long survival. Radiotherapy is often used in compression of the oesophagus, superior vena cava, and spinal cord, though clinical re- sponse is variable. Mesothelioma can invade sites of pleural procedures (Fig. 18.19.3.7), but the reported incidence varies among studies. Three (small) ran- domized studies on the use of prophylactic radiotherapy have shown conflicting results. Longitudinal series have revealed that the risks of needle track metastases are related to the size of the pleural pro- cedures (with needle aspiration the lowest and thoracotomy the highest). All efforts should be taken to minimize the number of pleural procedures in patients with possible mesothelioma to min- imize the frequency of unpleasant chest wall tumour invasion. A re- cent multicentred randomized trial did not find a role for routine prophylactic radiotherapy after large bore pleural interventions such as chest drain/thoracoscopy. Surgery and multimodality treatment Mesothelioma spreads along serosal surfaces and infiltrates under­ lying structures instead of growing as a discrete mass; hence com- plete surgical resection is not feasible. Fig. 18.19.3.6  An indwelling pleural catheter in a patient with recurrent pleural effusions. Fig. 18.19.3.7  Needle tract metastases in malignant pleural mesothelioma. This patient with mesothelioma developed a painful lump on the posterolateral chest wall (left panel, arrow) along the needle tract of a previous thoracentesis which was confirmed on CT imaging (right panel, arrow). The CT also revealed tumour involvement of the left hemidiaphragm and an indwelling pleural catheter in situ for management of his recurrent malignant pleural effusion.

section 18  Respiratory disorders 4366 Radical surgery to provide tumour cytoreduction has been at- tempted in combination with adjuvant radiotherapy and chemo- therapy. Extrapleural pneumonectomy (EPP) and pleurectomy with decortication (P/​D) are the two commonest approaches practised. EPP involves removal of the entire lung, parietal pleura, pericar- dium, diaphragm, and mediastinal lymph nodes. EPP carries sig- nificant mortality (5–​10% from surgery alone) and morbidity (>25% life-​threatening complications). A randomized clinical trial has now confirmed that patients who underwent EPP had a significantly shorter median survival than those who were randomized not to have EPP (14 vs. 19 months, respectively). Two studies have shown that EPP significantly impaired quality of life. P/​D is an alternative debulking procedure which does not involve pneumonectomy. It failed to show any survival benefit in a recent multicentre, randomized trial but increased postoperative compli- cation when compared with talc pleurodesis. Metastatic pleural malignancy Most cancers can spread to the pleura resulting in a pleural effusion and associated dyspnoea. Up to 30% of patients with lung and breast carcinomas (Fig. 18.19.3.8) and 10% of those with lymphoma will suffer from a malignant effusion. Ovarian and colon carcinomas as well as adenocarcinomas from unknown primary site also occur. Metastatic malignant disease may follow direct spread or haema- togenous embolization of tumour to the peripheral lung paren- chyma, followed by visceral pleural invasion. The parietal pleura is assumed to be secondarily affected by shedding of malignant cells from the visceral pleura, or from tumour migration via adhesions. Pleural involvement from direct cancer invasion (e.g. from breast cancer) or haematogenous spread can also occur. In lung cancer, the presence of malignant involvement of the pleura often denotes more advanced staging and prohibits curative surgery. The importance of pleural involvement in lung cancer has attracted strong interests. The latest TNM staging for non-​small cell lung cancer included a classification of visceral pleural inva- sion (VPI). VPI denotes poorer prognosis in lung cancer patients who undergo resection. Also, in c.5% of lung cancer patients under- going surgery, tumour cells can be detected if a pleural lavage is performed during the operation. A positive lavage predicts a higher risk of cancer recurrence and poorer prognosis (median survival 12 months, vs. 49 months for those with a negative lavage). Malignant effusions develop primarily as a result of increased vas- cular permeability and resulting plasma leakage. Reduced pleural fluid outflow, secondary to tumour blockage of parietal pleural stomata and/​or the downstream lymphatic drainage pathways, also contributes. Clinical features Dyspnoea results from altered respiratory mechanics when the pleural cavity expands to accommodate the extra (often litres) volume of fluid. The weight of large effusions often everts the diaphragm and may result in its paradoxical movements. Small malignant effusions can be asymptomatic. Underlying lung disease (e.g. lymphangitis, airway obstruction, comorbid chronic obstructive pulmonary dis- ease, or pulmonary embolus) and extrapulmonary causes (e.g. peri- cardial effusion or anaemia) often contributes to breathlessness and must not be overlooked. Pleuritic pain is common and implies malignant infiltration of the parietal pleura, as the visceral pleura is devoid of pain sensation. Diagnosis The diagnosis of malignant pleural metastases should be made by histological or cytological assessment of pleural fluid or pleural tissue samples (see Chapter 18.17). Clinical assessment, radiological appearances (e.g. on CT or PET) or tumour marker measurements cannot provide a definitive diagnosis. Imaging can, however, guide biopsy and improve yield. It is important to obtain a histocytological diagnosis of the type of malignancy (e.g. between mesothelioma and metastatic carcinoma): this alters treatment strategies and has prog- nostic implications. Management A tumour that has spread to the pleura is incurable in most cases. Surgery and radiotherapy are unable to eradicate pleural metastases. In patients whose primary tumour is highly responsive to chemo- therapy (e.g. lymphoma or small cell carcinoma), treatment may control the pleural effusion, but most cases of malignant effusion are not responsive to chemotherapy. Indications for pleurodesis If the patient is symptomatic from a malignant effusion, drainage is required and consideration should be given to attempts to pre- vent fluid re-​accumulation. The conventional strategy is to create pleurodesis—​the adherence of the parietal and visceral pleura—​ either surgically or by introducing a chemical agent. This can be achieved in about 70% of cases, although reported success rates vary markedly with the agents employed, clinical methods, and defin- itions of success. No clinical or biochemical markers reliably predict the outcome of pleurodesis in individual patients, but a low pleural Fig. 18.19.3.8  Thoracoscopy showing scattered tumour from metastatic breast carcinoma on the parietal pleural surface.

18.19.3  Pleural tumours 4367 fluid pH (<7.20) or glucose (<1 mmol/​litre) is associated with a lower pleurodesis success rate and shorter survivals. Many breathless patients with a malignant effusion do not gain significant benefit after pleural fluid drainage: pleurodesis should be considered only in those who do. The presence of a trapped lung is a relative contraindication to pleurodesis as poor apposition of the pleural surfaces will render pleurodesis ineffective. Pleurodesis should be reserved for patients with good short-​term prognosis (arbitrarily defined as expected survival >3 months) al- though predicting survival in individual patients is notoriously dif- ficult. The LENT score has been shown to help predict survival in malignant effusion patients: high pleural fluid LDH, poor ECOG performance status, high Neutrophil:Lymphocyte ratio in blood, and tumour types predict prognosis. There are no controlled studies that define the best timing of pleurodesis, with most physicians recommending the procedure when the patient has had one or more episode of fluid recurrence. An alternative approach is to attempt pleurodesis of large effusions when they first present, as the recurrence rate is high (>70%) and early pleurodesis, before trapped lung ensues, may be more suc- cessful. This strategy avoids some episodes of unpleasant dyspnoea as fluid recurs. Pleurodesis produces adherence of the pleural surfaces by pro- voking acute pleural injury, which results in pleural inflamma- tion. If the inflammatory process is sufficiently intense, chronic inflammation and fibrosis ensues, resulting in pleural adhesions and eventual obliteration of the pleural cavity (successful pleurodesis). This process is often painful, as the parietal pleura is heavily infil- trated by sensory nerves. It is probable that the more intense the induced pleural inflammation, the higher the likelihood of suc- cess, but at the expense of producing more pain and distress to the patient. Methods of pleurodesis Pleurodesis can be performed by various surgical means (e.g. abra- sion of the pleura or pleurectomy). A  thoracoscopic approach is preferred to thoracotomy. Alternatively, pleurodesis agents can be delivered intrapleurally via a chest tube when complete lung re-​expansion is confirmed on radiographs following drainage of effusions. The most commonly used agent worldwide is talc, followed by tetracycline/​doxycycline/​minocycline, and bleomycin, though other agents (e.g. iodopovidone, silver nitrate, and picibanil (OK432)) have also been employed. A meta-​analysis of 11 studies showed that talc is superior in efficacy to tetracycline and bleomycin. Talc can be delivered via a chest tube (as a slurry) or insuf- flated (as a poudrage) during thoracoscopy. Three published randomized trials have found no significant differences in their success rates. If a patient undergoes thoracoscopy for diagnostic purposes, talc poudrage can be performed at the same setting, otherwise pleurodesis can be performed by either talc slurry or poudrage, depending on availability, in patients with an estab- lished diagnosis. Pain is the most common side effect of pleurodesis, and narcotic analgesics and/​or conscious sedation (e.g. midazolam) should be used where possible. Rotation of the patient does not improve the success rates of pleurodesis. In animal studies, systemic cortico- steroids and heparin can significantly reduce effective pleurodesis by inhibiting pleural inflammation and the coagulation cascade re- spectively; their relevance in humans is unknown. Talc pleurodesis toxicity Talc can induce fever and pain, which usually subsides within 72 h. Systemic absorption of talc particles and embolization to distant organs have also been reported if preparations containing small talc particles (<10 µm) is used. Marked systemic and pul- monary inflammation with resultant hypoxaemia can occur, presumably from systemic absorption of small talc particles. Talc-​ related adult respiratory distress syndrome (ARDS) occurred in 6% of patients and caused the death of 2.3% in a study of 484 pa- tients. Talc-​related ARDS can occur with either talc poudrage or slurry, and with doses from 2 to 10 g, but no cases of the condition were observed in a study of over 550 patients in which a graded talc preparation (with median particle size >20 µm) was used—​ though even in this study patients had a higher oxygen require- ment after the pleurodesis. Recurrent pleural effusions For patients where pleurodesis fails, another attempt with a dif- ferent agent, implantation of an indwelling pleural catheter (IPC), pleuroperitoneal shunting, serial therapeutic thoracentesis, or a surgical pleurodesis are possible. Repeated thoracenteses combined with narcotics and oxygen are appropriate when a very short life expectancy (<2 weeks) is likely. A pleuroperitoneal shunt is contra- indicated in the presence of ascites. Indwelling pleural catheters IPCs are increasingly used for ambulatory drainage of recurrent (es- pecially malignant) pleural and peritoneal effusions, allowing patients to perform fluid drainage when symptoms arise (Fig. 18.19.3.6). Spontaneous pleurodesis can occur in up to 50% of patients (who do not have a trapped lung) over time. IPC is accepted as the preferred treatment in patients who failed pleurodesis or have a trapped lung. Increasingly, it is used as an alter- native to talc pleurodesis as the first choice of definitive therapy for recurrent effusions. A recent randomized trial suggested that IPC provides equally good improvement in quality of life and symptom- atic relief when compared with talc pleurodesis. IPC insertion can be performed on an outpatient basis and re- quires significantly shorter hospital stay than pleurodesis, as shown in two randomized studies. A pilot, nonrandomized study showed that patients treated with IPC spent significantly fewer days in hos- pital than those pleurodesed in their remaining lifespan. This obser- vation has recently been validated in a multicentred trial. It is important that patients fitted with an IPC be provided with sufficient aftercare. The adverse event rates associated with IPC use are low, as shown in large longitudinal series. Infection, often the major concern from clinicians, occurs in c.5% of patients and is gen- erally mild and easily controlled with antibiotics. Interestingly infec- tion (especially from Staphylococcus aureus) can induce pleurodesis in a significant proportion of patients, allowing removal of the IPC. Symptomatic loculation of the effusion can occur and may response at least in the short-​term to intrapleural fibrinolytics. Catheter tract metastases develop most commonly in mesothelioma patients and can be treated with radiotherapy without removing the IPC beforehand.

18.19.4 Mediastinal tumours and cysts 4368 Y.C. Ga

18.19.4 Mediastinal tumours and cysts 4368 Y.C. Gary Lee and Helen E. Davies

section 18  Respiratory disorders 4368 Future developments Current treatments for malignant pleural effusion are crude. Compounds such as iodine and silver nitrate have been used in some countries, as alternatives to talc, and have shown effectiveness with acceptable side effect profiles. The development of novel pleurodesis agents that induce fibrosis without pleural inflammation, for example, tumour growth factor-​β (TGFβ), may allow effective pleurodesis without the adverse events associated with talc use. IPC and pleurodesis are approaches with completely different pros and cons; trials are underway to combine both strategies. Instilling talc via IPC inserted has shown benefits in a randomized trial. Placement of IPC in the same setting of thoracoscopic talc poudrage has shown promise. Sclerosant-​ eluded IPC produced effective pleurodesis in animal studies. Direct inhibition of pleural fluid accumulation (via manipulation of vascular permeability mediators) may become possible, and will be preferable over interventional procedures of secondary preven- tion of fluid recurrence. Studies to date have mostly considered malignant effusions as a single disease entity. Work is underway to better phenotype pa- tients with malignant effusions to identify subgroups of patients who will benefit symptomatically from fluid drainage, and to tailor available therapies to patients with different underlying cancers, staging, effusion biology (e.g. rate of recurrence) and comorbidity. Patient-​reported outcome measures are increasingly adopted as key measures of treatment outcome instead of radiological determin- ation of fluid accumulation. Acknowledgements Prof Lee is a National Health & Medical Research Council (NHMRC) Career Development Fellow and receives research project grant funding from the NHMRC, New South Wales Dust Disease Board, Sir Charles Gairdner Research Advisory Committee, Westcare, and the Cancer Council of Western Australia. FURTHER READING Azzopardi M, et al. (2014). Current controversies in the management of malignant pleural effusions. Semin Respir Crit Care Med, 35, 723–​31. Bhatnagar R, et al. (2018). Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion. N Engl J Med, 378, 1313–22. Bott M, et al. (2011). The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet, 43, 668–​72. Boutin C, et  al. (1993). Thoracoscopy in pleural malignant meso- thelioma: a prospective study of 188 consecutive patients. Part 2: prognosis and staging. Cancer, 72, 394–​404. Brims FJ, Lee YC, Creaney J (2013). The continual search for ideal biomarkers for mesothelioma: the hurdles. J Thorac Dis, 5, 364–​6. Clive AO, et al. (2014). Predicting survival in malignant pleural ef- fusion: development and validation of the LENT prognostic score. Thorax, 69, 1098–​104. Davies HE, et al. (2012). Effect of an indwelling pleural catheter vs. chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA, 307, 2383–​9. Davies HE, Musk AW, Lee YC (2008). Prophylactic radiotherapy for pleural puncture sites in mesothelioma: the controversy continues. Curr Opin Pulm Med, 14, 326–​30. Dresler CM, et al. (2005). Phase III intergroup study of talc poudrage vs. talc slurry sclerosis for malignant pleural effusion. Chest, 127, 909–​15. Fysh ET, et al. (2012). Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion. Chest, 142, 394–​400. Fysh ET, et al. (2013). Clinical outcomes of indwelling pleural catheter-​ related pleural infections: an international multicenter study. Chest, 144, 1597–​602. Fysh ET, et al. (2015). Predictors of clinical use of pleurodesis and/​or indwelling pleural catheter therapy for malignant pleural effusion. Chest, 147, 1629–​34. Peto J, et al. (1999). The European mesothelioma epidemic. Br J Cancer, 79, 666–​72. Putnam JBJ, et  al. (2000). Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter. Ann Thorac Surg, 69, 369–​75. Rintoul RC, et  al. (2014). Efficacy and cost of video-​assisted thoracoscopic partial pleurectomy versus talc pleurodesis in pa- tients with malignant pleural mesothelioma (MesoVATS): an open-​ label, randomised, controlled trial. Lancet, 384, 1118–​27. Robinson BWS, et al. (2003). Mesothelin-​family proteins and diag- nosis of mesothelioma. Lancet, 362, 1612–​16. Robinson LA (2006). Solitary fibrous tumor of the pleura. Cancer Control, 13, 264–​9. Sugarbaker DJ, et al. (1999). Resection margins, extrapleural nodal status, and cell type determine postoperative long-​term survival in trimodality therapy of malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg, 117, 54–​65. Tapias LF, et al. (2015). Validation of a scoring system to predict recurrence of resected solitary fibrous tumors of the pleura. Chest, 147, 216–​23. Thomas R, et al. (2015). Physiology of breathlessness associated with pleural effusions. Curr Opin Pulm Med, 21, 338–​45. Treasure T, et al. (2011). Extra-​pleural pneumonectomy versus no extra-​ pleural pneumonectomy for patients with malignant pleural meso- thelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol, 12, 763–​72. Vogelzang NJ, et al. (2003). Phase III study of pemetrexed in combin- ation with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol, 21, 2636–​44. Zalcman G, et al. (2016). Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet, 387, 1405–14. 18.19.4  Mediastinal tumours and cysts Y.C. Gary Lee and Helen E. Davies ESSENTIALS Mediastinal masses are most conveniently categorized by their anatomical site in the anterior, middle, or posterior mediastinum.

18.19.4  Mediastinal tumours and cysts 4369 Most present as a radiographic abnormality alone, or in association with symptoms arising from compression of other mediastinal struc- tures. Systemic symptoms such as fever or weight loss are more likely with malignant tumours such as lymphomas or thymomas. Anterior mediastinal masses—​commonly caused by thymic tu- mours (including thymic lymphoma), germ cell tumours, and thy- roid masses. Thymomas are often benign, but they can be locally invasive and associated with para-​neoplastic phenomena such as myasthenia gravis (in 30%). Middle mediastinal masses—​most commonly caused by lymph node enlargement (e.g. secondary to carcinoma, lymphoma, sar- coidosis, tuberculosis, or histoplasmosis), bronchogenic carcinomas and cysts arising from mediastinal structures such as the pericar- dium, bronchi, or oesophagus. Giant follicular lymph node hyper- plasia (Castleman’s disease or angiofollicular lymphoid hyperplasia) is a rare condition; patients may present with symptoms secondary to compression of local structures or with constitutional features; frank malignant transformation may arise. Posterior mediastinal masses—​neurogenic tumours account for most; if benign they tend to be asymptomatic, while pressure effects are frequently seen with malignant tumours. Introduction and anatomy The mediastinum encompasses all the intrathoracic structures with the exclusion of the lungs and pleura. It encompasses the heart, great vessels, trachea, oesophagus, thymus, nerves, thoracic duct, and lymph nodes. The superior boundary is the thoracic inlet represented by a plane at the level of the first rib. The inferior boundary is the diaphragm. The mediastinum has traditionally been subdivided into several compartments: a superior and inferior compartment, with the latter being subdivided into anterior, middle, and posterior divisions. In fact there are no true anatomical boundaries and structures in the superior mediastinum are contiguous with those inferiorly, hence a more logical subdivision is simply into anterior, middle, and pos- terior compartments (Figs 18.19.4.1 and 18.19.4.2). Such a division helps to compartmentalize what is complex anatomy and give some guide to the most likely pathology occurring in any particular area. Detailed knowledge of normal mediastinal anatomy is a prerequisite to the interpretation of both normal and abnormal chest radiographs. It is not within the remit of this chapter to describe the anatomy in de- tail, but major structures can be identified on CT imaging. • Anterior mediastinum: This is bounded anteriorly by the sternum and posteriorly by the pericardium, aorta, and brachiocephalic vessels. It contains the remnant of the thymus gland, branches of the internal mammary artery, veins, and associated lymph nodes. • Middle mediastinum: This contains the heart and pericardium, as- cending aorta, and aortic arch, lower half of the superior vena cava with azygos vein tributary, inferior vena cava, brachiocephalic vessels, pulmonary arteries and veins, bifurcation of the trachea and major bronchi, bronchial lymph nodes, phrenic nerves, and the vagus nerve. • Posterior mediastinum: The area located behind the pericardium and in front of the vertebral bodies. It is bordered laterally by the mediastinal pleura. It contains structures in the paravertebral Fig. 18.19.4.1  Posteroanterior chest radiograph with diagrammatic overlay to illustrate normal mediastinal structures: (1) trachea, (2) right main bronchus, (3) left main bronchus, (4) left main pulmonary artery, (5) right upper lobe pulmonary vein, (6) right interlobular artery, (7) right lower and middle lobe vein, (8) aortic knuckle, (9) superior vena cava, (10) azygos vein. Anterior Middle (b) Posterior (a) Posterior Middle Anterosuperior Fig. 18.19.4.2  A schematic representation of the mediastinal compartments: (a) lateral projection showing division into
anterior (or anterosuperior), middle and posterior compartments; (b) cross-​sectional depiction.

section 18  Respiratory disorders 4370 gutter as well as the descending thoracic aorta, oesophagus, azygos, and hemiazygos veins, thoracic duct, lymph nodes, and autonomic nerves. Lymph nodes are present in all three compartments thereby knowledge of their anatomical relationships, together with sites of drainage, is important when interpreting radiographic medias- tinal enlargement. The most important group of visceral nodes lie in the middle mediastinum and are predominantly subcarinal and paratracheal. Bronchopulmonary and hilar nodes are numerous but not visible radiographically unless pathologically enlarged. Clinical investigation Radiological assessment Most mediastinal cysts and tumours are discovered incidentally following a chest radiograph. Occasionally there may be symp- toms such as cough, chest pain, or breathlessness, or features re- sultant from compression of the numerous surrounding mediastinal structures. CT imaging is the most appropriate subsequent investigation for any patient with a suspected mediastinal mass and frequently facili- tates accurate diagnosis. It allows localization, characterization, and definition of the relationship of the mass to adjacent structures. The presence of calcification, fluid attenuation, heterogeneity, and vascu- larity can also be ascertained. Radio-​labelled 18fluorodeoxyglucose-​positron emission tomog- raphy (18FDG-​PET) combined with CT scanning (PET-​CT) is in- creasingly used in the evaluation of mediastinal masses. It is a useful tool for predicting loco-​regional involvement of lung or thyroid ma- lignancies, and for detection of distant disease. False positives may result from inflammatory processes such as granulomatous disease. MRI is more sensitive in the assessment of spinal tumours and de- tection of neural or vascular invasion than CT and may be favoured in some patients due to the lower adherent radiation dose. Tissue sampling Fine needle aspiration sampling is of limited use in assessment of mediastinal abnormalities and histological confirmation is favoured. Anterior mediastinal lesions can be readily approached percutan- eously, and while aspiration of clear fluid will supplement the radio- logical suspicion of a cyst, cytological examination alone may be insufficient for a pathological diagnosis. Anterior mediastinotomy will allow open biopsy of such lesions. Endobronchial ultrasound-​guided transbronchial needle as- piration (EBUS-​TBNA) is increasingly used in the assessment of middle mediastinal lymph nodes. This technique has superseded conventional ‘blind’ transbronchial needle aspiration, affording image guided aspiration of subcarinal, pretracheal, paratracheal, and hilar nodes. Endoscopic ultrasound-​guided fine needle aspiration (EUS-​FNA) may be used to sample aorto-​pulmonary window (AP or subaortic), subcarinal, para-​oesophageal, and pulmonary ligament nodes. Mediastinoscopy is performed through an incision in the neck and allows inspection of structures surrounding the superior vena cava and trachea as far as the carina. It is particularly useful in obtaining lymph node biopsies prior to possible surgery for lung cancer, especially in areas inaccessible to EBUS-​TBNA. Bronchoscopy alone is of limited value when evaluating medias- tinal masses unless there is a suspicion of a concomitant bronchial neoplasm. Neural tumours arising in the posterior mediastinum usually require surgical resection and there is little to be gained by preceding this with fine needle aspiration. Clinical features It is not surprising that the diversity of anatomical structures in the mediastinum is reflected by an equally diverse range of neo- plastic, developmental, and inflammatory masses (Table 18.19.4.1). Table 18.19.4.1  Mediastinal masses Anterior compartment Thymus Thymoma Carcinoma Hyperplasia Cyst Lymphoma Ectopia Germ cell tumours Benign Malignant Thyroid Lipoma, lipomatosisa Middle compartment Lymphadenopathya Sarcoidosis Infection including tuberculosis Malignancy: metastatic, lymphoma Giant follicular lymph node hyperplasia (Castleman’s disease) Mediastinal cysts Pericardial cysts Bronchogenic cysts Posterior compartment Oesophageal Enteric cysts Oesophageal duplication Neurenteric cysts Leiomyoma Carcinoma Vascular abnormalitiesa Aneurysm Haemangioma Anomalous vessels Neural tumours Neurilemmoma or schwannoma Neurofibroma Malignant schwannoma Ganglioneuroma, ganglioneuroblastoma Neuroblastoma Phaeochromocytoma Ependymoma Bochdalek diaphragmatic hernia a May be present in more than one compartment.

18.19.4  Mediastinal tumours and cysts 4371 Although clinical symptoms and signs may give diagnostic clues, many mediastinal masses, particularly those that are benign, are asymptomatic and usually detected on routine chest radiography. Many studies have documented the relative frequency of different causes of primary mediastinal tumours and cysts, with neurogenic tumours and thymic tumours being the commonest (approximately 20% each), followed by lymphoma, reduplication cysts, germ cell tu- mours, and thyroid masses. Mediastinal masses in children are more likely to be malignant than in adults. Common symptoms are cough and chest pain, which arise as a consequence of distortion of the normal mediastinal anatomy. Non-​ specific constitutional symptoms such as fever or weight loss are more likely to occur with a malignant tumour (e.g. lymphoma or thymoma). Compression of vital structures can also result in specific symp- toms: tracheal or bronchial compression leads to breathlessness with stridor or wheeze; oesophageal narrowing results in dysphagia; su- perior vena caval compression produces the characteristic features of facial and periorbital oedema, chemosis, and distended veins; involvement of the recurrent laryngeal nerve results in hoarseness and a bovine cough (this usually results from a malignant tumour but can develop with a benign lesion such as aneurysm of the aortic arch); involvement of the sympathetic chain (also likely to be due to malignant infiltration) results in the characteristic features of Horner’s syndrome with enophthalmos, miosis, ptosis, and unilat- eral facial anhidrosis; compression of intercostal nerves may pro- duce neuralgia; and intraspinal extension of tumours may lead to long tract signs. Anterior mediastinal masses Thymus The normal thymus is located in the superior portion of the anterior mediastinum. Its main function is the production of T lymphocytes. Radiologically, the normal thymus can only be seen in childhood and regression occurs during adolescence. Enlargement of the thymus is the commonest single cause of an anterior mediastinal mass and may be due to the development of a thymoma, thymic carcinoma, thymic hyperplasia, or a thymic cyst. The thymus can also be the site of involvement by lymphoma, particularly Hodgkin’s disease. Thymomas These arise due to neoplastic epithelial proliferation of the thymus gland and can present at any age, peak incidence being in middle age (Fig. 18.19.4.3). They are often benign with no overt cellular atypia, but can rarely behave in a malignant fashion with invasion of adja- cent structures and the occurrence of distant metastases (invasive thymoma). Histologically, thymomas are classified into subtypes A, AB, B1, B2, and B3 according to the morphological appearance of the neo- plastic epithelial cells and relative epithelial cell: lymphocyte propor- tions. This classification correlates closely with the Masaoka staging system, modified by Koga et al., and predicts tumour behaviour: I: Completely encapsulated IIA: Microscopic transcapsular invasion IIB: Transcapsular infiltration into thymus or, mediastinal soft tissue; not breaching pleura or pericardium III: Macroscopic invasion of neighbouring organ IVA: Pleural or pericardial dissemination IVB: Distant metastases; lymphatic or haematogenous spread Localized symptoms of chest pain and cough are more common with malignant disease. Systemic symptoms may arise; myasthenia gravis affects approximately 30% of patients; other rare associations include red-​cell aplasia, hypogammaglobulinaemia, systemic lupus erythematosus, and polymyositis. Surgical resection is curative in most cases. Minimally invasive operative approaches without sternotomy are favoured whenever possible. Local invasion is less common, but often precludes com- plete removal and recurrence is the rule. In these patients, therapy is palliative, and consists of a combination of surgical debulking, radiotherapy, and chemotherapy. Long-​term follow up is advocated in all cases as delayed recurrence may occur. Thymic carcinoma Thymic carcinoma (or type C thymoma) is an aggressive malignancy of thymic epithelial cells exhibiting cellular atypia no longer specific to the thymus. There is a male preponderance. Patients commonly pre- sent with loco-​regional metastases (e.g. lymph node and pulmonary). Treatment is with surgical resection and adjuvant chemotherapy, but the overall prognosis is poor (5 year survival approximately 30%). Thymic hyperplasia Thymic enlargement may be ‘true’ or ‘follicular’. The former typ- ically arises in childhood, peaking in adolescence; retention of normal histological and architectural features is seen. Follicular thymic hyperplasia is characterized by the presence of lymphoid fol- licles in the thymus regardless of its size. It occurs in approximately two-​thirds of patients with myasthenia gravis. It is also known as lymphoid hyperplasia or autoimmune thymitis. Thymic cysts These are uncommon. They can be unilocular or multilocular and usually contain straw-​coloured fluid. Most patients are asymptom- atic, but since cystic change can occur in some thymomas and in Hodgkin’s disease, thorough cytological examination of the cyst’s contents and its wall is required to exclude malignant disease. Thymic lymphoma This is fairly common, particularly in patients with nodular scler- osing type Hodgkin’s disease. The presence of systemic symptoms and other mediastinal and/​or hilar nodes should alert the clinician to the possibility of lymphoma. Ectopic thymus Ectopic and accessory thymic tissue may occur anywhere along the path of embryonic thymic development as a result of failure of des- cent, sequestration, or involution. It is rare in adults, but may be in- cidentally detected in childhood. Histological examination reveals normal thymic tissue. Germ cell tumours Extragonadal germ cell tumours account for about 15% of all me- diastinal cysts and tumours, and approximately 5–​10% of all germ cell tumours are found in the mediastinum. Their exact aetiology is unknown, but they are thought to derive from abnormal migration

section 18  Respiratory disorders 4372 of primitive germinal cells or developing thymic cells exhibiting germ cell potential. Germ cell tumours may be malignant or benign (80%), the former being more common in childhood. Malignant tumours are more prevalent in men (approximately 9:1), typically in their third to fifth decades; benign tumours exhibit an equal sex differential. Elevation of serum tumour markers such as alpha-​fetoprotein (α-​FP) or β-​human chorionic gonadotrophin (β-​HCG) is present in most cases. Benign germ cell tumours These consist of a disorganized mixture of ectodermal, mesodermal, and endodermal tissues and may include skin, hair, cartilage, bone, epithelium, teeth, and neural tissue. Tumours include mature (be- nign) teratomas, teratodermoids, epidermoid cysts, and dermoid cysts. Mature teratomas account for up to 70% of mediastinal germ cell tumours, and CT appearances give a strong indication of this diagnosis. Surgical excision is the treatment of choice to minimize risk of expansion and exclude malignant change. Malignant germ cell tumours These are classically divided into seminomas and nonseminomatous germ cell tumours. Most nonseminomatous tumours are malig- nant teratomas; teratocarcinomas, choriocarcinomas, embryonal carcinomas, and yolk-​sac carcinomas are less common. Histological analysis often reveals a spectrum of malignant tissue; and mixed germ cell tumours are now recognized. Nonseminomatous germ cell tumours range from well differen- tiated to trophoblastic; in most patients elevated serum levels of β-​ human chorionic gonadotrophin (β-​hCG) and α-​fetoprotein (AFP) are seen, which can be used both diagnostically and to monitor treatment response. Seminomas tend to be nonsecretory. Both types of tumour are highly malignant and invade adjacent mediastinal structures. They are not curable by surgery, although this may be needed for diagnostic purpose and utilized as part of a multimodality treatment approach, particularly for non-​ seminomatous tumours, following adjuvant chemotherapy. Both types are responsive to cisplatin based chemotherapy; response rates are high, although cure rates are lower than for gonadal germ cell tumours. Radiotherapy may be used in the treatment of seminomas. Thyroid masses Retrosternal extension of an enlarged thyroid is one the commoner causes of a mass in the superior mediastinum. Women are more frequently affected. Most are benign multinodular goitres that arise in the neck and extend into the mediastinum through the thoracic inlet. They may contain cystic areas, sometimes with haemorrhage and areas of calcification. Radiographically, they have a sharply de- fined and often lobulated outline. While they rarely cause symp- toms, compression of the trachea at the thoracic inlet can result in respiratory distress and is an indication for surgical resection. Thyroid cancer may also involve the mediastinum, either by direct extension or by metastasizing to intrathoracic nodes. Lipoma, lipomatosis Lipomata are well-​circumscribed mesenchymal tumours originating from adipose tissue. Localized lipomata may arise throughout the mediastinum (more common anteriorly), or diffuse accumulations of unencapsulated adipose tissue (lipomatosis) be seen. Detection is frequently incidental, although symptoms may develop from their mass effect. The diagnosis is made radiologically, with homogeneous fat attenuation masses described. Middle mediastinal masses Lymphadenopathy Enlarged lymph nodes are not confined to the middle mediastinum, although this is the commonest site of intrathoracic lymphadenop- athy. Reactive changes occur in association with many pulmonary infections, but in most cases the nodes are not significantly enlarged and remain undetected on plain chest radiography. Gross lymph- adenopathy is a feature of carcinoma and lymphoma, with sarcoid- osis, tuberculosis, and histoplasmosis being other possibilities. Treatment depends on the underlying cause. Giant follicular lymph node hyperplasia (Castleman’s disease) This is a rare condition of unknown aetiology characterized by nonclonal lymph node hyperplasia. It may be classified by site: localized to a single lymph node (unicentric) or involving multiple nodes (multicentric); or histologically into the more common hya- line vascular type with lymphoid follicles and penetrating capil- laries, or a plasma cell type with sheets of mature plasma cells within interfollicular tissues surrounding germinal centres. Multicentric dis- ease may be associated with human herpes virus-​8 (HHV-​8) positivity. Fig. 18.19.4.3  An incidentally detected anterior mediastinal mass on the chest radiograph (panel (a)) of an asymptomatic 45-​year-​old woman. Computed tomography (b) axial and (c) coronal views were highly suggestive of a thymic tumour and surgical resection confirmed a type B1 thymoma.

18.19.4  Mediastinal tumours and cysts 4373 Unicentric Castleman’s disease is often detected incidentally, but patients with multicentric disease frequently develop systemic symp- toms with fever, anaemia, and weight loss. Hepatosplenomegaly may be evident, and an association with POEMS syndrome is rec- ognized (POEMS is an acronym for features of the syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin abnormalities). There are no diagnostic radiographic features (Fig. 18.19.4.4) and the diagnosis is usually made after surgical resection or biopsy. Single site Castleman’s disease is generally benign and surgical resection is curative. In patients with multicentric disease, progres- sive hyperplasia with generalized lymphadenopathy may develop as a consequence of malignant transformation. There is no standard treatment: corticosteroids, chemotherapy, and immunomodulation (e.g. anti-​IL-​6 monoclonal antibodies) may be considered. Antiviral agents may be given if HHV-​8 is detected. Mediastinal cysts Cysts within the mediastinum are a relatively common cause of a me- diastinal mass. They can arise in association with the pericardium, bronchi, gut, or thoracic duct. Most patients are asymptomatic. Pericardial cysts These develop embryologically in relationship to the pericar- dium, although direct communication with the pericardial sac is rare. Radiographically they appear as smooth, clearly demarcated densities, which can be mistaken for a pericardial fat pad or a hernia through the foramen of Morgagni. Aspiration reveals clear fluid. Surgical excision is not recommended. Bronchogenic cysts Bronchogenic cysts arise in association with the major airways and are thought to reflect ventral budding of the primitive foregut. They are lined by respiratory epithelium and may contain inspis- sated mucus. Symptoms are uncommon, but local pressure on the trachea or bronchi can result in cough or wheeze. Occasionally the cysts communicate with the trachea and trigger repeated infec- tions. Surgical excision is the treatment of choice, particularly if there are associated symptoms (Fig. 18.19.4.5). Fig. 18.19.4.4  Chest radiograph (a) and CT scan (b) showing a large middle mediastinal mass (arrows) which on histology showed features of Castleman’s disease. Fig. 18.19.4.5  Chest radiograph (a) and CT scan (b) showing a large mass in the mediastinum (arrows) due to a bronchogenic cyst that had been present for 20 years. It was removed when compression of the oesophagus resulted in dysphagia.

section 18  Respiratory disorders 4374 Posterior mediastinal masses Enteric cysts Enteric cysts (oesophageal duplication and neurenteric cysts) are rare. Oesophageal duplication cysts adhere to the oesophagus and arise from abnormal development of the dorsal foregut. They are typically lined by gastric or oesophageal mucosa, and may also be evident in the middle mediastinum. Neurenteric cysts arise from developmental areas where the dorsal foregut and notochord are in close proximity. They are classically lined by enteric and neural tissue and are commonly associated with vertebral anomalies. Both types may coexist with other gastro- intestinal malformations. Surgical resection is recommended and the prognosis good. Oesophageal tumours are commonly symptomatic prior to vis- ible radiographic change (Fig. 18.19.4.6). Vascular abnormalities Vascular anomalies are not limited to the posterior mediastinum (Fig. 18.19.4.7). However, aneurysms of the descending thoracic aorta can result in abnormal shadows in the posterior mediastinum. Contrast enhanced imaging will differentiate from other posterior mediastinal lesions. Neural tumours Tumours, particularly those found in the paravertebral gut- ters, are likely to be neural in origin. Benign tumours tend to be asymptomatic, while malignant tumours cause pressure effects. Occasionally, spinal cord compression results from direct exten- sion into the intravertebral foramen. Tumours arising from peripheral nerve cell sheaths include neurilemmoma (schwannoma) and neurofibroma, and also their malignant counterparts. Tumours of the autonomic chain include ganglioneuroma and neuroblastoma. A neurilemmoma is the commonest neural tumour arising in the mediastinum. These are most common in middle age, and most are asymptomatic. Neurilemmomas can extend into the intravertebral foramen, producing a dumb-​bell appearance, and may erode adjacent bone, hence CT scanning or MRI should be undertaken prior to surgical excision. Neurofibromata are also common. These may be solitary, with clinical and radiological features very similar to those of a neurilemmoma, or more generalized in neurofibromatosis. Surgical resection is recommended, partly because of the small risk of developing malignant neurosarcoma which carries a poor prognosis. Ganglioneuroma arise from the autonomic plexus and are usu- ally perispinal in position. Associated endocrine symptoms in- clude hypertension, flushing, sweating, and diarrhoea. These tumours are often very large before they become clinically ap- parent. Prognosis is good after surgical resection. Ganglioneuroblastoma and neuroblastoma represent the malignant end of the spectrum and predominantly arise in childhood. Neuroblastoma in particular are highly invasive, with metastatic spread and systemic symptoms common at the time of presentation. Surgical resection is preferred, with adjuvant chemotherapy and radiotherapy considered on an individual basis. Ependymomas rarely occur in the mediastinum and are thought to derive from paravertebral ependymal rests. They have a predilection for the posterior mediastinum. Bochdalek posterior diaphragmatic hernia Developmental diaphragmatic defects may result in congenital her- niation of gastrointestinal contents through the posterior part of Fig. 18.19.4.6  Following presentation with worsening dysphagia; a benign oesophageal leiomyoma was confirmed histologically following endoscopic biopsy.

18.19.4  Mediastinal tumours and cysts 4375 the diaphragm. These often present clinically in infancy, although may be incidentally detected in approximately 6% of adults. FURTHER READING Adkins RB, Maples MD, Ainsworth J (1994). Primary malignant me- diastinal tumours. Ann Thorac Surg, 38, 648–​59. Bower RJ, Kiesewetter WB (1977). Mediastinal masses in infants and children. Arch Surg, 112, 1003–​9. Duwe BV, et  al. (2005). Tumors of the mediastinum. Chest, 128, 2893–​909. Hejna M, Haberl I, Raderer M (1999). Non surgical management of malignant thymoma. Cancer, 85, 1871–​84. Jeung M-​Y, et al. (2002). Imaging cystic masses of the mediastinum. RadioGraphics, 22, S79–​S93. Kim D-​J, et al. (2005). Prognostic and clinical relevance of the World Health Organization scheme for the classification of thymic epithe- lial tumors. Chest, 127, 755–​61. Koga K, et al. (1994). A review of 79 thymomas: modification of sta- ging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int, 44, 359–67. Medford AR, et  al. (2010). Endobronchial ultrasound-​guided transbronchial needle aspiration (EBUS-​TBNA):  applications in chest disease. Respirology, 15, 71–​9. Moran CA, et al. (2012). Thymomas II: a clinicopathologic cor- relation of 250 cases with a proposed staging system with emphasis on pathologic assessment. Am J Clin Pathol, 137, 451–​61. Morrissey B, et al. (1993). Percutaneous needle biopsy of the medi- astinum: review of 94 procedures. Thorax, 48, 632–​7. Shields TW, Reynolds M (1988). Neurogenic tumours of the thorax. Surg Clin North Am, 68, 645–​68. Thomas CR Jnr, Wright CD, Loehrer PJ Snr (1999). Thymoma: state of the art. J Clin Oncol, 17, 2280–​9. Weissferdt A, et al. (2018). Thymoma: a clinicopathological correl- ation of 1470 cases. Hum Pathol, 73, 7–15. Fig. 18.19.4.7  Aneurysmal dilatation of the superior vena cava (a and b) resulting in incidentally detected radiographic abnormality (arrows).

SECTION 19 Rheumatological disorders Section editor: Richard A. Watts 19.1 Joints and connective tissue—​structure and function   4379 Thomas Pap, Adelheid Korb-​Pap, Christine Hartmann,
and Jessica Bertrand 19.2 Clinical presentation and diagnosis of rheumatological disorders   4386 Christopher Deighton and Fiona Pearce 19.3 Clinical investigation   4395 Michael Doherty and Peter C. Lanyon 19.4 Back pain and regional disorders   4406 Carlo Ammendolia and Danielle Southerst 19.5 Rheumatoid arthritis   4415 Kenneth F. Baker and John D. Isaacs 19.6 Spondyloarthritis and related conditions   4441 Jürgen Braun and Joachim Sieper 19.7 Infection and arthritis   4457 Graham Raftery and Muddassir Shaikh 19.8 Reactive arthritis   4464 Carmel B. Stober and Hill Gaston 19.9 Osteoarthritis   4470 Andrew J. Barr and Philip G. Conaghan 19.10 Crystal-​related arthropathies   4482 Edward Roddy and Michael Doherty 19.11 Autoimmune rheumatic disorders and vasculitides   4495 19.11.1 Introduction   4495 David A. Isenberg and Ian Giles 19.11.2 Systemic lupus erythematosus and
related disorders   4499 Anisur Rahman and David A. Isenberg 19.11.3 Systemic sclerosis (scleroderma)   4513 Christopher P. Denton and Carol M. Black 19.11.4 Sjögren’s syndrome   4532 Wan-​Fai Ng 19.11.5 Inflammatory myopathies   4537 Ingrid E. Lundberg, Hector Chinoy, and Robert Cooper 19.11.6 Large vessel vasculitis   4546 Raashid Luqmani and Cristina Ponte 19.11.7 ANCA-​associated vasculitis   4556 David Jayne 19.11.8 Polyarteritis nossdosa   4569 Loïc Guillevin 19.11.9 Small vessel vasculitis   4573 Richard A. Watts 19.11.10 Behçet’s syndrome   4579 Sebahattin Yurdakul, Izzet Fresko, and Hasan Yazici 19.11.11 Polymyalgia rheumatica   4584 Bhaskar Dasgupta and Eric L. Matteson 19.11.12 Kawasaki disease   4590 Brian W. McCrindle 19.12 Miscellaneous conditions presenting to
the rheumatologist   4598 Stuart Carter, Lisa Dunkley, and Ade Adebajo

18.3 Clinical investigation of respiratory disorde

18.3 Clinical investigation of respiratory disorders 3956

18.3.1 Respiratory function tests 3956 G.J. Gibson

18.3.1 Respiratory function tests 3956 G.J. Gibson

18.3 Clinical investigation
of respiratory disorders CONTENTS 18.3.1 Respiratory function tests  3956 G. J. Gibson 18.3.2 Thoracic imaging  3970 Susan J. Copley and David M. Hansell 18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy  3992 Pallav L. Shah 18.3.1  Respiratory function tests G. J. Gibson ESSENTIALS Respiratory function tests are used in diagnosis, assessment, and prognosis and in monitoring the effects of treatment of various re- spiratory conditions. Their use as a diagnostic tool is in recognizing patterns of abnormality which characterize particular types of disease; they are also used to quantify the severity of functional disturbance or to locate the likely anatomical site(s) of disease (airways, alveoli, or chest wall). The commonly applied tests are most conveniently classified as (1) tests of respiratory mechanics, (2) carbon monoxide uptake, (3) arterial blood gases and acid–​base balance, and (4) exercise. Tests of respiratory mechanics Spirometers record the volume of air that is displaced from the lungs in tidal breathing or with forced inspiratory and expira- tory manoeuvres. This allows measurement of the tidal volume, inspiratory capacity, forced expiratory volume in 1 s (FEV1), and vital capacity. Residual volume remains in the lungs after full ex- piration. Total lung capacity represents the volume of air in the lungs after full inspiration—​the sum of vital capacity and residual volume. Residual volume cannot be measured by spirometric methods: inert gas dilution and whole-​body plethysmography are the two main clinical methods used for the measurement of absolute lung volume. Forced expiratory tests are simple to perform, do not require com- plex equipment, and are relatively independent of the effort applied by the patient. The characteristic feature of diffuse airway obstruction is a slowing of the rate of expiration, so that the ratio of FEV1 to forced vital cap- acity (or FEV1 to vital capacity) is reduced, which defines an ‘ob- structive’ ventilatory defect. In the alternative ‘restrictive’ pattern of ventilatory function, total lung capacity is reduced and both FEV1 and vital capacity are reduced in approximate proportion. Measurement of FEV1 and vital capacity is not sensitive to local- ized narrowing of the central airway: airflow during forced expiration and inspiration should be examined as maximum flow–​volume curves if this is suspected. Measurements of respiratory muscle function are indicated in evaluation of patients with various neuromuscular diseases. Carbon monoxide uptake Carbon monoxide (CO) diffusing capacity (DLco) or transfer factor (TLco) is widely used as a simple test of the integrity of the alveolar capillary membrane and the overall gas-​exchanging function of the lungs. Arterial blood gases and acid–​base balance The primary measurements made by modern blood gas analysers are the arterial partial pressures of oxygen (Pao2) and carbon dioxide (Paco2), and hydrogen ion concentration [H+] or pH. A reduction in Pao2 can occur by various mechanisms, but in dis- ease the commonest is mismatching of alveolar ventilation (V’A) and perfusion (Q’). Respiratory failure is defined in terms of the arterial blood gas ten- sions as a reduction in Pao2 below 8 kPa (60 mm Hg) at sea level, either without (‘type I’) or with (‘type II’, ‘ventilatory failure’) CO2 retention. The ratio of Pao2/​FIo2 is widely used in the assessment of pa- tients with severe oxygenation problems:  in acute lung injury, a value greater than 300 (Pao2 in mm Hg, FIo2 as a fraction) indicates

18.3.1  Respiratory function tests 3957 relatively mild hypoxaemia, while a value of less than 100 represents very severe disturbance of gas exchange. Abnormal acid–​base disturbances are traditionally classified as one of four types:  respiratory acidosis and respiratory alkalosis—​ where the primary disturbance is reduced or increased CO2 excretion, respectively—​and metabolic acidosis and metabolic alkalosis—​where the primary disturbance is increased or decreased [H+], respectively. A mixed picture is frequently seen. The likely cause(s) of metabolic acidosis are usefully classified in terms of the ‘anion gap’, which is calculated simply by subtracting the concentrations of the most abundant anions in blood (chloride and bicarbonate) from the most abundant cations (sodium and potassium). Exercise Formal cardiopulmonary exercise testing usually involves controlled exercise on a bicycle ergometer or treadmill. The commonest in- dications are evaluation of breathlessness or exercise intolerance (particularly when breathlessness appears out of proportion to ab- normality demonstrated by other investigations), evaluating prog- nosis and monitoring of patients with congestive cardiac failure, and preoperative assessment for prediction of morbidity and mortality. Introduction Respiratory function tests are used in diagnosis, assessment, and prognosis and in monitoring the treatment of various respiratory conditions. In the diagnosis of specific diseases, respiratory function tests—​like functional tests of other organs—​inevitably have limita- tions. Their use as a diagnostic tool is usually in recognizing patterns of abnormality which characterize particular types of disease, as well as identifying the likely anatomical site(s) of disease (airways, alveoli, or chest wall). In addition, they are commonly used to quantify the severity of functional disturbance The commonly applied tests are most conveniently classified as: (1) tests of respiratory mechanics; (2) carbon monoxide uptake; (3) arterial blood gases and acid–​base balance; and (4) exercise. Measurements made during sleep are de- scribed elsewhere (see Chapter 18.5.2). Tests of respiratory mechanics Mechanics of breathing The volume of air in the lungs at the end of tidal expiration at rest (functional residual capacity—​FRC) represents the ‘neutral’ volume of the thorax, that is, the volume pertaining when the respiratory muscles are inactive (as also during anaesthesia with muscle par- alysis). Expansion of the lungs above FRC is achieved by contrac- tion of the inspiratory muscles (predominantly the diaphragm), while normal resting tidal expiration is essentially passive, with the driving force provided by elastic recoil of the lungs. The main ex- piratory muscles are those of the abdominal wall; their contraction increases abdominal pressure which is transmitted to the thorax. In health the expiratory muscles become active when ventilation is in- creased markedly, as on exercise, or during coughing when a high intrathoracic pressure aids the clearance of airway secretions. Measurements of ventilation Measurements of tidal breathing (tidal volume, respiratory fre- quency) are rarely made in the resting awake subject, other than recording respiratory rate as part of clinical examination. Measurement of ventilation is, however, of importance in patients receiving ventilatory support, during detailed exercise testing, and during sleep investigations. During exercise testing, ventilation is usually obtained by electrical integration of airflow measured at the mouth, but this approach is impracticable for prolonged monitoring (such as during sleep) and the application of a mouthpiece and nose clip may itself disturb the pattern of resting breathing. Less intrusive methods of varying complexity are available, based on measuring external movement of the chest wall (ribcage and abdomen). Most are at best semiquantitative. They include the traditional mercury/​ rubber tube stethograph (measuring chest circumference), mag- netometers (diameter), and the inductance plethysmograph (cross-​ sectional area). To obtain an estimate of ventilation, measurements of both ribcage and abdominal motion are required, together with an appropriate calibration procedure using a spirometer. The more complex technique of optoplethysmography, which is largely a re- search tool, uses several small reflectors on the chest and abdomen illuminated by infrared light, with the reflected signals captured and processed electronically to allow three-​dimensional reconstruction of dynamic chest wall volume, for example, during exercise testing. Elastic properties of the lungs and chest wall In principle the mechanical function of the respiratory system can be characterized by the compliance (‘stiffness’) of the lungs and chest wall and the resistance of the airway. In practice, however, neither lung compliance nor airway resistance is commonly measured dir- ectly in clinical testing. For measurement of lung compliance, the pressure required to distend the lungs can be obtained by recording oesophageal pressure, which equates to pleural pressure. In clinical investigation, the elastic properties of the lungs are usually inferred from measurements of lung volumes, because lungs which are un- usually stiff and poorly compliant (as in pulmonary fibrosis) are usu- ally shrunken and reduced in volume, while lungs with abnormally high compliance (as in emphysema) are easily distensible and are associated with increased total lung capacity. The traditional sub- divisions of lung volume are illustrated in Fig. 18.3.1.1 and typical changes seen in disease in Fig. 18.3.1.2. The elasticity of the total respiratory system (i.e. lungs and chest wall together) is sometimes measured in intubated patients re- ceiving positive pressure ventilation, with acute respiratory distress syndrome (ARDS), for example. Sophisticated ventilators allow pre- cise measurement and computation, and monitoring of respiratory mechanics in this way has been shown to improve prognosis by al- lowing optimal ventilation strategies to be devised. Airway and respiratory resistance Direct measurement of airway resistance requires estimation of the pressure difference along the airway, between the alveoli and mouth. The various techniques available for estimating alveolar pressure in- clude oesophageal pressure monitoring, body plethysmography, and transient interruption of airflow. The plethysmographic method can be combined with measurement of lung volumes (see next section, ‘Measurements of lung volume’.). It requires the subject to make gentle panting efforts both with and without an occlusion at the

section 18  Respiratory disorders 3958 mouth, while seated in a body plethysmograph. With the interrup- tion method, mouth pressure during transient occlusion is assumed to equal the alveolar pressure immediately prior to occlusion. The technique tends to underestimate airway resistance. It is used more often in paediatric than adult practice as it requires little cooperation from the subject. Airway resistance varies with lung volume, falling as volume in- creases due to an expanding effect of more negative pleural pres- sure and the increased tension in the lung tissue surrounding the intrapulmonary airways. Resistance (RAW) is often expressed as its reciprocal conductance (GAW), which in turn can be divided by the lung volume at which it is measured (specific airway conductance, SGAW) to allow for variations in volume. Resistance is dominated by the narrowest part of the airway, which in the healthy subject is the upper airway (trachea and larynx). Although more peripheral air- ways are smaller individually, the great increase in their number with sequential branching creates a much larger overall cross-​sectional area. Since chronic airway disease usually has its greatest impact on peripheral airways, plethysmographic measurements of airway re- sistance are not sensitive to the earlier stages of disease. An alternative and increasingly popular method for evaluating respiratory resistance is by forced oscillation. This involves super- imposition of a small oscillating pressure and airflow at the mouth during tidal breathing. The frequency of oscillation is varied and computerized analysis of the consequent pressure and flow signals allows calculation of respiratory resistance, which includes elements related to lung tissue and chest wall, as well as the airway. The tech- nique has the advantages of portability and simplicity of use, with little cooperation required from the subject. In clinical practice, however, airway function is most commonly assessed by tests based on forced expiration. Measurement of lung volume A spirometer records only the air which can be displaced from the lungs and not their absolute volume, because the unmeasured re- sidual volume (RV) remains in the lungs after full expiration. The maximum volume expired after a full inspiration (or inspired after a full expiration) is known as the vital capacity (VC). while the total lung capacity (TLC) represents the volume of air in the lungs after full inspiration—​the sum of VC and RV (Fig. 18.3.1.1). Two main clinical methods are used for measurement of absolute lung volume—​inert gas dilution and whole-​body plethysmography. Inert gas dilution The subject breathes a gas mixture containing an inert marker gas, usually helium, from a closed circuit. The helium equilibrates grad- ually with the gas in the lungs so that its concentration falls progres- sively and stabilizes once mixing is complete. In a healthy individual this occurs in 5–​10 min, but in patients with diffuse airway disease, such as asthma or chronic obstructive pulmonary disease, the test gas is distributed very unevenly, equilibration is much slower, the endpoint is less definite and, consequently, lung volume is likely to be underestimated. The lung volume which is measured is that in the lungs when the subject was connected to the circuit (usually FRC). After disconnection from the rebreathing circuit, the subject in- spires fully and the volume inspired (inspiratory capacity, IC) added to FRC gives TLC (Fig. 18.3.1.1). In patients with moderate or se- vere airway disease, uneven distribution of the inspired gas and poor mixing in the lungs result in underestimation of lung volumes. Whole-​body plethysmography The subject sits within a large airtight rigid chamber and makes gentle breathing efforts against a shutter, which closes the airway at the mouth. According to Boyle’s law (pressure × volume = a con- stant), as intrathoracic pressure falls during an inspiratory effort, the air in the lungs is rarefied and lung volume increases by a small amount. This, in turn, causes the pressure in the plethysmograph TLC IC FRC RV VC FEV1 VT 1s Fig. 18.3.1.1  Subdivisions of lung volume illustrated by spirometric recording of volume against time during tidal breathing for three breaths, followed by maximal inspiration and then maximal forced expiration, before returning to tidal breathing in a normal subject. FEV1, forced expiratory volume in 1 s; FRC, functional residual capacity; IC, inspiratory capacity; RV, residual volume; TLC, total lung capacity; VC, vital capacity; VT, tidal volume. Note that TLC = FRC + IC = VC + RV. Pulmonary fibrosis COPD Severe obesity Normal Respiratory muscle weakness 0 50 100 150 Volume % predicted TLC TLC FRC RV VC Fig. 18.3.1.2  Patterns of lung volumes in disease. Overall height of bars represents total lung capacity (TLC) as % predicted; shaded areas show relative sizes of residual volume (RV); horizontal solid line shows functional residual capacity (FRC); vital capacity (VC) is represented by open bars. Dotted lines refer to normal TLC, FRC, and RV.

18.3.1  Respiratory function tests 3959 to increase. The converse occurs during expiratory efforts and the thoracic gas volume can be calculated from the pressure changes re- corded. Total lung capacity and residual volume are then derived by full inspiration and expiration immediately on opening the shutter. This method measures the volume of any air spaces within or without the lungs that share pressure changes during breathing efforts, hence poorly ventilated areas of lung (or even those totally unventilated, such as a bulla) are included. Abnormalities of lung volumes An increase in TLC occurs in most patients with symptomatic dif- fuse airway obstruction. A large increase is characteristic of emphy- sema, but is not specific for this condition. Increases are also seen in asthma, even in relative remission. A pathological reduction in TLC occurs in several conditions (Table 18.3.1.1), not only lung diseases such as pulmonary fibrosis, but also extrapulmonary conditions af- fecting the pleura, thoracic skeleton, or respiratory muscles, condi- tions which—​along with severe obesity—​all potentially impede full lung expansion (Fig. 18.3.1.2). Patients with airway disease develop marked increases in RV and FRC, and the latter (or more strictly, the end expiratory lung volume) increases further on exercise, a phenomenon known as dynamic hy- perinflation. Although this is a useful adaptation for such patients as breathing over a higher tidal volume range allows ventilation to in- crease on exertion, maintaining higher lung volumes requires more work by the inspiratory muscles, and hyperinflation contributes sig- nificantly to the dyspnoea which such patients develop on exertion. The extent of dynamic hyperinflation can be assessed by monitoring inspiratory capacity during exercise and having the subject inspire periodically to full inflation and then return to tidal breathing. Tests of forced expiration Spirometry The strengths of forced expiratory tests include the simplicity of both the manoeuvre and equipment required, and also the relative inde- pendence of the measurements of the effort applied by the patient. Forced expiratory tests are, however, effort-​dependent to the extent that a preceding full inspiration is required, but during forced expir- ation the larger intrathoracic airways are subjected to dynamic com- pression by the surrounding pleural pressure. The net result is that, provided a modest expiratory effort is applied, increasing the effort merely compresses the airway further and produces no increase in flow. This effort independence is more marked as forced expiration proceeds, and is also more marked in patients with airway obstruc- tion than in healthy subjects. Maximum expiratory flow is more dependent on effort at higher than at lower lung volumes (i.e. closer to full inflation). As peak ex- piratory flow (PEF) is attained very rapidly at the start of forced ex- piration, this measurement is therefore more effort-​dependent than the forced expiratory volume in 1 s (FEV1), which effectively inte- grates flow over a large proportion of the expired volume. PEF is measurable with a simple peak flow meter and is often used at home by patients with asthma to monitor their characteristically varying respiratory function. The most commonly used index of mechanical function of the lungs is the 1 s forced expiratory volume (FEV1)—​the volume ex- pired forcefully in 1 s following complete inspiration (Fig. 18.3.1.1). This is usually obtained together with the forced vital capacity (FVC), the maximum volume expired during a forced expiration. In healthy subjects the FVC is effectively the same as VC, but in patients with airway disease the FVC is often appreciably less than the true (‘relaxed’) VC obtained if the subject is encouraged to expire com- pletely without excessive initial effort. The characteristic feature of diffuse airway obstruction is a slowing of the rate of expiration, so that the ratio of FEV1 to FVC (or FEV1 to VC) is reduced. This defines an ‘obstructive’ ventilatory defect. In the ‘restrictive’ pattern of ventilatory function, both FEV1 and FVC are typically reduced in approximate proportion but, strictly, a re- strictive defect implies that TLC is reduced and this cannot be diag- nosed confidently by spirometry alone. In patients with symptomatic diffuse airway obstruction the FVC and VC are usually reduced, but the reduction is proportion- ally less than that in FEV1. Although a reduced ratio of FEV1 to (F) VC indicates the presence of airway obstruction, it is a poor guide to severity, which is better assessed by comparing the FEV1 alone with its predicted value. An obstructive spirometric pattern is seen in asthma, chronic obstructive pulmonary disease, and widespread bronchiectasis, while a restrictive ventilatory pattern is seen in nu- merous conditions (Table 18.3.1.1). A further feature of diffuse airway obstruction is an increase in RV and in the ratio RV/​TLC, but the latter is less specific than a re- duced FEV1/​VC ratio as it also occurs in some patients with cardiac disease or respiratory muscle weakness. Combined obstructive (low FEV1/​VC) and restrictive (low TLC) defects may be seen if dual pathology is present. Sometimes TLC may be within the normal range due to opposing influences with, for example, lung fibrosis tending to reduce it and airway obstruc- tion to increase it. Maximum flow–​volume curves Measurement of FEV1 and FVC is the best way of identifying the diffuse airway narrowing of chronic obstructive pulmonary disease or asthma, but is less sensitive to localized narrowing of the central airway. If the latter is suspected, it is particularly helpful to visualize airflow obtained during forced expiration and forced inspiration in the form of maximum flow–​volume curves, which relate instantan- eous flow to volume expired and inspired (Fig. 18.3.1.3). The maximum expiratory flow–​volume curve has a characteristic shape, with an early peak that is equivalent to the PEF obtained with a peak flow meter. Maximum expiratory flow then declines progres- sively as volume is expired. In young healthy subjects (Fig. 18.3.1.3a), Table 18.3.1.1  Common causes of reduced total lung capacity Intrapulmonary Surgical resection of lobes/​lung Pulmonary collapse Consolidation Pulmonary oedema Interstitial fibrosis Extrapulmonary Pleural effusion Pleural thickening Pneumothorax Ribcage deformity (e.g. scoliosis) Respiratory muscle weakness Severe obesity

section 18  Respiratory disorders 3960 the descending limb of the curve approximates a straight line, while in older normal subjects (Fig. 18.3.1.3b), maximum expiratory flow is less, particularly at lower lung volumes, and the curve becomes concave to the volume axis. In patients with diffuse intrathoracic airway obstruction (such as chronic obstructive pulmonary disease or asthma) the pattern is qualitatively similar to that of ageing, but greatly exaggerated, with expiratory flow reduced more markedly as lung volume declines (Fig. 18.3.1.3d). The shape of the flow–​ volume curve does not distinguish between different causes of dif- fuse airway narrowing and so cannot allow the distinction of asthma from chronic obstructive pulmonary disease or emphysema. In prin- ciple, measurements of maximum expiratory flow in the latter part of forced expiration should be more sensitive to milder degrees of airway narrowing. In practice, however, indices such as maximum flow after 75% of the FVC has been expired (FEF75) have proved disappointing because the very wide normal range seriously reduces their discriminating power. Another widely used measurement is the average maximum flow over the middle two-​quarters of expir- ation (FEF25–​75, formerly known as maximum mid-​expiratory flow). Again, however, the value of this index is seriously compromised by its wide variation in the healthy population and also by its depend- ence on VC, such that reductions are seen with both obstructive and restrictive ventilatory defects. The maximum inspiratory flow–​volume curve has a more sym- metrical appearance than the expiratory curve. In patients with dif- fuse airway narrowing there is an overall reduction in maximum inspiratory flow, but little change in shape (Fig. 18.3.1.3d). In pa- tients with a restrictive ventilatory defect caused, for example, by pulmonary fibrosis, the volume displaced is reduced but absolute flows are little affected (Fig. 18.3.1.3c). Characteristic features are seen in patients with localized nar- rowing of the central airway, with the pattern depending on whether the narrowing is extra-​ or intrathoracic. Extrathoracic narrowing (Fig. 18.3.1.3e), such as occurs with subglottic tracheal stenosis or upper tracheal tumours, has a relatively greater effect on maximum inspiratory than expiratory flow (this corresponds to the predomin- antly inspiratory timing of the stridor of upper airway narrowing). Maximum expiratory flow is also affected, but unlike chronic ob- structive pulmonary disease or asthma, the effects are most marked at higher lung volumes, often producing a virtual ‘plateau’ of expira- tory flow in the first part of forced expiration. If the central airway is narrowed within the thorax (e.g. lower trachea or carina) a similar plateau of expiratory flow, often with a small initial peak, may be seen, but maximum inspiratory flow is relatively less affected (Fig. 18.3.1.3f). These differing patterns can be quantified in terms of various ratios, such as that of maximum expiratory to inspiratory flow at 50% of VC, or the ratio of PEF (markedly reduced with upper airway obstruction) to FEV1 (proportionally less reduced). Such derived in- dices should be interpreted in light of the overall shape of the curves. The ‘plateau’ of maximum expiratory flow seen with upper airway obstruction has implications for the shape of the forced expiratory spirogram (volume vs. time). On the spirogram, flow is represented by the gradient of the curve and therefore a plateau on the flow–​volume curve implies a ‘straight’ (rectilinear) appear- ance of the spirogram over the same volume range. Such an ap- pearance should therefore raise the possibility of a narrowing of the central airway, rather than the more common diffuse airway obstruction seen with asthma and chronic obstructive pulmonary disease (Fig. 18.3.1.4). Respiratory muscle function Forcible static inspiratory and expiratory efforts against a closed airway allow measurement of maximum expiratory and inspira- tory pressures (PE max, PI max). In general, the expiratory (pre- dominantly abdominal) muscles perform most effectively at high lung volumes and the inspiratory muscles (predominantly the diaphragm) at lower volumes. PE max is therefore usually meas- ured after full inspiration and PI max at FRC or RV. Unfortunately, the normal ranges for these tests are wide and some patients find difficulty in performing the manoeuvres, which are by definition completely effort-​dependent. Alternatively, inspiratory muscle strength can be assessed during a forceful sniff, with the pres- sure measured in the nose via an occluded nostril. Many (though not all) patients find this easier than performing maximum static ­inspiratory manoeuvres, so the maximal sniff technique may give more reproducible results. Many laboratories ask patients to per- form both maximum inspiratory tests and report the numerically greater result. These measurements all assess the global strength of the ­inspira­tory or expiratory muscles. More specific information on dia- phragmatic function requires measurement of transdiaphragmatic pressure using pressure-​sensing devices in both oesophagus and stomach—​a specialized investigation available in only a few centres. VImax (a) (b) (c) (d) (e) (f) Volume VEmax VImax VEmax Fig. 18.3.1.3  Schematic maximum expiratory and inspiratory flow–​ volume curves in: (a) normal young adult; (b) normal older adult; (c) patient with pulmonary fibrosis and reduced FVC; (d) patient with moderately severe chronic obstructive pulmonary disease showing overall reduction in maximal flow but particularly in V˙E max, at lower lung volumes; (e) patient with subglottic (extrathoracic) tracheal stenosis showing markedly reduced V˙I max at all volumes and reduced V˙E max at higher volumes; (f) patient with central intrathoracic (e.g. carinal) tracheal narrowing showing similar plateau of expiratory flow to (e) but greater reduction of V˙E max than of V˙I max.

18.3.1  Respiratory function tests 3961 A simple indirect index of disproportionate diaphragmatic weakness or paralysis is a large (>25%) reduction in VC in the supine compared with the erect posture. However, isolated bilateral diaphragmatic par- alysis or severe weakness is very uncommon, and most patients with respiratory muscle weakness have disease affecting all the muscles. Causes include not only primary neuromuscular diseases such as myopathies, muscular dystrophies, motor neuron disease, and my- asthenia gravis, but also drug treatment (corticosteroids), several endocrine and connective tissue disorders, and cachexia from what- ever cause. Respiratory muscle weakness is often an important factor preventing weaning from assisted ventilation. Respiratory muscle function in diagnosis Measurements of respiratory muscle function are indicated in the evaluation of patients with various neuromuscular diseases, condi- tions in which they have been shown to have important prognostic value. They are also helpful in confirming or excluding muscle problems in those with otherwise unexplained dyspnoea and in pa- tients with a restrictive ventilatory defect in whom the cause of the lung volume reduction is not apparent on clinical and radiographic grounds. Interpretation may be complicated in patients with airway obstruction (such as chronic obstructive pulmonary disease or asthma) because the associated hyperinflation of the lungs itself im- pairs inspiratory muscle function. Maximum expiratory pressure is not affected by hyperinflation, however, and can be used as a guide to the presence of true muscle weakness in this situation. Carbon monoxide uptake Carbon monoxide (CO) diffusing capacity (DLco) (also known as transfer factor, TLco) is widely used as a simple test of the integrity of the alveolar capillary membrane and the overall gas exchanging function of the lungs. It has good sensitivity but poor specificity, as impairment can result from several pathological processes (Table 18.3.1.2). In the commonest method, the subject inspires fully a gas mix- ture containing a very low concentration of CO and the rate of uptake of gas is measured during breath-​holding for 10 s. The most important determining factor in most conditions is the effective surface area of alveoli available for gas exchange. Consequently DLco is reduced, for example, after resection of the lung, but also with widespread emphysema, in which normal-​sized alveoli are replaced by much larger air spaces, with a consequently greatly diminished area. DLco is also reduced when there is loss of the ‘effective’ alveolar volume (VA) in which the test gas is distrib- uted (see next section on interpretation). Other factors affecting the DLco include the haemoglobin concentration and disease involving the pulmonary capillaries. The transfer coefficient (Kco), which is obtained along with DLco, represents the uptake of CO per litre of ‘effective’ alveolar volume, that is, Kco = DLco/​VA. The ‘effective’ alveolar volume is measured simultaneously by an inert gas (such as helium) in the inspired gas mixture. This represents the alveolar volume relevant to that inspir- ation (i.e. the volume with which the inspired gas equilibrates during the 10 s breath-​hold), hence if there is uneven ventilation, VA is less than the true alveolar volume (i.e. less than TLC). (a) Volume expired (litres) Time (seconds) 6 5 4 3 2 1 1 2 3 4 5 6 0 1 2 3 4 5 6 (b) Volume expired (litres) 6 5 4 3 2 1 0 Time (seconds) Fig. 18.3.1.4  Schematic spirograms of two patients with airway obstruction and similar FEV1. (a) Diffuse intrathoracic airway narrowing (chronic obstructive pulmonary disease or asthma). Note that forced expiration is continuing after 6 s. (b) Upper airway narrowing with ‘straight’ spirogram which corresponds to plateau of flow in earlier part
of expiration in Fig. 18.3.1.3e. Table 18.3.1.2  Common causes of reduced carbon monoxide diffusing capacity (transfer factor) Pulmonary diseases COPD/​emphysemaa Asthma (with severe airway obstruction) Pneumonectomy Pulmonary fibrosisa Sarcoidosis Pulmonary vascular diseasea Cardiac diseases Pulmonary oedemaa Mitral valve diseasea Congenital right-​to-​left shuntsa Systemic diseases Anaemiaa Renal failurea Hepatic cirrhosisa Rheumatoid disease Systemic sclerosisa Systemic lupusa COPD, chronic obstructive pulmonary disease. a Kco usually also reduced.

section 18  Respiratory disorders 3962 Kco is typically normal or increased after lung resection, when both DLco and VA are reduced. It is usually normal (or sometimes mildly increased) in asthma, where any reduction in DLco is due only to maldistribution of ventilation secondary to airway nar- rowing. By contrast, DLco is reduced in widespread emphysema not only due to maldistribution of inspired gas, but also because even in the relatively better ventilated parts of the lung the gas exchanging surface area is diminished, hence Kco is also reduced. Some of the diseases associated with low DLco and Kco are listed in Table 18.3.1.2. In some conditions Kco and, less commonly, DLco may be high (Table 18.3.1.3). Both increase with an increase in red blood cells in the lungs due to increased capillary blood volume, alveolar haemorrhage, or polycythaemia. Kco is also increased if, at full inflation, the density of pulmonary capillaries per unit alveolar volume is greater than normal. This occurs most commonly in patients with extrapulmonary volume restriction (e.g. muscle weakness), when the density of pulmonary capillaries is unusually high in relation to the (restricted) TLC at which the measurement is made. Interpretation of respiratory function tests Reference values The results of respiratory function tests should be compared with reference values obtained in an appropriate healthy popu- lation. The main factors determining the results of most tests in the normal population are sex, age, body size (usually de- fined by height), and ethnicity. Worldwide, more than 300 ref- erence equations for spirometric volumes have been published, but none is universally applicable. To date, the most commonly used in Europe have been summary equations published origin- ally in 1993. However, these take no account of ethnicity and it has been conventional for readings from nonwhite individuals to apply a proportional reduction to predicted values of spirometric and static lung volumes, most commonly multiplying by 0.88. Variation due to ethnicity is gradually being incorporated, for in- stance, in the third National Health and Nutrition Examination Survey (NHANES III) equations now recommended for use in North America, and in those derived by the ongoing Global Lung Function Initiative of the European Respiratory Society (see ‘Further reading’). Normal or abnormal? After standardizing for the variables mentioned in the previous section, most lung function measurements are distributed normally in the healthy population. Classification of ‘normal’ or ‘abnormal’ is best done in terms of the number of standardized residuals by which a given measurement deviates from the mean predicted value (z score). With this approach, a z score ranging from –​2 to + 2 would encompass 95% of a normally distributed population and –​1.645 to + 1.645 encompasses 90%. When evaluating spirometric results, the need is to identify a unidirectional abnormality (e.g. a low, ra- ther than high, FEV1). It is therefore conventional to regard z values outside the 90% confidence intervals as ‘abnormal’. Thus, a z value more negative than –​1.645 represents the lower fifth percentile of the normal range (i.e. only 1 in 20 of the healthy population would be expected to have a result below this value). The choice of this level is of course a compromise between sensitivity and specificity, and should not be regarded as an absolute ‘cut-​off’ which will accurately classify every individual. One contentious point of interpretation is the definition of a ‘normal’ ratio of FEV1 to FVC, which is important because airway obstruction is defined by this metric. A ratio less than 0.7 is com- monly used as the cut-​off that indicates airway obstruction. This has the advantage of simplicity, and it is used in some diagnostic criteria for identifying chronic obstructive pulmonary disease (COPD), but it ignores the normal age-​related decline of the ratio. Since many healthy elderly individuals have values less than 0.7, its use as a blanket cut-​off between ‘normal’ and ‘abnormal’ results in significant overdiagnosis of COPD in populations older than 60 years. Conversely, a value of FEV1/​FVC of 0.7 in a 25-​year-​old would be very abnormal, hence use of this arbitrary value also risks failure to recognize significant airway obstruction in young adults. The alternative, and preferred, approach is to use appropriate refer- ence data for the FEV1/​FVC ratio to define the limits of normality with which to compare the z score in the same manner as for other measurements. The test results should be examined for internal consistency and interpreted in the light of the clinical and radiographic information available. A  number of characteristic patterns of abnormality of spirometry, lung volumes, and CO diffusing capacity are recognized (Table 18.3.1.4). Arterial blood gases The primary measurements made by modern blood gas analysers are the arterial partial pressures of oxygen (Pao2) and carbon di- oxide (Paco2), and hydrogen ion concentration [H+] or pH. The alternative, commonly used, method of assessing oxygenation is by pulse oximetry, which estimates arterial oxygen saturation (Sao2). An oximeter has the advantage of allowing continuous monitoring, but it provides no information on Paco2. Easy to use transcutaneous electrodes for estimating Paco2 are becoming more widely available. Table 18.3.1.3  Conditions producing increased carbon monoxide diffusing capacity and/or Kco ↑ DLco ↑ Kco Asthma Sometimes + Pneumonectomy –​ + Extrapulmonary restriction   Pleural disease –​ +   Ribcage deformity –​ +   Respiratory muscle weakness –​ +   Obesity –​ + Left-​to right-​shunts + + Polycythaemia + + Lung haemorrhage +a +a a May be an increase from an initially reduced value (e.g. Goodpasture’s syndrome).

18.3.1  Respiratory function tests 3963 Haemoglobin–​oxygen dissociation curve The general relation between the oxygen partial pressure in blood and haemoglobin saturation is defined by the oxygen–​haemoglobin dissociation curve (Fig. 18.3.1.5). The position of the curve is in- fluenced by the prevailing pH, temperature, and Pco2, as well as by the concentration of 2,3-​diphosphoglycerate (2,3-​DPG) in red cells. Approximate values for normal arterial and resting mixed venous Po2 and saturation are shown in Fig. 18.3.1.5. One clinically useful ‘landmark’ is a saturation of 90% which, with a normally positioned curve, represents a Po2 of approximately 8 kPa (60 mm Hg). Also shown in Fig. 18.3.1.5 is the P50, that is, the Po2 at a saturation of 50%, which for normal adult haemoglobin is approximately 3.5 kPa (27 mm Hg). This is measured in vitro and used to characterize ab- normal haemoglobin molecules associated with increased (low P50) or decreased (high P50) affinity for oxygen. Ventilation–​perfusion mismatching A reduction in Pao2 can occur by various mechanisms (Table 18.3.1.5). In disease, the commonest is mismatching of alveolar ventilation (V’A) and perfusion (Q’). Even in healthy lungs, distribution of both ventilation and perfusion is uneven, due mainly to gravity. In dis- ease, these relatively small effects are outweighed by unevenly distributed pathological changes affecting the distribution of venti- lation or perfusion or both. Alveoli with greater than average V’A/​Q’
have higher than average local Po2 and lower Pco2 (i.e. closer to those of inspired air). Conversely, alveoli with lower than average V’A/​Q’ have lower Po2 and higher Pco2, that is, closer to the values in mixed venous (pulmonary arterial) blood. Within a single al- veolus, complete equilibration of local gas tensions usually occurs, but in different pulmonary capillaries the gas tensions reflect those of the alveoli which they subtend. For CO2 the effects of high V’A/​ Q’ and low V’A/​Q’ areas on the final arterial Pco2 approximately cancel out, so that the arterial Pco2 is close to the average value in all the capillaries draining the alveoli. With oxygen, however, blood draining alveoli with high V’A/​Q’ (and therefore relatively high local Po2) cannot compensate for the areas with low V’A/​Q’ (and low Po2). This arises mainly because of the shape of the oxygen dissoci- ation curve: the relatively flat upper part of the curve implies that increasing Po2 adds very little to oxygen saturation or concentration (content). Consequently, mixed pulmonary venous (and therefore systemic arterial) blood has an appreciably lower Po2 than would be found in mixed alveolar air. An approximate assessment of the overall effects of V’A/​Q’ mismatching on arterial oxygenation and Pao2 is given by cal- culation of the alveolar to arterial oxygen pressure gradient (P(A –​ a)o2 = PAo2 –​ Pao2). This requires estimation of the average alveolar Po2 (PAo2), which depends on the inspired Po2 (PIo2) and the average alveolar Pco2 (PAco2). For the reasons discussed earlier, alveolar and arterial Pco2 (unlike Po2) are virtually the same. The alveolar Po2 is given approximately by: PAO PIO PaCO 2 2 2 0 8

− / . (Equation 18.3.1.1). The PIo2 breathing room air at sea level (moistened and warmed to body temperature) is approximately 20 kPa (150 mm Hg). In normal young subjects the upper limit for P(A –​ a)o2 is about 2 kPa (15 mm Hg). This limit increases with age and in healthy subjects aged Table 18.3.1.4  Common patterns of abnormal lung volumes and carbon monoxide diffusing capacity Condition FEV1 VC FEV1/​VC RV TLC D L co K co COPD/​emphysema ↓↓ ↓ ↓ ↑↑ ↑ ↓↓ ↓ Asthma ↓↓ ↓ ↓ ↑↑ ↑ → → or ↑ Interstitial lung disease ↓ ↓ → → ↓ ↓↓ ↓ or → Extrapulmonary volume restriction ↓ ↓ → ↑ or → ↓ → ↑ Pulmonary vascular disease → → → → → ↓↓ ↓↓ Combined pathology (e.g. COPD + interstitial fibrosis) ↓↓ ↓ ↓ ↑ or → → or ↓ ↓↓ ↓↓ COPD, chronic obstructive pulmonary disease. →, normal; ↓, moderately reduced; ↓↓, markedly reduced. 100 100 (mm Hg) 0 25 25 5 10 (kPa) Po2 50 c v b a Saturation (%) 50 75 75 Fig. 18.3.1.5  Normal haemoglobin–​oxygen dissociation curve relating saturation to PO2. Point a represents normal arterial values (PO2 90 mm Hg, 12 kPa; SaO2 98%) and v¯ normal resting mixed venous values (Pv¯O2 40 mm Hg, 5.3 kPa; SaO2 75%). Also shown are the PO2 (approx. 60 mm Hg, 8 kPa) corresponding to 90% saturation (point b) and the P50 (point c), that is, PO2 corresponding to 50% saturation (approx. 27 mm Hg, 3.5 kPa). Table 18.3.1.5  Mechanisms of arterial hypoxaemia Mechanism Cause Low inspired Po2 Altitude (including air travel) Hypoventilation Neuromuscular diseases Drugs depressing ventilatory drive V’A/​Q’ mismatching All pulmonary diseases Anatomical shunt Intracardiac right-​to-​left shunt Pulmonary arteriovenous malformations Limitation of oxygen diffusion Pulmonary fibrosis (on exercise)

section 18  Respiratory disorders 3964 60–​70 years may be as high as 4.7 kPa (35 mm Hg). Unfortunately, interpretation of the P(A –​ a)o2 is complicated by the fact that its relation to the severity of V’A/​Q’ mismatching is not constant. For a given degree of V’A/​Q’ mismatching, the P(A –​ a)o2 increases as the alveolar Po2 increases. It therefore increases if the inspired oxygen is increased or if Paco2 falls (see Equation 18.3.1.1). Alternative indices which relate more predictably to the severity of V’A/​Q’ mismatching are the ratios of arterial to alveolar Po2
(a/​A Po2), and of arterial Po2 to the inspired oxygen fractional con- centration (Pao2/​FIo2). The former is normally greater than 0.75 and changes little as FIo2 increases, whereas the more traditional P(A –​ a)o2 difference increases. The ratio of Pao2/​FIo2 is widely used in assessment of patients with severe problems of oxygen- ation. For example, in acute lung injury a value greater than 300 (Pao2 in mm Hg, FIo2 as a fraction) indicates relatively mild hyp- oxaemia, while a value of less than 100 represents very severe dis- turbance of gas exchange. Estimation of ‘anatomical’ shunt The dependence of P(A –​ a)o2 on inspired oxygen is exemplified by the effects of breathing pure oxygen. This is sometimes used as a test for the presence of anatomical right-​to-​left shunting, since the effects of V’A/​Q’ mismatching on Pao2 are effectively eliminated by breathing pure oxygen: even in diseased lungs, nitrogen is gradually ‘washed out’ of all the alveoli and the only remaining cause of arterial hypoxaemia is the anatomical shunt via channels which bypass the lungs, or through the capillaries supplying any alveoli that are to- tally unventilated. Although prolonged breathing of 100% oxygen encourages alveolar atelectasis which would exaggerate the shunt, in practice the technique is often helpful in investigating the causes of hypoxaemia. The usually quoted normal upper limit for the ‘ana- tomical’ shunt measured in this way is 5% of the cardiac output. In terms of the Pao2, a value greater than 500 mm Hg (>73 kPa) is usu- ally achieved. Respiratory failure Respiratory failure is defined in terms of the arterial blood gas tensions as a reduction in Pao2 below 8 kPa (60 mm Hg) at sea level, either without (‘type I’) or with (‘type II’) CO2 retention. Hypercapnic (type II) respiratory failure is also known as venti- latory failure. The causes of type I respiratory failure are legion and include virtually all diseases which can affect the alveoli or the airways, either primarily or secondarily (e.g. cardiac failure). Hypercapnic (type II) respiratory failure is most commonly due to severe chronic airway disease. Less often it results from reduced ventilation as, for example, with severe respiratory muscle weak- ness or scoliosis. The mechanisms of elevation of Paco2 in type II respiratory failure are twofold. Sustained ‘pure’ hypoventilation—​ reduction in overall ventilation resulting in hypercapnia—​is rare. It is seen with inadequate performance of the respiratory ‘bel- lows’ (e.g. in neuromuscular disease, or because of reduced drive to breathe in the unconscious subject). Much more commonly, as in chronic airway disease, the ‘effective’ alveolar ventilation is re- duced as a consequence of mismatching of ventilation and per- fusion. In this situation, there is often a considerable amount of ineffectual or wasted ventilation (‘physiological dead space’) and consequently in such patients the total ventilation is often greater than normal, even in the presence of hypercapnia. Acid–​base balance The carriage of CO2 by the blood and its excretion by the lungs to- gether constitute one of the two homeostatic mechanisms for regu- lating the acid–​base status of the body. Owing to the ease with which CO2 excretion can normally be increased, the lungs are able to adjust acid–​base balance much more rapidly than the kidneys. The carbonic acid association/​dissociation equation is: CO H O H CO H HCO 2 2 2 3 3 + ⇔ ⇔ + + − (Equation 18.3.1.2). This defines the chemical relation between the three variables, Pco2, hydrogen ion concentration [H+], and bicarbonate concentra- tion [HCO3–​]. If two are measured, the third is readily calculated. Hydrogen ion concentration is usually expressed as pH, its nega- tive logarithm to the base 10. This has the dubious advantage of expressing a very small numerical value as a more easily accessible number, but the pH scale is deceptive as it obscures the fact that the hydrogen ion concentration in blood and the changes seen in disease are exquisitely small in comparison to other commonly measured ions. Thus, a normal arterial pH of 7.4 represents [H+] of 40 × 10–​9 mol/​litre (i.e. approximately 1 millionth the concentration of other ions, which are usually expressed in units of 10–​3 mol/​ litre). Doubling [H+] to 80 × 10–​9 mol/​litre or halving it to 20 × 10–​9 mol/​litre are equivalent to reducing pH to 7.1 or increasing it to 7.7, respectively (since the log10 of 2 is c.0.3, and pH is the negative log10 of [H+], 0.3 is simply subtracted from, or added to, the normal value of 7.4 if [H+] is multiplied or divided by 2). Abnormal acid–​base disturbances are traditionally classified in terms of these variables as four types (Table 18.3.1.6 and Fig. 18.3.1.6), but combined disturbances are frequently seen. The more common causes of each are given in Table 18.3.1.7. Respiratory acidosis and alkalosis In respiratory acidosis the prime event is accumulation of CO2 due to inadequate or ineffective ventilation. This causes the equilibrium of Equation 18.3.1.2 to shift to the right, generating hydrogen and bicarbonate ions. An immediate increase in bicarbonate concentra- tion is dictated by this chemical relationship and not by the physio- logical response, which occurs subsequently. The vast majority of hydrogen ions produced are buffered by proteins and the increase in [HCO3–​] (measured in 10–​3 mol/​litre) is actually very much greater than the measured increase in hydrogen ion concentration (10–​9 mol/​litre). Conventionally the effects of acute respiratory acid- osis are distinguished from those of chronic respiratory acidosis, Table 18.3.1.6  Types of acid–​base disturbance Arterial [H+] pH Paco2 [HCO3 –​] Respiratory acidosis:   Acute ↑↑ ↓↓ ↑ ↑   Chronic ↑ ↓ ↑ ↑↑ Respiratory alkalosis ↓ ↑ ↓ ↓ Metabolic acidosis ↑ ↓ ↓ ↓ Metabolic alkalosis ↓ ↑ ↑ or → ↑ →, normal; ↓, moderately reduced; ↓↓, markedly reduced; ↑, moderately increased; ↑↑, markedly increased.

18.3.1  Respiratory function tests 3965 which results after several hours or days. This follows renal retention of even more bicarbonate, which in turn tends to correct the pH towards normal (Table 18.3.1.6). In respiratory alkalosis, the primary event is increased CO2 ex- cretion resulting from hyperventilation, so that both [HCO3–​] and [H+] fall (pH rises), but, again, most of the change in [H+] is buffered. Metabolic acidosis and alkalosis In metabolic acidosis [H+] rises (pH falls) and [HCO3–​] falls. The physiological response (hyperventilation) is so rapid that acute and chronic phases are not distinguishable. Any tendency for Paco2 to rise (equilibrium of Equation 18.3.1.2 shifted to the left) is more than offset by the increased drive to breathe resulting from production of acid, and the measured effect is a reduction in Paco2. The likely cause(s) of metabolic acidosis are usefully classified in terms of the ‘anion gap’, which is calculated simply by subtracting the concentrations of the most abundant anions in blood (chloride and bicarbonate) from the most abundant cations (sodium and po- tassium). The difference represents other anions (mostly protein and inorganic phosphate) normally present in blood. An increase above the normal anion gap therefore implies an excess of other anions as- sociated with metabolic acidosis (e.g. lactate, ketoacids). In metabolic alkalosis there is an increase in [HCO3–​] and a re- duction in [H+] (pH increases). The measured result is somewhat variable due to opposing influences: any increase in Paco2 tends to stimulate breathing, but the reduced acidity tends to inhibit it. In subjects with healthy lungs, the net effect is often maintenance of Paco2 in the high normal range, unless the alkalosis is profound (e.g. as seen with vomiting due to pyloric stenosis and severe deple- tion of acid). However, in patients with chronic airway disease and pre-​existing or incipient hypercapnia, an increase in Paco2 occurs more readily. This is particularly relevant to patients with chronic obstructive pulmonary disease receiving treatment with diuretics and corticosteroids, both of which tend to produce a metabolic alkalosis. Other acid–​base indices Several other indices of acid–​base status have their advocates. Standard bicarbonate, base excess and deficit, and total buffer base are often derived when blood gases are measured by automated equipment. They are obtained by titration of the blood in vitro to specified standard values of pH and/​or Pco2. Indices such as standard bicarbonate and base excess are used mainly to distin- guish ‘respiratory’ and ‘metabolic’ components of an acid–​base dis- turbance, but in this context the ‘metabolic’ component comprises not only a primary metabolic disturbance, but also renal compen- sation for a primary respiratory disturbance. Consequently, in a Fig. 18.3.1.6  Relations of pH and [H+] to PCO2 in acid–​base disorders. Bands indicate the expected ranges in uncomplicated respiratory (acute and chronic) and metabolic disorders. Isopleths represent corresponding estimates of arterial [HCO3 –​] (× 10–​3 mol/​litre). Values outside these bands indicate intermediate or combined disturbances. For example: patient a with an acute exacerbation of chronic obstructive pulmonary disease has an ‘acute-​on-​chronic’ respiratory acidosis (PaCO2 10.6 kPa, pH 7.24, [H+] 58 × 10–​9 mol/​litre, [HCO3 – ​] 34 × 10–​3 mol/​litre); patient b with both respiratory and circulatory failure has a combined respiratory and metabolic acidosis (PaCO2 8 kPa, pH 7.04, [H+]
95 × 10–​9 mol/​litre [HCO3 –​] 15 × 10–​3 mol/​litre). Table 18.3.1.7  More common causes of acid–​base disturbance Disturbance and site
of disease Cause Respiratory acidosis Cerebral Drugs (sedatives, hypnotics, anaesthetics) Raised intracranial pressure Primary alveolar hypoventilation (very rare) Spinal cord Trauma Motor neurons Motor neuron disease, poliomyelitis Peripheral nerves Guillain–​Barré syndrome Motor endplate Myasthenia gravis, neuromuscular blocking agents Respiratory muscles Myopathies, dystrophies Ribcage Scoliosis, trauma, thoracoplasty Lung parenchyma ARDS, pulmonary oedema (severe), interstitial fibrosis (very advanced) Airways COPD, asthma (severe), upper airway obstruction (very severe) Respiratory alkalosis Cerebral Anxiety, central neurogenic hyperventilation (very rare), drugs (aspirin) Pulmonary Pulmonary fibrosis, pneumonia, pulmonary embolism, asthma, pulmonary oedema Iatrogenic Mechanical overventilation Metabolic acidosis Increased anion gap Ketoacidosis, uraemia, lactic acidosis, drugs (aspirin), poisons (ethylene glycol) Normal anion gap Renal tubular acidosis, severe diarrhoea Metabolic alkalosis Severe vomiting Pyloric stenosis Iatrogenic Diuretics, corticosteroids, bicarbonate infusion ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease.

section 18  Respiratory disorders 3966 respiratory acidosis, an increased standard bicarbonate indicates a degree of chronicity. Conversely, the severity of acidaemia in a hypercapnic patient is a useful practical index of the ‘acute’ com- ponent of an acute-​on-​chronic respiratory acidosis and is widely used, for example, when deciding on the need for noninvasive ventilation. Another simple and frequently available index of acid–​base status is the venous ‘bicarbonate’ concentration (strictly total CO2 con- tent), which is often obtained routinely when electrolytes are meas- ured. A raised value is seen with primary metabolic alkalosis, but in patients with respiratory disease it may also be a useful clue to unsuspected ventilatory failure. ‘Strong ion’ approach The analysis of acid–​base balance presented in the previous section is oversimplified. A more comprehensive (but more complex) ap- proach based on the principles of physical chemistry was proposed by Stewart and subsequently developed by others. This focuses on the factors that independently determine [H+], reducing the emphasis on [HCO3–​], as both are regarded as dependent variables. According to this analysis, there are three independent variables controlling acid–​base balance: the Pco2; the ‘strong ion difference’ (SID); and the total weak acid concentration (a weak acid is one which is partly dissociated rather than completely ionized). SID is the difference be- tween the charge of the strong (completely dissociated) cations and anions in plasma and is determined largely by [Na+] + [K+] –​ [Cl–​]. A higher value of SID reduces acidity (higher pH). The weak acids in blood are predominantly proteins, particularly albumin, with a small contribution from inorganic phosphate. This approach defines six rather than four primary acid–​base dis- orders. Respiratory disturbances remain as before, but metabolic acidosis and alkalosis can each be either of two types, resulting from increases or decreases either in SID or total weak acid concentration. Decreasing SID or increasing [weak acid] produces acidosis, while increasing SID or decreasing [weak acid] produces alkalosis. In practice, the strong ion approach is of most value in under- standing complex metabolic disturbances, as commonly occur in patients receiving intensive care. In particular it highlights the important role of albumin concentration: since albumin is a weak acid, a reduction in its concentration has an alkalinizing effect, such that a metabolic acidosis resulting from a reduction in SID may be underestimated or concealed in patients with hypoalbuminaemia. Again, it is well recognized that infusion of large volumes of normal saline can result in an acidosis; in terms of the strong ion theory, this is readily explicable as due to a reduction in plasma SID as plasma [Cl–​] increases proportionally more than [Na+]. An important de- terminant of SID is renal function, in particular the regulatory ef- fect of the kidneys on plasma chloride concentration. Thus, in ‘renal compensation’ for a respiratory acidosis, the strong ion approach emphasizes increased excretion of chloride (rather than retention of bicarbonate); this increases plasma SID and therefore reduces acidaemia. Exercise testing The increased supply of oxygen to, and removal of carbon dioxide from, exercising muscles depends on the coordinated responses of the cardiovascular and respiratory systems. The efficiency of this process requires the integration of several factors, with the respiratory muscles, lungs, chest wall, pulmonary circulation, heart, systemic circulation, blood and limb muscles all contrib- uting. Functional defects in any one (or more) of these are likely to impair overall efficiency and limit the exercise ability of the individual. Normal physiological responses to exercise Metabolic response In healthy individuals, muscle metabolism during moderate ex- ercise generates ATP mainly via aerobic pathways, but with more strenuous exercise the delivery of oxygen to the muscles is insuf- ficient to support completely aerobic metabolism, and anaerobic metabolism—​which produces CO2 without consuming oxygen—​is increasingly important and results in the production of lactic acid. During aerobic exercise, the respiratory quotient (RQ, i.e. the ratio of CO2 produced to oxygen consumed) in the muscles varies from 0.7 to 1.0 (averaging about 0.9), depending on the substrate(s) util- ized. This value increases as anaerobic metabolism increases. The ratio of CO2 production (V’CO2) to oxygen consumption (V’O2) measured at the mouth is termed the respiratory exchange ratio (R). R and RQ are identical in a completely steady state, but under the conditions of most exercise tests, their values are likely to differ to some extent. The ‘anaerobic threshold’ (AT) is defined as the level of V’O2 at which the onset of anaerobic metabolism is detected. However, anaerobic metabolism does not ‘switch on’ abruptly, but increases gradually as exercise becomes more strenuous. The true maximum oxygen uptake is measured only once a plateau value is reached despite further increases in workload, a situation achieved only in very fit healthy individuals. Although in progres- sive exercise it is more correct to use the terms ‘symptom-​limited V’O2 max’ or ‘peak V’O2 max’, the term ‘V’O2 max’ is used here be- cause of its common use in clinical testing. Ventilatory response During progressive exercise, both ventilation (V’E) and V’CO2 in- crease with V’O2, initially in linear fashion, but—​at higher levels of exercise as anaerobic respiration increases—​the lactic acid gen- erated stimulates ventilation further. Consequently, both V’E and V’CO2 increase disproportionately to V’O2 (Figs. 18.3.1.7, 18.3.1.8a), though the relation of V’E to V’CO2 is close to a straight line. The increasing ventilation during progressive exercise results from increases in both tidal volume and breathing frequency, with the former dominating at lower levels of exercise until it approaches a plateau level (determined by respiratory mechanics), after which further increases are achieved by increasing frequency alone. Cardiovascular response Cardiac output also increases progressively on exercise in relation to V’O2, but the relationship is slightly curvilinear, with a diminishing rate of increase at higher workloads. During mild exercise, increases in stroke volume and heart rate both contribute. Stroke volume, however, approaches a maximum at a relatively low level of exercise, and subsequent increases in cardiac output depend on a more rapid heart rate. The increased stroke volume is due partly to an increase in venous return and partly to a larger ejection fraction. The oxygen

18.3.1  Respiratory function tests 3967 provided to the exercising muscles increases relatively more than the cardiac output because they extract a greater proportion of the oxygen in arterial blood than at rest. The ‘oxygen pulse’, defined as the V’O2 divided by the heart rate, represents the volume of oxygen extracted by the metabolizing tissues per beat, and is sometimes used as an indirect estimate of stroke volume An abnormally high slope of the relationship between heart rate and V’O2 usually implies a small stroke volume. Limits to progressive exercise Maximum heart rate (beats/​min) declines with age and is commonly predicted using one of two simple equations, either: 220 −age in years or 210 0 65 − × ( ) age in years . . Each gives similar values for subjects under the age of 40 years, but the second tends to be more accurate in older healthy individuals. For predicting maximum ventilation, the equation for predicting maximum voluntary ventilation (MVV) from FEV1 is often used: MVV FEV l min

× 1 35 / . In general, in healthy individuals the maximum oxygen uptake on exercise is determined by the capacity of the circulation to supply oxygen to the exercising muscles, rather than by the ventilatory system. At the breaking point of a progressive exercise test, healthy individuals approach their predicted maximum heart rate, while they usually reach only 50–​75% of their ventilatory capacity so that, normally, there is an appreciable ‘ventilatory reserve’. In most pa- tients with lung disease, the maximum attainable ventilation is reduced and this determines their exercise capacity. However, in patients with moderate or severe airway obstruction (e.g. COPD) the maximum exercise ventilation may exceed that predicted from FEV1 and a more realistic maximum is predicted approximately by the formula: Maximum exercise ventilation 20 min

× + [ ] / . FEV l 1 20 Values of maximum ventilation and maximum heart rate during progressive exercise are often used as guides to the main factor(s) limiting exercise and in directing attention to disease of the respira- tory or circulatory systems as the likely main cause of breathlessness in the individual patient. The limits to exercise are, however, often 60 40 20 0 1 2 V'E (Lmin–1) V'O2 (Lmin–1) Fig. 18.3.1.7  Relationship of oxygen consumption (V’O2) to ventilation (V’E) during exercise. Fig. 18.3.1.8  (a) Relationship of oxygen consumption (V’O2) to CO2 production (V’CO2) during exercise: the gradient of the line changes at the anaerobic threshold (AT). (b) Relationship of the ‘ventilatory equivalent’ for oxygen (V’E divided by V’O2 (i.e. the ventilation ‘required’ for each litre of oxygen consumed) against V’O2 during exercise: the nadir value is taken as the AT.

section 18  Respiratory disorders 3968 multifactorial; for example, comorbid cardiovascular disease as well as deconditioning (unfitness) contribute to the breathlessness of many patients with respiratory disease. Indications for exercise testing Exercise tests may be performed for diagnostic, prognostic, or thera- peutic indications, or for objective assessment of exercise ability (Table 18.3.1.8). However, apart from using exercise to provoke exercise-​induced asthma (see next section on exercise tests), the diagnostic role of exercise tests is limited. Types of exercise test Simple walk tests Exercise tests vary considerably in complexity and in the number and types of measurements made. Simple self-​paced tests of walking dis- tance, most commonly in 6 min, aim to mimic the real-​life situation and are widely used for global assessment of disability and for docu- mentation of exercise-​related oxygen desaturation. Desaturation is seen in some (but not all) patients with advanced chronic obstructive pulmonary disease, and also in those with interstitial lung disease or pulmonary vascular disease. Walk tests are used to identify patients who might benefit from the use of ambulatory oxygen, which is in- dicated only if repeat testing while breathing oxygen improves SpO2, as well as breathlessness and/​or performance. Walk tests are insensitive to mild disease and there is a signifi- cant learning effect, as well as dependence on motivation and encouragement. An alternative to the self-​paced test is the shuttle walk test in which the walking speed is increased each minute; this gives more reproducible results than the 6 min walk and is more akin to laboratory-​based tests of maximum performance. Cardiopulmonary exercise tests Formal testing involves controlled exercise on a bicycle ergometer or treadmill. Use of a bicycle is less prone to movement artefacts, and exercise is easier to standardize as the external work rate is more readily quantified, but cycling is less familiar to many middle-​ aged patients and it puts relatively more strain on the leg muscles. A treadmill allows more natural exercise but is less convenient for use with a mouthpiece and nose clip, and sometimes more difficult for the patient. The subject’s bodyweight has more effect on V’O2 while walking on a treadmill than when seated on a bicycle and, in practice, a bicycle ergometer is preferred by most pulmonary func- tion laboratories. The electrocardiograph (ECG) is monitored throughout and the commonly made measurements include work rate (usually in Watts), heart rate, blood pressure, minute ventilation, tidal volume, breathing frequency, V’O2, V’CO2, end-​tidal PO2, and PCO2 (PETO2, PetCO2) and oxygen saturation by oximetry. Arterial blood gases are rarely measured directly in clinical testing; arterialized earlobe capillary sampling is sometimes used but requires experience to obtain valid samples. PETO2 and PETCO2 are sometimes used as surrogates for alveolar gas tensions, but—​while this assumption may be valid in healthy individuals—​it does not hold in patients with sig- nificant lung disease. The degree of breathlessness at each workload can be assessed using simple self-​rating scales (visual analogue scale or Borg scale). After a few minutes for acclimatization and resting measure- ments, the workload is increased progressively by a constant amount, usually between 10 and 30 Watts depending on the subject’s likely capacity, with periods of 1–​3 min at each level. The subject, wearing a nose clip and breathing via a mouthpiece, exercises until no longer able to continue because of discomfort or until halted by the investigator. Measurements are averaged over the final 15–​30 s of exercise at each workload, or breath-​by-​breath using appropriate computer software. Due to technological advances, breath-​by-​breath measure- ments are increasingly common, but are inevitably more ‘noisy’ than averaged data, and from the large number of measurements a po- tentially bewildering array of graphical displays can be constructed. Several issues should be borne in mind when interpreting the re- sults of cardiopulmonary exercise tests. These include the reason for performing the test, relevant clinical information, and the results of other cardiac and respiratory investigations, the technical quality of the test, including a subjective assessment by the operator of ef- fort (especially if the predicted physiological limits have not been reached), and why the patient discontinued exercise (e.g. whether due to breathlessness, leg discomfort, or chest pain). It is reasonable to assume that the subject has exercised maximally if any of pre- dicted V’O2 max, ventilation, or heart rate has been reached. Although several algorithms for interpretation have been pro- posed, there is no general consensus. The most commonly used indices include both maximal values measured at the end of exer- cise, and submaximal values recorded as workload increases. The former comprise the change in SpO2 compared to the resting value and peak ventilation, heart rate, and V’O2 (V’O2 max). V’O2 max is often ‘normalized’ by dividing by bodyweight, but this does not correct fully for weight as lighter individuals have higher weight–​ corrected values than obese individuals. Submaximal indices can be evaluated in many different ways, most commonly by plotting them against the simultaneous V’O2 or V’CO2 as an indication of the ‘metabolic load’ (Figs 18.3.1.7, 18.3.1.8). The externally measured work rate (in Watts) can be used as an alternative, but the relation between V’O2 and workload varies between individuals of differing bodyweight. Obesity adds to the ‘cost’ of exercise such that the graph of V’O2 versus work rate is displaced upwards in obese people (i.e. to a higher V’O2 for a given work rate), although the slope of the rela- tionship is not affected. The anaerobic threshold can be measured by direct monitoring of blood lactate concentration, but more commonly it is estimated indirectly by recognizing a ‘break point’ in graphical displays of various indices plotted against V’O2. The most commonly used are the plots of V’CO2 against V’O2 (Fig. 18.3.1.8a) and the ‘venti- latory equivalent’ for oxygen (V’E divided by V’O2, i.e. the venti- lation ‘required’ for each litre of oxygen consumed) against V’O2 Table 18.3.1.8  Indications for exercise testing Diagnosis Assessing unexplained breathlessness Identifying factors limiting exercise Identifying exercise-​induced asthma Assessment Objective assessment of exercise capacity Monitoring progress and effects of treatment Prognosis Heart failure Preoperative evaluation Treatment Ambulatory oxygen assessment Planning rehabilitation

18.3.1  Respiratory function tests 3969 (Fig. 18.3.1.8b). With the former ‘V slope’ method, linear regres- sions are fitted to each of the two phases of the relationship and the point of intersection of the two straight lines is taken as the AT. With the latter ‘ventilatory equivalents’ method, the decreasing ventilatory equivalent during modest exercise subsequently in- creases as anaerobic metabolism provides an additional stimulus to ventilation and the nadir value is taken as the AT. The AT is defined as the V’O2 at which the inflection points occur and is expressed as a percentage of the predicted value of V’O2 max (%V’O2 max predicted). The two values obtained are likely to differ somewhat and, if both are measured, the average is usually reported. Rather than interpreting the AT literally, it is more appropriate to regard it as a pragmatic way of recognizing a disproportionate increase in ventilation and the effects of this on gas exchange during progres- sive exercise. In healthy sedentary individuals, its value is typically 50–​60% of V’O2 max predicted. It has been suggested that, in patients who cease exercise prema- turely because of symptoms, the AT, as a submaximal index, is an effort-​independent measurement that can assist clinical decision-​ making. However, since the AT is reduced in a broad range of clin- ical conditions, it has little discriminatory ability between different diseases. As with V’O2 max, a reduced value is rather nonspecific (Table 18.3.1.9). Clinical uses of cardiopulmonary exercise tests Typical patterns of abnormality are shown in Table 18.3.1.9, but it should be noted that there is considerable variation and overlap be- tween diagnostic categories. Of note, the findings in unfit (decon- ditioned) normal subjects are qualitatively similar to those of heart failure, and it can be difficult to distinguish mild cardiac impairment from lack of fitness. In practice, the commonest indications for detailed cardiopul- monary exercise tests are evaluation of breathlessness or exercise intolerance (particularly when simpler tests have not revealed a diagnosis or breathlessness appears out of proportion to the ob- jective evidence of abnormality on other investigations), evaluating prognosis and monitoring of patients with congestive cardiac failure (including assessment for transplantation), and preoperative assess- ment (aiming to predict morbidity and mortality of patients under- going lung resection or other major surgery). Most conclusions about the clinical value of cardiopulmonary exercise tests are based on observational studies and consensus rather than randomized trials, and in some studies the prognostic value of the results has not been compared with that of simpler tests such as spirometry. The best evidence for the value of cardiopulmonary exercise tests in assessing prognosis is in patients with chronic heart failure, where studies have consistently shown that a useful threshold for V’O2 max is 14  ml/​min/​kg bodyweight. Lower values are associated with a rapidly diminishing survival rate. Other indices, in particular V’E/​ V’CO2, also have strong prognostic value in this population. Values of V’O2 max less than 10 ml/​min/​kg are widely accepted as a strong indication for heart transplantation, which may also be considered with values between 10 and 14 ml/​min/​kg. Management of patients with lung cancer is often complicated by compromised respiratory function due to coexistent COPD, hence preoperative risk assessment is particularly important in this popu- lation. Assessment may include cardiopulmonary exercise tests as a guide to the likelihood of serious complications after lung resection, with values of V’O2 max less than 15 ml/​min/​kg predicting a high complication rate. In this clinical situation, however, simpler tests of respiratory function such as spirometry and DLCO also have useful prognostic value. Consequently, some guidelines suggest that car- diopulmonary exercise tests be limited to patients with borderline resting function. The position of cardiopulmonary exercise tests in preoperative assessment for other major surgery is less clear. Some evidence sup- ports its use for risk assessment before major noncardiopulmonary surgery, but a recent systematic review of patients being assessed for repair of an abdominal aortic aneurysm or other major vascular surgery cautioned that the paucity of evidence did not justify its routine use. Exercise-​induced asthma The identification of exercise-​induced asthma has rather different requirements. During exercise, most subjects with asthma show bronchodilatation, and those who have exercise-​induced asthma develop bronchoconstriction after exercise. Of course, many pa- tients with asthma become unduly breathless during exercise, but in most this is due to the increased work of breathing associated with a degree of pre-​exercise airway obstruction, or to deconditioning, rather than to exercise-​induced bronchoconstriction. In susceptible individuals, the intensity of exercise necessary to provoke asthma is relatively high, and consequently exercise-​induced asthma is rele- vant mainly to children and young adults. It is demonstrated opti- mally after exercising for at least 5 min at a constant rate, chosen to increase ventilation to around 50% maximal or to increase heart rate to around 80% maximal. FEV1 or peak flow should be measured be- forehand and for up to 30 min afterwards. Table 18.3.1.9  Typical patterns of abnormality seen in cardiopulmonary exercise testing Condition Maximal indices Submaximal indices V’O2 max HR max Ventilatory reserve SpO2 a V’E/​V’CO2 slope AT Unfitness/​deconditioning ↓ → or ↓ → → ↑ or → → or ↓ COPD ↓ ↓ ↓ or 0 variable ↑ or → → or ↓b Interstitial lung disease ↓ ↓ ↓ ↓ ↑ → or ↓ Heart failure ↓ → or ↓ → → ↑ ↓ Pulmonary vascular disease ↓ → → ↓ ↑ ↓ Key: ↓ reduced; → normal or unchanged; ↑ increased. a compared to resting value; b if severe may not be achieved.

18.3.2 Thoracic imaging 3970 Susan J. Copley and D

18.3.2 Thoracic imaging 3970 Susan J. Copley and David M. Hansell

section 18  Respiratory disorders 3970 Miscellaneous tests Analysis of expired air has traditionally been limited to oxygen and carbon dioxide, but recently attention has turned to other gases which are present in very low concentrations. The concentration of exhaled carbon monoxide has been used for some years as a guide to its inhal- ation and as a valuable method for confirming nonsmoking claims. The measurement can now be made very simply with a portable analyser. Breath carbon monoxide is also increased in nonsmoking subjects with asthma, where it appears to be released as a result of airway inflamma- tion. In similar fashion, expired nitric oxide concentration is increased as a consequence of airway inflammation and it has been proposed as a noninvasive way of assessing airway inflammation and monitoring its treatment, particularly in asthma. Care needs to be taken to avoid contamination of expired air from the bronchial tree with that from the nose and nasal sinuses, which contain higher concentrations of NO. FURTHER READING General Gibson GJ (2009). Clinical tests of respiratory function, 3rd edition. Hodder Arnold, London. Hughes JMB (2009). Physiology and practice of pulmonary func- tion. association for respiratory technology and physiology. Boldmere, UK. West JB (2012). Respiratory physiology:  the essentials, 9th edition. Lippincott, London. Performance and interpretation of respiratory function tests American Thoracic Society/​European Respiratory Society (2002). ATS/​ERS statement on respiratory muscle testing. Am J Respir Crit Care Med, 166, 518–​624. Culver BH, et al. (2017). Recommendations for a standardized pul- monary function report: an official American Thoracic Society statement. Am J Respir Crit Care Med, 196, 1463–72. MacIntyre N, et al. (2005). Standardisation of the single-​breath deter- mination of carbon monoxide uptake in the lung. Eur Respir J, 26, 720–​35. Miller MR, et  al. (2005). General considerations for lung function testing. Eur Respir J, 26, 153–​61. Miller MR, et al. (2005). Standardisation of spirometry. Eur Respir J, 26, 319–​38. Oostveen E, et al. (2003). The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J, 22, 1026–​41. Pellegrino R, et al. (2005). Interpretative strategies for lung function tests. Eur Respir J, 26, 948–​68. Wanger J, et al. (2005). Standardisation of the measurement of lung volumes. Eur Respir J, 26, 511–​22. Sources of normal reference values Cerveri I, et al. (1995). Reference values of arterial oxygen tension
in middle-​aged and elderly. Am J Respir Crit Care Med, 152, 934–​41. Hankinson JL, Odenkrantz JR, Fedan KB (1999). Spirometric ref- erence values from a sample of the general U.S. population. Am J Respir Crit Care Med, 159, 179–​87. Quanjer PH, et al. (2012). Multi-​ethnic reference values for spirometry for the 3–​95-​yr age range: the global lung function 2012 equations. Eur Respir J, 40, 1324–​43. Stanojevic S, et al. (2017). Official ERS technical standards: Global lung function initiative reference values for the carbon monoxide transfer factor for Caucasians. Eur Respir J, 50, 1700010. doi.org/10.1183/13 993003.00010.2017. Interpretation of blood gases Berend K, de Vries AP, Gans RO (2014). Physiological approach to as- sessment of acid-​base disturbances. N Engl J Med, 371, 1434–​45. Seifter JL (2014). Integration of acid-​base and electrolyte disorders.
N Engl J Med, 371, 1821–​31. Exercise tests Ward SE, Palange P (eds) (2007). Clinical exercise testing. Eur Respir Monogr, 40, 1–​35. Wasserman K, et al. (2011). Principles of exercise testing and interpreta- tion, 5th edition. Lippincott, London. Miscellaneous Dweil RA, et al. (2011). An official ATS clinical practice guideline:
interpretation of exhaled nitric oxide levels (FeNO) for clinical ap- plications. Am J Respir Crit Care Med, 184, 602–15. 18.3.2  Thoracic imaging Susan J. Copley and David M. Hansell ESSENTIALS Radiographic findings should always be interpreted in conjunction with the clinical picture. Chest radiography—​this remains the commonest technique in the investigation of suspected thoracic disease. Advantages are cost, availability, and a lower radiation dose than CT, but even with an op- timal technique nearly one-​third of the lungs are partially obscured by the overlying mediastinum, diaphragm, and ribs. CT—​is more sensitive and specific than chest radiography in a range of pulmonary disorders, including airways disease and diffuse interstitial lung disease. In the latter condition, high-​resolution CT images of the lung correlate closely with the microscopic appear- ances of pathological specimens and are a substantial improvement over chest radiography in terms of sensitivity, specificity, and diag- nostic accuracy. In many centres CT has supplanted ventilation–​ perfusion radionuclide imaging in the investigation of patients with suspected pulmonary embolism. Radiation dose is always a con- sideration in CT, particularly in children and young adults, however recent advances make this less of an issue. Ventilation/​perfusion radionuclide scanning—​is the commonest radionuclide study of the lungs and is most frequently used to con- firm or exclude the diagnosis of suspected pulmonary embolism, but is increasingly being supplanted by CT. Due to the reduced radiation

18.3.2  Thoracic imaging 3971 dose (particularly to breast tissue) of a perfusion only study, the tech- nique may be useful in specific circumstances (e.g. in young females with a normal chest radiograph and suspected pulmonary embolism). Positron emission tomography (PET) and CT/​PET—​usually employed with the isotope 18F-​fluorodeoxyglucose for investigation and staging of lung cancer. Transthoracic ultrasonography—​the use of this technique for the imaging of lung parenchyma is limited because high-​frequency sound waves do not traverse normally aerated lung, but fluid can be readily detected and the main use of ultrasound is for the localization of small or loculated pleural effusions and guiding biopsy of periph- eral lung lesions, anterior mediastinal masses, and intercostal chest drain insertion. Ultrasound is also used for evaluating diaphragmatic movement in suspected diaphragmatic paralysis or dysfunction. MRI—​imaging of the mediastinum by CT scanning and MRI are comparable, but MR images of the lungs are generally inferior to those obtained by CT because of their very low water (and therefore proton) content. Other disadvantages are respiratory and cardiac motion arte- fact (unless respiratory and cardiac gating are used), relatively long scan- ning time, and difficulties with the monitoring of critically ill patients. However, there have been recent advances in techniques evaluating lung ventilation and perfusion. MRI may also have a role in patients who are allergic to iodinated intravenous contrast for the evaluation of suspected pulmonary embolus or malignancies such as malignant mesothelioma. Introduction Despite recent technological advances, chest radiography remains the cornerstone of thoracic imaging. The chest radiograph is justifiably re- garded as an integral part of the examination of the patient in respira- tory medicine. Because of the wealth of information available from chest radiography, careful interpretation of the chest radiograph remains a necessary clinical skill. Advances in cross-​sectional imaging have had a great impact in improving the diagnosis of thoracic pathology, not only for the assessment of mediastinal disease but also in the evaluation of patients with suspected diffuse lung disease. Nevertheless, a chest radio- graph should be obtained and looked at carefully before submitting a patient to more sophisticated imaging techniques. In the case of CT, the expense and radiation burden are important considerations. Techniques in thoracic imaging Chest radiography The first chest radiograph was taken over 100 years ago and chest radiography is now the most frequently requested radiological in- vestigation worldwide. The technique has changed surprisingly little over the years, although digital technology has recently been used to overcome some of the shortcomings of film-​based radiography. Technical considerations An ideal chest radiograph is taken with the patient standing erect, sus- pending respiration at total lung capacity and with the X-​ray beam traversing the thorax from back to front (the posteroanterior (PA) or frontal view). Because of the wide range of densities within the chest (soft tissues of the mediastinum through to aerated lung), perfect exposure of every part of the chest radiograph is impossible. The ­resulting ­suboptimal exposure of the denser part of the chest can be ­partially overcome with a high-​kilovoltage technique (120–​150  kVp). With this technique there is greater penetration of the mediastinum, which improves visualization of the trachea and main bronchi. However, a disadvantage of high-​kilovoltage radiography is the relatively poor demonstration of calcified structures so that rib fractures and calcified pulmonary nodules or pleural plaques are less conspicuous. Even with optimal technique, nearly one-​third of the lungs are partially obscured by the overlying mediastinum, diaphragm, and ribs. Automatic exposure devices have been developed to optimally ­expose the various parts of the chest. Digital image capture devices (including flat panel detectors and high-​density line-​scan solid state detectors) have largely replaced conventional film radiography. High-​density line-​ scan solid state detectors consist of a photostimulable phosphor plate in a conventional cassette (which does not contain film) and which is exposed in the normal way. The energy of the incident X-​ray beam is stored as a latent image. The phosphor plate is then scanned with a laser beam and the light emitted from the excited latent image is de- tected by a photomultiplier. Thereafter, this signal is processed in digital form. The digital image is then viewed on a monitor. The advantage of phosphor plate computed radiography is that it can retrieve an image of diagnostic quality from an imperfect exposure which would result in a non-​diagnostic conventional film radiograph. Manipulation or post-​ processing of the digital image (e.g. ‘edge enhancement’), aids the detec- tion of linear structures, such as the edge of a pneumothorax or central venous catheters (see Fig. 18.3.2.1). Some centres may have access to techniques such as digital tomosynthesis, when X-​ray tube rotation and flat panel detectors produce multiple ‘slices’ through the thorax in a single exposure, which may be of value in pulmonary nodule ­detection and characterization without the distraction of overlying bony and soft tissue structures. Digital subtraction radiography utilizes the different absorption of high and low kV photons by varying anatomical struc- tures (e.g. bone and soft tissue), allowing bony structures to be ‘sub- tracted’, which may be of value in pulmonary nodule detection. With the advent of picture archiving and communication systems that ­enable storage and transfer of digital images, most radiology departments in the developed world are now ‘filmless’, with images available to view simultaneously on both local and distant workstations. Standard radiographic views of the chest The PA projection is the standard view (see Fig. 18.3.2.20a). The pa- tient is positioned with the anterior chest wall against the detector panel and the arms are abducted to rotate the scapulae away from the pos- terior chest. Chest radiographs in the anteroposterior (AP) projection are usually taken when the patient is too ill to stand for a formal PA radiograph. A consequence of this view is that the heart is magnified because it lies further from the detector. Moreover, the shorter distance from X-​ray tube to detector, which is inevitable when a portable AP radiograph is taken, causes further magnification that must be taken into account when assessing the heart size on an AP chest radiograph. The lateral radiograph is obtained by placing the patient at right ­angles to the detector. The lateral projection provides the third dimen- sion and helps to determine the site of a lesion identified on the PA projection, although it is surprising how often an opacity clearly seen on the PA radiograph is invisible on the lateral radiograph. As well as allowing accurate localization of lesions and devices, the lateral radio- graph may reveal abnormalities that lie behind the heart or diaphragm.

section 18  Respiratory disorders 3972 Over the years a number of supplementary projections have been developed to provide information about areas that are not easily seen on the standard PA and lateral radiograph. With the advent of cross-​ sectional imaging, notably CT, many of these extra views have be- come obsolete. However, even with access to CT, some of these views supply extra anatomical detail readily and inexpensively. The lateral decubitus projection is sometimes useful for the demonstration of small pleural effusions, for which view the patient lies on their side (suspected effusion downwards). However, ultrasonography is a reli- able technique for demonstrating small pleural effusions and can be performed at the patient’s bedside. Other supplementary projections (e.g. apical and lordotic views), used to improve visualization of the lung at the extreme apices, are now less commonly performed: CT is much more effective at showing pathology in these difficult areas. Transthoracic ultrasonography High-​frequency sound waves do not traverse air and are completely reflected at interfaces between soft tissue and air. The use of this technique for the routine evaluation of lung parenchyma is there- fore limited because of normally aerated lung. However, fluid can be readily detected, and the main use of ultrasound examination is for the localization of pleural effusions (Fig. 18.3.2.2). Furthermore, ultrasonography can differentiate between pleural fluid and pleural thickening in cases where radiography cannot make this distinction. Detection of a pneumothorax is also possible with transthoracic ultrasonography, and may be of particular use in the context of major trauma (Fig. 18.3.2.3). Ultrasonography is also an extremely useful technique for guid­ ing percutaneous needle biopsy of masses arising from the chest wall or pleura (see Video 18.3.2.1), or peripheral pulmonary masses or consolidation, and for aiding the accurate placement of a chest drain within a pleural collection. Ultrasound-​guided bi- opsy of supraclavicular lymph nodes is of use as an alternative to Fig. 18.3.2.1  Chest radiographs of an individual post right subclavian central venous catheter insertion. The image (b) has been inverted post-​ processing to aid detection of the tip of the catheter, which is incorrectly placed within the right internal jugular vein (arrow). Fig. 18.3.2.2  Ultrasonography showing an empyema. Thick fibrinous septations traverse the pleural space. The diaphragm and liver are seen on the right of the image. Fig. 18.3.2.3  Ultrasound of the pleura demonstrating normal ‘comet’ tails (arrows) in (a) and a lack of comet tails at the chest wall/​pleural interface (b) in a patient with a pneumothorax.

18.3.2  Thoracic imaging 3973 bronchoscopic or image-​guided lung biopsy in the diagnosis and staging of lung cancer, especially in patients with poor respiratory reserve. CT CT depends on the same basic principle as conventional radiog- raphy, namely the differential absorption of X-​rays by tissues of disparate densities, although CT has much greater sensitivity to dif- ferences in attenuation of X-​rays by various tissues. A CT machine consists of an X-​ray source and an array of detectors that surround the patient. The X-​ray source rotates around the patient and the resulting attenuated beam is measured by the detectors. The sig- nals from the detectors are used to construct an image by a math- ematical technique. The reconstructed images are transverse (axial) cross-​sections of the patient and are viewed as if from the feet end of the patient (i.e. on the image, the patient’s right side is to the viewer’s left). Each CT section is a matrix of three-​dimensional elements (voxels) containing a measurement of X-​ray attenuation, arbitrarily expressed as Hounsfield units (HU): water measures 0 HU and air –​ 1000 HU (so that lung parenchyma are approximately –​600 HU), fat is –80 HU, soft tissue 40–​80 HU, and bone 800 HU. If a voxel is completely occupied by a tissue of uniform density (most fre- quently the case with narrow sections, e.g. 1 mm), then the HU will be truly representative of that tissue. If the section contains tis- sues of two different densities (more likely to occur with thicker sections, e.g. 5 mm), for example, half a lung and a half dome of diaphragm, then the attenuation value will be a weighted average of the two components—​the so-​called ‘partial volume’ effect. The cross-​sectional nature of CT means that it can accurately lo- calize lesions seen on only one view on chest radiography. The su- perior contrast resolution of CT gives exquisite detail of the various components of mediastinal anatomy (e.g. lymph nodes and ves- sels) and density differences (e.g. calcifications within a pulmonary nodule). Different image settings are needed to view the soft tissue structures of the mediastinum and the aerated lung parenchyma, re- spectively (Fig. 18.3.2.4). The principle of continuous volume acquisition (formerly known as spiral or helical CT) involves continuous rotation of the X-​ray beam and detectors around the patient while the table moves into the gantry. Markedly reduced scan times are possible with this tech- nique, allowing the entire thorax to be imaged in a single breath-​ hold. An examination of sufficient diagnostic quality can be obtained in breathless patients and young children during quiet respiration. Another advance has been the development of multidetector CT (MDCT), where multiple rows of detectors rotate around the pa- tient acquiring volumetric data, allowing even further reduced scan times—​hence most modern CT scanners are termed ‘volumetric’. The technique allows for accurate timing of an intravenous in- jection of contrast medium for optimum opacification (e.g. of the pulmonary arteries), enabling pulmonary emboli to be detected (Fig. 18.3.2.5). In many centres, contrast-​enhanced CT has sup- planted ventilation/​perfusion (V/​Q) radionuclide imaging in the investigation of patients with suspected pulmonary embolism and often demonstrates an alternative cause for the patient’s symptoms in ‘negative’ cases. Computer software can perform multiplanar two-​ and three-​ dimensional image reconstructions of volumetric data sets, including views of the bronchial tree which can elegantly demonstrate normal variants (Fig. 18.3.2.6) and aid interventional techniques such as bronchial stent placement (Fig. 18.3.2.7). In addition MIP (max- imum intensity projection) and MinIP (minimum intensity projec- tion) images project the voxels with either high or low density from a ‘slab’ of thin sections. MIPS are used to increase the conspicuity of spherical pulmonary nodules by comparison with branching pulmonary vessels (Video 18.3.2.2). MinIPs increase the conspi- cuity of low attenuation areas within the lung such as emphysema (Fig. 18.3.2.8). With the advent of MDCT and the use of ECG gating, evaluation of structures such as coronary arteries is routine due to reduction in motion artefact and increased spatial resolution. High-​resolution CT utilizes thin sections (1–​2 mm) and a high spatial frequency reconstruction algorithm to produce highly de- tailed sections of the lung parenchyma (Fig. 18.3.2.9). Most centres with MDCT routinely obtain high-​resolution reconstructions from the volumetric data, by contrast to the dedicated ‘interspaced’ 1 mm sections every 10 mm obtained with the first-​generation single slice CT scanners. Reformats in the coronal and sagittal planes can be helpful for demonstrating the distribution of interstitial lung dis- eases (Fig. 18.3.2.10) and may allow more accurate and confident Fig. 18.3.2.4  CT section through the mid-​thorax. The window settings have been adjusted to show details of (a) the lungs and (b) the soft tissues of the mediastinum.

section 18  Respiratory disorders 3974 identification of individual features (particularly the distinction be- tween honeycomb cysts and traction bronchiectasis). Submillimetre structures can be resolved with this technique, allowing the subtle and sometimes complex morphology of interstitial lung diseases to be shown with great clarity. Since the mid-​1980s, the development of high-​resolution CT has changed the radiological approach to the diagnosis of diffuse lung disease. High-​resolution CT images of the lung correlate closely with the macroscopic appearances of patho- logical specimens, and high-​resolution CT represents a substantial improvement over chest radiography in terms of sensitivity, specifi- city, and diagnostic accuracy. Furthermore, CT samples a far greater volume of lung than even the most generous lung biopsy, making it less prone to sampling errors. High-​resolution CT has also been shown to provide useful in- formation regarding prognosis and response to treatment in some diffuse lung diseases. Nevertheless, despite the increased confi- dence with which a specific diagnosis of diffuse lung disease can often be made with high-​resolution CT, a multidisciplinary ap- proach (including histopathological examination of a lung biopsy in some cases) is still required. The extent of diffuse lung disease (a) (b) Fig. 18.3.2.5  CTPA of a patient with acute pulmonary emboli. Coronal (a) and axial (b) images show filling defects in contrast media opacification within the pulmonary arteries bilaterally (arrows). Fig. 18.3.2.6  Volume-​rendered 3D reconstruction of the trachea and main bronchi. Note the anatomical variant (tracheal or ‘pig bronchus’ where a bronchus supplying the right upper lobe arises from the trachea; see arrow). Fig. 18.3.2.7  Reconstructed three-​dimensional image from spiral CT showing the carina and the right and left main bronchi viewed from above.

18.3.2  Thoracic imaging 3975 can be precisely estimated on high-​resolution CT and, when a bi- opsy is indicated, the distribution of disease will indicate whether a transbronchial biopsy or an open lung biopsy is more likely to obtain a representative specimen. Dual source CT was initially designed to decrease gantry rotation time by utilizing two orthogonal X-​ray beams and detectors sim- ultaneously rotating around the patient. A spin-​off from this tech- nology was the use of X-​ray beams of different energy, so-​called dual-​energy. This utilizes the different absorption characteristics of photons of different energy (keV) to improve differentiation of various tissues, particularly post-​iodinated intravenous contrast en- hancement. Either a single ‘source’ (with fast kilovoltage switching to produce photons of different energy levels) or a dual source CT scanner can be used. With both types of scanner, the patient is sim- ultaneously exposed to X-​ray photons of both high (140 kVp) and low (80 kVp) energies. Clinical applications include the assessment of lung perfusion, particularly in the context of pulmonary embolic disease. The disadvantages of all CT techniques are relatively high cost and high radiation exposure to the patient, particularly by comparison with chest radiography. Manufacturers have responded to the chal- lenge of dose reduction, but CT should still not be regarded as a routine investigation (especially in children and young adults) and examinations should always be tailored to solve questions not an- swered by less sophisticated investigations. The commonest indica- tions for thoracic CT are summarized in Box 18.3.2.1. MRI The physical principles of MRI are very different from those governing CT. An MR image is obtained by placing the subject in a strong magnetic field that polarizes some of the ubiquitous hydrogen protons (which can be thought of as behaving like randomly orien- tated bar magnets) in the body so that they have the same alignment. The application of radiofrequency wave pulses of specified lengths and repetition (pulse sequences) displaces the protons and some of this transmitted energy is absorbed by them. With the cessation of the radiofrequency pulse, the protons return to their initial alignment and in so doing they emit, as a weak signal, some of the energy they have absorbed; this signal is received and then amplified and handled in digital form and is subsequently reconstructed into an image. (a) (b) Fig. 18.3.2.8  Standard coronal reconstructions (a) compared with coronal MinIP reconstructions (b) in a patient with emphysema. Note the areas of emphysema are more conspicuous on the MinIPs (b). Fig. 18.3.2.9  High-​resolution CT of a patient with lymphangioleiomyomatosis showing thin-​walled cysts throughout the lungs. These cysts were not apparent on chest radiography. Fig. 18.3.2.10  MDCT with coronal reconstructions of a patient with advanced pulmonary Langerhan’s cell histiocytosis. Note the upper and mid-​zone distribution of cystic lung destruction with relative sparing of the lung bases. Box 18.3.2.1  Indications for CT of the thorax • Elucidation of abnormal mediastinal or hilar contour on chest radiography • As part of the staging procedure in the evaluation of a patient with known lung cancer (the findings on CT must be interpreted in con- junction with other investigations) • Detection of pulmonary disease in the face of a questionably ab- normal or apparently normal chest radiograph (notably diffuse inter- stitial disease and bronchiectasis) • Investigation of a patient with haemoptysis in whom chest radio­ graphy and bronchoscopy are normal • Detection of pulmonary embolism • Assessment of complex pleural or chest wall pathology when chest radiography does not adequately show the extent of disease • As a means of guiding the percutaneous needle biopsy of pulmonary lesions or mediastinal masses

section 18  Respiratory disorders 3976 The advantages of MRI include the improved contrast resolution between different soft tissues compared with CT (Fig. 18.3.2.11), and the use of special sequences which give functional information (e.g. the velocity of blood flow). An important advantage of MRI is the lack of any known hazard to the patient, in contrast to CT with its small attendant risk from ionizing radiation. The technique may also be of value in patients who are allergic to iodinated contrast for the detection of pulmonary emboli, or in the evaluation of chronic thomboembolic disease (Fig. 18.3.2.12). Disadvantages of MRI in- clude the long scan time (although this is continually being short- ened), reduced spatial resolution compared with CT, the inability to image calcium, reduced acceptability to patients because of the claustrophobic bore of the magnet, and important contraindications such as permanent cardiac pacemaker devices and ferromagnetic intraocular foreign bodies. In many respects, the imaging of the mediastinum by CT and MRI are comparable. However, MR images of the lungs are currently in- ferior to CT because of their very low water (and therefore proton) content, meaning that the signal produced by normal lung is small and not visualized by conventional sequences. However, the rela- tively recent introduction of hyperpolarized gases, including helium-​ 3, has enabled evaluation of pulmonary function. The use of such agents by inhalation is largely still a research tool, but may provide valuable insights into pulmonary ventilation and small airways func- tion in the future. The use of oxygen ventilation MRI may be a more practical technique and avoid the inherent difficulties in the pro- duction and storage of hyperpolarized inert gases (Fig. 18.3.2.13). Diffusion-​weighted MRI allows the mapping of diffusion processes of molecules (particularly water) in vivo. The technique is particu- larly valuable in neuroimaging, but may be useful in the future for differentiating benign from malignant pulmonary masses and pleural disease, and for assessing tumour response to therapy. Radionuclide imaging V/​Q radionuclide scanning is an effective noninvasive method of providing both anatomical and physiological information about the lung. It is the commonest radionuclide study of the lungs and most frequently used to confirm or exclude the diagnosis of suspected pulmonary embolism. Regional pulmonary capillary perfusion can be assessed following the intravenous injection of a bolus of particles that have been labelled with technetium-​99m. The minute particles are microspheres or macroaggregates of human albumin (15–​70 µm in diameter). These are evenly dispersed by the time they reach the pulmonary circula- tion and they can become temporarily lodged in a very small fraction (<0.5%) of the precapillary arterioles and capillaries of the lungs. The distribution of γ-​ray emission from the technetium-​labelled particles is directly proportional to the regional pulmonary flow and a sig- nificant defect in perfusion is usually readily detected. However, it is important to appreciate that such defects may be due to a variety of conditions other than pulmonary embolism, including any cause of hypoxic vasoconstriction such as an area of subsegmental collapse or a space-​occupying lesion not supplied by the pulmonary circulation. However, in these cases the affected area of lung will be neither venti- lated nor perfused, whereas in acute pulmonary embolism there is no corresponding defect of ventilation. Thus, to improve the specificity of the diagnosis of pulmonary embolism, ventilation scintigraphy is usually performed at the same time as perfusion scanning. Evaluation of ventilation of the lungs depends on filling the distal air spaces with a γ-​ray-​emitting radionuclide. The radionuclides suit- able for inhalation are the inert gases xenon-​133 and krypton-​81m, Fig. 18.3.2.12  Reformatted image from an MRI of the thorax
(viewed posteriorly) in a patient with chronic thomboembolic pulmonary hypertension showing tortuous pulmonary arteries and intravascular webs (arrows). Fig. 18.3.2.11  MRI (T2-​weighted coronal section) showing the relationship of an apical bronchial carcinoma (Pancoast tumour) to the chest wall and adjacent mediastinum. Note the multiple high signal (bright) areas within the vertebral bodies consistent with bony metastases.

18.3.2  Thoracic imaging 3977 or a technetium-​99m aerosol (Technegas). The characteristic abnor- mality of pulmonary embolism is the so-​called ‘mismatched defect’ in which a regional defect in perfusion is not matched by a defect in ventilation (Fig. 18.3.2.14). Because of the importance of establishing a correct diagnosis of pulmonary embolism, V/​Q scans should always be interpreted in the light of current chest radiographs and clinical information. Even then a substantial proportion of V/​Q scans remain indeterminate, (B) 0.0 0 94 188 ∆pO2 (mm Hg) 282 370 470 564 60.0 120.0 Time (sec) Change in partial pressure of oxygen (∆pO2) in healthy lungs 180.0 240.0 (A) (C) (D) Fig. 18.3.2.13  Example of changes in partial pressure of oxygen as measured with dynamic oxygen-​enhanced MRI in a healthy individual. The colour map overlaid on the dynamic images
(A to D, left to right) represents the changes in partial pressure of oxygen (oxygen-​enhanced MRI) in a healthy individual. Images provided courtesy of Jose Ulloa and Geoff Parker, Bioxydyn Limited. Fig. 18.3.2.14  Images from ventilation/​perfusion lung scintigraphy showing multiple perfusion defects (top two of images), which are not matched by ventilation defects (bottom two images) consistent with a high probability of pulmonary emboli.

section 18  Respiratory disorders 3978 hence the increasing use of CT angiography. However, due to the decreased radiation burden, low-​dose perfusion scanning remains a satisfactory first-​line investigation in young patients with no pre-​ existing lung disease and a low pretest probability for pulmonary embolism, but availability ‘out of hours’ remains a problem. Positron emission tomography Positron emission tomography (PET) relies on tissue uptake of radio-​ isotopes that decay by positron emission. Detectors located around the patient map the site of origin of the two resultant photons emitted at 180° from each other. The most widely used isotope for the detec- tion of pulmonary malignancy is 18F-​fluorodeoxyglucose (FDG), a d-​glucose analogue. The increased uptake and retention of glucose by malignant cells allows differentiation of benign from malignant pulmonary masses, detection of lymph node involvement by tumour, and identification of distant metastases. Limitations of the technique include false positive results caused by granulomatous infection and acute inflammation, and false negative results with certain tumours (e.g. indolent adenocarcinomas and carcinoid tumours). Small (<1 cm diameter) malignant lesions may also give false negative results. CT/​PET is where a helical CT is performed simultaneously with PET and the images then coregistered (Fig. 18.3.2.15). The fusion of CT images (which give good anatomical resolution) with PET im- ages (which provide functional data) is an advantage in the staging of thoracic malignancies including lung carcinoma and mesothelioma, particularly for the detection of unsuspected distant metastases. The avidity of tumour uptake may provide prognostic information and assessment of response to treatment. Pulmonary and bronchial arteriography:
Superior vena cavography The ‘gold standard’ for identifying emboli within the pulmonary arteries has traditionally been pulmonary arteriography, which re- quires the catheterization of an antecubital, jugular, or femoral vein, and guidance of the catheter through the right heart under fluoro- scopic control. Although the complication rate is low, it is a time-​ consuming procedure that requires an experienced angiographer (now a rare species). The technique allows embolization of pul- monary arteriovenous malformations—​a specialized technique available in only a few centres (Fig. 18.3.2.16). The bronchial arteries that supply the airways become hyper- trophied in chronic inflammatory pulmonary disease, notably bronchiectasis. Rupture of these vessels can cause severe and life-​ threatening haemoptysis. The bronchial arteries are selectively catheterized by the passage of a catheter via the femoral artery and aorta. Having identified the abnormally hypertrophied bronchial arteries (Fig. 18.3.2.17), they can be therapeutically embolized. This technique is usually successful in treating massive haemoptysis. Superior vena cavography was previously used to evaluate the exact site of narrowing in patients with symptoms of obstruction of the su- perior vena cava, but has largely been supplanted by CT. However, patients with symptoms of superior vena cava obstruction—​most frequently due to neoplastic nodal involvement—​may be success- fully palliated by radiotherapy or the insertion of an expandable metallic wire stent at the site of the narrowing (Fig. 18.3.2.18). A transvenous biopsy at the time of stent insertion may also provide a histopathological diagnosis. Percutaneous lung biopsy Percutaneous needle biopsy of a pulmonary lesion or mediastinal mass is a useful method of obtaining tissue for diagnostic purposes (including for genomic studies) in patients with suspected lung cancer. The procedure is often performed as a day case. Complications include pneumothorax, haemoptysis, and extremely rarely, air em- bolism. Percutaneous biopsy is performed under local anaesthesia with either CT or ultrasound guidance (if the mass abuts the pleura). Contraindications to the procedure include any patient with poor Fig. 18.3.2.15  CT/​PET image showing increased uptake of 18F-​fluorodeoxyglucose (FDG) in the left lung corresponding to a primary bronchial carcinoma. The image on the left is the coronal MDCT image, the central image is the coronal PET, and the image on the right is the coregistered CT/​PET. Note the central necrosis resulting in central photopenia, also the physiological uptake of tracer in the liver, spleen, kidneys, and bladder.

18.3.2  Thoracic imaging 3979 respiratory reserve who is unable to withstand a pneumothorax, clotting disorders, and pulmonary arterial hypertension. Very small lesions (less than a centimetre in diameter), central lesions and those difficult to access because of overlying bony structures may not be possible sample using this technique however. There has been increased interest in the use of CT-​guided ‘labelling’ of small subcentimetre pulmonary nodules using methylene blue dye and fi- ducial markers to aid subsequent surgical identification and resection. Image-​guided ablation Radiofrequency ablation (which employs a small electrode that produces radiofrequency waves), and more recently microwave ab- lation, are usually performed under CT guidance and general an- aesthesia to treat either primary or secondary lung tumours using thermal energy (Fig. 18.3.2.19). The common indications are small primary lung tumours in a patient too unwell to undergo thora- cotomy, debulking of large primary tumours, and treatment of small numbers of pulmonary metastases. Complications are similar to those of percutaneous lung biopsy. Normal radiographic anatomy The mediastinum On a PA chest radiograph (see Fig. 18.3.2.20a) the mediastinal struc- tures are superimposed on one another and thus cannot be distin- guished individually. The mediastinum is conventionally divided into superior, anterior, middle, and posterior compartments: the practical use of these arbitrary divisions is that specific mediastinal patholo- gies show a definite predilection for individual compartments (e.g. a superior mediastinal mass is most frequently due to intrathoracic extension of the thyroid gland, a middle mediastinal mass is usually due to enlarged lymph nodes). However, it should be borne in mind that the position of a mass within one of these compartments is no guarantee of a specific diagnosis, nor do these boundaries preclude disease from spreading from one compartment to the next. Because only the outline of the mediastinum and the air-​ containing trachea and bronchi are clearly seen on a PA chest radio- graph, the mediastinal anatomy will be considered in more detail in the description of CT anatomy. On a chest radiograph, the right superior mediastinal border is formed by the right brachiocephalic vein and superior vena cava. The mediastinal border to the left of the trachea above the aortic arch represents the sum of the left carotid and left subclavian arteries together with the left brachiocephalic and jugular veins. The left cardiac border comprises the left atrial appendage which merges inferiorly with the left ventricle. The car- diac silhouette is always sharply outlined: any blurring of the border denotes replacement of the aerated lung, usually by collapse or con- solidation, in the immediately adjacent lung (see ‘Silhouette sign’ in ‘Common radiological signs of disease’). The density of the cardiac shadow to the left and right of the ver- tebral column should be identical and any difference signals pul- monary pathology (e.g. consolidation in a lower lobe). A density with a convex lateral border is often seen through the right heart border on a well-​penetrated film: this apparent mass is due to the confluence of the pulmonary veins as it enters the left atrium and is of no pathological significance. The trachea and main bronchi are visible through the upper and middle mediastinum. The trachea is rarely straight and is often to the right of the midline at its midpoint. In elderly patients, the tra- chea may appear dramatically displaced by a dilated aortic arch. The angle of the carina is usually somewhat less than 80°. Splaying of the carina is a sign of gross disease, either in the form of massive subcarinal lymphadenopathy, or a markedly enlarged left atrium. A  more sensitive sign of a subcarinal mass is obliteration of the azygo-​oesophageal line which is usually visible on a well-​penetrated chest radiograph. The origins of the lobar bronchi, where they are projected over the mediastinal shadow, can usually be made out but the segmental bronchi within the lungs are not generally seen on plain radiography. The hilar structures The hilar shadows on a chest radiograph are a complex summa- tion of the pulmonary arteries and veins with virtually no contri- bution from the overlying bronchial walls or normal-​sized lymph nodes. The hila are approximately the same size and the left hilum always lies between 0.5 cm and 1.5 cm above the level of Fig. 18.3.2.16  Images from a digital subtraction angiogram of a patient with multiple pulmonary arteriovenous malformations (note the multiple metallic embolization coils) demonstrating a pre-​ (a) and post-​ (b) embolization pulmonary arteriovenous malformation at the right base.

section 18  Respiratory disorders 3980 the right hilum. The size and shape of the hila in normal individ- uals show remarkable variation so that subtle abnormalities are difficult to detect. At least as important as an abnormal contour in detecting a mass at the hilum is a discrepancy in density be- tween the two hila: both hilar shadows, at equivalent points, will be of equal density and a mass at the hilum (or an intrapulmonary mass in line with the hilum) will be evident as increased density of that hilum. The pulmonary fissures, vessels, and bronchi The lobes of each lung are surrounded by visceral pleura: the upper and lower lobes of the left lung are separated by the major (or ob- lique) fissure. The upper, middle, and lower lobes of the right lung are separated by the major (or oblique) and minor (horizontal or transverse) fissures. The minor fissure is visible on about 60% of normal PA chest radiographs. In normal individuals, this fissure runs horizontally and any deviation from this course represents loss of volume of a lobe. The major fissures are inconstantly identifiable on lateral radiographs. Other fissures are occasionally seen (e.g. in Fig. 18.3.2.17  A patient with massive haemoptysis from an aspergilloma at the right apex (arrows) (a). Digital subtraction images demonstrating hypertrophied bronchial arteries which have subsequently been embolized (c). Fig. 18.3.2.18  Images from a superior vena cava stent procedure. Image (a) shows narrowing of the superior vena cava (SVC) from extrinsic compression due to a small cell lung cancer. Post-​stent image shows stent placement across the previously narrowed segment.

18.3.2  Thoracic imaging 3981 the left lung a minor fissure can occur which separates the lingula from the remainder of the upper lobe). All of the branching structures seen within the lungs on a chest radiograph represent either pulmonary arteries or veins. The larger pulmonary vessels can be traced back to the hila and mediastinum. The pulmonary veins can sometimes be differentiated from the pul- monary arteries:  the superior pulmonary veins have a distinctly vertical course, but in practice it is often impossible to distinguish arteries from veins in the outer two-​thirds of the lung on chest radi- ography. In the erect position, there is a gradual increase in the diameter of the vessels, at equidistant points from the hilum, travel- ling from lung apex to base; this is a gravity-​dependent effect and is abolished if the patient is supine or in cardiac failure. The lobes of the lung are divided into segments, each of which is supplied by its own segmental bronchi. The walls of the segmental bronchi are rarely seen on the chest radiograph, except when lying parallel with the X-​ray beam, when they are seen end-​on as ring shadows measuring up to 8 mm in diameter. The diaphragm and thoracic cage The interface between aerated lung and the domes of the diaphragm is sharp and in general the highest point of each dome is medial to the midclavicular line. The right dome of the diaphragm is higher than the left by up to 2 cm in the erect position unless the left dome is temporarily elevated by air in the stomach. Laterally, the diaphragm dips steeply downwards to form an acute angle with the chest wall. Filling in or blunting of these costophrenic angles usually represents pleural disease, either pleural thickening or an effusion. Localized humps on the dome of the diaphragm are common and represent minor weaknesses or defects of the diaphragm. Similarly, interposition of the colon in front of the right lobe of the liver is a frequently seen normal variant. Deformities of the thoracic cage may cause distortion of the normal mediastinum and so simulate disease. One of the com- monest deformities is pectus excavatum which, by compressing the heart between the depressed sternum and vertebral column, causes displacement of the apparently enlarged heart to the left and causes blurring of the right heart border. High-​kilovoltage chest radiographs often allow the vertebral bodies to be seen through the cardiac shadow. However, with this technique the ribs, and particularly their posterior parts, are often rendered invisible. Anatomy on the lateral chest radiograph It is useful to become accustomed to viewing a lateral film (Fig. 18.3.2.20b) in the same orientation, whether it is a right or left lateral projection. Familiarity with the same orientation improves the viewer’s ability to detect deviations from normal. The trachea is angled slightly posteriorly as it runs towards the carina, and the posterior wall of the trachea is always visible as a fine stripe. Furthermore, the posterior walls of the right main bron- chus and the right intermediate bronchus are outlined by air and are also seen as a continuous stripe on the lateral radiograph. The spines of the scapulae are invariably seen running almost vertically in the upper part of the lateral radiograph and they should not be confused with intrathoracic structures. Further spurious shadows are formed by the soft tissues of the outstretched arms which are projected over the anterior and superior mediastinum. Although the carina is not visible on the lateral radiograph, the two transradiancies projected over the lower trachea represent the right main bronchus (super- iorly) and the left main bronchus (inferiorly). More lung is obscured by overlying structures on a lateral radio- graph than on the PA view. The unobscured lung in the retrosternal and retrocardiac regions should be of the same transradiancy. Furthermore, as the eye travels down the dorsal spine, the viewer should be aware of a gradual increase in transradiancy. The loss of this phenomenon suggests the presence of disease in the posterobasal segments of the lower lobes (sometimes not visible on the frontal radiograph). The two major fissures are seen as diagonal lines, often incom- plete and of a hair’s breadth, running from the upper dorsal spine to the anterior surface of the diaphragm. Care must be taken not to Fig. 18.3.2.19  Image from a CT-​guided radiofrequency ablation procedure for colorectal metastasis demonstrating the radiofrequency probe in situ (a) and subsequent follow-​up CT (b) demonstrating typical post-​procedural changes within the lung.

section 18  Respiratory disorders 3982 confuse the obliquely running edges of ribs with fissures. The minor fissure extends horizontally from the mid-​right major fissure. It is often not possible to distinguish the right from the left major fissures with confidence. Similarly, although the two hemidiaphragms may be identified individually (especially if the gastric bubble is visible under the left dome of the diaphragm), the distinction between the right and the left is often not possible. A helpful sign is the relative heights of the two domes: the dome furthest from the film is usually higher because of magnification. The summation of both hila on the lateral radiograph generates a complex shadow. However, there are some generalizations which aid the interpretation of this difficult area. The right pulmonary artery lies anterior to the trachea and right main bronchus, whereas the left pulmonary artery hooks over the left main bronchus so that a large part of it lies posterior to the major bronchi. As a result, any mass identified on a PA and lateral radiograph that lies anterior to the left hilum or posterior to the right hilum is not vascular in origin and is most likely to represent enlarged hilar lymph nodes. A band-​like opacity is often seen along the lower third of the anterior chest wall behind the sternum. This represents a normal density and occurs because there is less aerated lung in contact with the chest wall because the space is occupied by the heart; it should not be confused with pleural disease. Points in the interpretation of a chest radiograph Even when there is an obvious radiographic abnormality, there is much to recommend a careful and systematic method in reviewing a chest radiograph. Such an approach will allow an appreciation of normal variations of anatomy to be built up with time. With increasing experience, an appreciation of deviation from normal ap- pearances becomes more rapid and this leads quickly to a directed search for related abnormalities. Before interpreting a chest radiograph, it is vital to establish whether there are any previous radiographs for comparison: the sequence and pattern of change is often as important as the iden- tification of a radiographic abnormality. Information gained from preceding radiographs, particularly the lack of serial change, will often prevent needless further investigation. Demographic details, particularly the age and racial origin of the patient, should be noted since this information may increase the probability of a differential diagnosis which is based on the radiographic findings alone. A quick check that the radiograph is of satisfactory quality in- cludes an estimation of the radiographic exposure, depth of inspir- ation, and position of the patient. As a general rule, the intervertebral disc spaces of the entire dorsal spine should be visible on a correctly exposed radiograph; the midpoint of the right hemidiaphragm lies at the level of the anterior end of the sixth rib if the patient has taken a satisfactory breath in. The patient is axially rotated if the medial ends of the clavicles are not equidistant from the spinous process of the thoracic vertebral body at that level. The order in which the structures on a chest radiograph are analysed is unimportant. A  suggested sequence is to start with a scrutiny of the position of the trachea, of the mediastinal con- tour (which should be sharply outlined in its entirety), and then the position, outline, and density of the hilar shadows. Only then are the lungs examined, taking into account their size, the relative transradiancy of each zone, and the position of the horizontal fis- sure (and any other indirect signs of volume loss—​see later section on lobar collapse). Pulmonary vessels are seen as far as the outer third of the lung and the number of vessels should be roughly symmetrical on the two sides. Next, the position and clarity of the hemidiaphragms should be noted, followed by an assessment of the ribs and soft tissues of the chest wall. Special care should be taken to look for pleural thickening along the lateral chest walls, which may be easily overlooked. Before deciding that a chest radiograph is normal, it is worth re- viewing areas that are either poorly demonstrated on chest radi- ography or often misinterpreted. These include:  (1) the central mediastinum, where even a large mass may be barely noticeable on Fig. 18.3.2.20  Normal radiographic anatomy on (a) pa and (b) lateral chest radiographs. (a) 1, trachea; 2, aortic arch; 3, left main pulmonary artery; 4, right main pulmonary artery; 5, right atrial border; 6, left atrial appendage; 7, left ventricular border; 8, right ventricle; 9, right dome of diaphragm; 10, costophrenic angle; 11, breast shadow. (b) 1, trachea; 2, scapulae; 3, anterior aortic arch; 4, right pulmonary artery; 5, left pulmonary artery; 6, right ventricle; 7, breast shadows; 8, gastric bubble under the left hemidiaphragm; 9, left main bronchus.

18.3.2  Thoracic imaging 3983 the PA view; (2) the areas behind the heart and hemidiaphragms; (3) the lung apices, often obscured by overlying clavicle and ribs; and (4) the lung and pleura just inside the chest wall. Once a radiographic abnormality has been detected it should be considered in terms of gross pathology. Both the site and the radio- graphic characteristics of the lesion will allow the observer to pro- duce, at the very least, a generic diagnosis. A precise diagnosis can only occasionally be achieved from the radiographic appearances alone without knowledge of the clinical context. Normal CT anatomy of the mediastinum CT provides unique information about the anatomy of the medi- astinum and is often used to provide further information about abnormalities which are seen merely as a deformity of the medias- tinal contour on chest radiography. The normal structures that are always identified on a CT of the mediastinum are the blood vessels (which make up the bulk of the superior mediastinum), the major airways, the oesophagus, and mediastinal fat. An appreciation of the relationship of these structures to each other is crucial for the correct interpretation of CT scans; four important levels are shown in Fig. 18.3.2.21. Normal lymph nodes surrounded by fat may be identified throughout the mediastinum. Many schemes have been de- vised to map their precise locations but they can be broadly div- ided into (1) anterior mediastinal, (2) posterior mediastinal, and (3)  tracheobronchial. The tracheobronchial can be further sub- divided into the following regions: (1) right and left paratracheal, (2) subaortic, (3) pretracheal, and (4) subcarinal. It is important to appreciate that the absolute size of lymph nodes identified on CT (or by direct inspection at mediastinoscopy) should not be regarded as a foolproof criterion for significant disease, particularly in the context of lung cancer. Although markedly enlarged lymph nodes (>2 cm diameter) almost invariably signify important pathology, moderate enlargement of mediastinal lymph nodes may represent reactive hyperplasia of little clinical significance. Conversely, small volume lymph nodes or lymph nodes not identified by CT may sometimes contain micrometastases, particularly if the primary neoplasm is an adenocarcinoma. Fig. 18.3.2.21  CT with contrast enhancement to show the normal anatomy at four levels through the mediastinum. 1, trachea; 2, superior vena cava; 3, brachiocephalic artery; 4, left common carotid artery; 5, left subclavian artery; 6, oesophagus; 7, aortic arch; 8, azygos vein; 9, ascending aorta; 10, descending aorta; 11, main pulmonary artery; 12, right pulmonary artery; 13, left pulmonary artery; 14, right main bronchus; 15, left main bronchus; 16, left atrium; 17, left inferior pulmonary vein; 18, segmental bronchi of the left lower lobe; 19, right atrium; 20, right ventricular outflow; 21, left ventricle.

section 18  Respiratory disorders 3984 The thymus gland occupies a large part of the anterior medias- tinum in children. In adult life remnants of the normal thymus are usually small or inconspicuous on CT. Common radiological signs of disease Pulmonary consolidation Consolidation is a pathological description of the state of the lungs when the normal air-​filled spaces, distal to the bronchi, are occu- pied by the products of disease (e.g. water, pus, or blood). The most important radiographic signs of pulmonary consolidation are: (1) an area of increased opacification in the lungs which obscures the underlying blood vessels and has a poorly defined margin—​unless it is surrounded by a fissure; (2) an ‘air bronchogram’; and (3) the ‘silhouette sign’ (Fig. 18.3.2.22). The air bronchogram is a dis- tinctive and certain sign of intrapulmonary pathology and is seen as a radiolucent (grey) branching structure of the bronchi against a more opaque (white) background of airless lung. Although an air bronchogram is seen almost invariably in consolidation, a lung which has become collapsed and airless—​for example, due to a large surrounding pleural effusion—​ may also show an air bronchogram. The silhouette sign is seen when the normally clear border of a struc- ture is lost because the air-​filled lung outlining the border is replaced by fluid or a mass. Recognition of this sign can help to localize the area of abnormality within the lungs; for example, consolidation in the lingula will make the left heart border indistinct. As with the air bronchogram sign, the silhouette sign may be seen in either pul- monary consolidation or collapse; for example, loss of a clear right heart border may be due to right middle lobe consolidation with or without lobar collapse; the common feature is loss of normal aeration of the affected lung. The causes of widespread pulmonary consolidation are numerous but may be broadly divided into five categories, as shown in Table 18.3.2.1. Pulmonary collapse This is the term used to describe loss of aeration and therefore infla- tion in part or all of a lung. Depending on the cause, collapse may occur at any level from small, subsegmental areas of lung through to an entire lung. Small areas of subsegmental collapse occur very com- monly in debilitated and postoperative patients, where they are seen as linear, usually horizontal, opacities. At the other end of the spec- trum, collapse of an entire lung, usually due to an endobronchial lesion or inhaled foreign body, has a dramatic radiographic appear- ance with complete opacification of the affected lung and loss of volume of that hemithorax. At the lobar level, the signs of collapse of an individual lobe are characteristic, but depending on the lobe, may be very subtle. Recognition of the collapse of individual lobes is important and these are described in detail. Collapse of individual lobes Right upper lobe On the frontal radiograph there is elevation of the minor fissure and of the right hilum. If the collapse is complete the nonaerated lobe is seen as a density alongside the superior mediastinum (Fig. 18.3.2.23). On the lateral view, the minor fissure moves up- wards and the major fissure moves forwards. The retrosternal area becomes progressively more opaque and the anterior margin of the ascending aorta becomes obscured. Right middle lobe On the frontal radiograph the lateral part of the minor fissure moves down. There is blurring of the normally sharp right heart border and this may be a subtle abnormality which is easily overlooked Table 18.3.2.1  Causes of widespread pulmonary consolidation Pulmonary oedema Cardiogenic/​fluid overload Diffuse alveolar damage (acute respiratory distress syndrome) Inhalational injury (noxious gases) Sepsis Aspiration Traumatic (fat embolism) Exudate Infective consolidation Eosinophilic lung disease Cryptogenic organizing pneumonia Radiation pneumonitis Neoplasm Mucinous adenocarcinoma Lymphoproliferative disorders Blood Contusion Infarction Idiopathic pulmonary haemorrhage Other Alveolar proteinosis Sarcoidosis Fig. 18.3.2.22  Widespread pulmonary consolidation in a patient with alveolar proteinosis. The right heart border is obscured confirming that a large part of the consolidation is in the right middle lobe (the silhouette sign).

18.3.2  Thoracic imaging 3985 (Fig. 18.3.2.24). On the lateral view, the minor fissure moves down- wards and lower half of the major fissure moves forwards giving rise to a triangular shadow with its apex at the hilum and the base behind the lower sternum. Right lower lobe There is an increase in density overlying and obscuring the medial portion of the right hemidiaphragm, and the right hilum is displaced inferiorly on the frontal radiograph (Fig. 18.3.2.25). In contrast to right middle lobe collapse, the right heart border usu- ally remains sharply defined since this is in contact with the aer- ated right middle lobe. On the lateral view the major fissure moves backwards and downwards; with increasing collapse there is a loss of definition of the posterior part of the right hemidiaphragm as well as increased density overlying the lower dorsal vertebral column. Left upper lobe The main finding on the frontal radiograph is a veil-​like increase in density, without a sharp margin (quite unlike right upper lobe col- lapse), spreading outwards and upwards from the elevated left hilum (Fig. 18.3.2.26). The outlines of the aortic knuckle, left hilum, and left heart border become ill defined. As the collapse increases, the lobe moves centrally and the apical segment of the left lower lobe expands to fill the space left by the collapsed upper lobe—​this is the cause of the relatively transradiant lung apex. With complete left upper lobe collapse, a sharp border may return to the aortic arch because it is surrounded by the hyperinflated apical segment of the lower lobe. On the lateral view the major fissure moves superiorly and anteriorly while remaining relatively vertical and roughly par- allel to the anterior chest wall (Fig. 18.3.2.26b). Left lower lobe On the frontal radiograph there is a triangular density behind the heart with loss of the medial part of the left hemidiaphragm (Fig. 18.3.2.27), but even on a properly exposed radiograph it may be difficult to appreciate the collapsed lobe. Supplementary signs in- clude inferior displacement of the left hilum, loss of volume, and in- creased transradiancy of the left hemithorax. On the lateral view there is posterior displacement of the major fissure. As with right lower lobe collapse, there is increased density over the lower dorsal vertebral column and the posterior part of the left hemidiaphragm is effaced. Fig. 18.3.2.24  Right middle lobe collapse. Fig. 18.3.2.23  Posterior–​anterior chest radiograph showing a right upper lobe collapse secondary to a right hilar mass. Note the superior displacement of the horizontal fissure (arrow). Fig. 18.3.2.25  A chest radiograph showing right lower lobe collapse. Note the incorrect position of the nasogastric tube tip within a left lower lobe segmental bronchus (and patchy adjacent consolidation).

section 18  Respiratory disorders 3986 Complete opacification (a ‘white-​out’) of a hemithorax is generally due to either collapse of a lung or a large pleural effusion or tumour. Shift of the mediastinum to the affected side implies that volume loss (i.e. collapse of the lung) has occurred. In contrast, a pleural effusion or soft tissue mass which is large enough to cause com- plete opacification of a hemithorax will almost invariably displace the mediastinum away from the side of the opacified hemithorax. An important exception is an advanced mesothelioma which may encase one lung and ‘freeze’ the mediastinum and prevent contralat- eral mediastinal shift. Occasionally, when there is no obvious shift of the mediastinum, it is surprisingly difficult to differentiate between these two completely different causes of an opacified hemithorax. In these instances, ultrasonography and CT allow the distinction to be made with confidence and may give further information about the underlying disease. Increased transradiancy of a hemithorax There are many causes of increased transradiancy (darkening) of one lung. These may range from a loss of soft tissues of the chest wall (e.g. a mastectomy) through to reduced perfusion of one lung due to hypoxic vasoconstriction resulting from underventilation of the lung because of an inhaled foreign body or a tumour in a main bronchus. It is surprisingly easy to overlook this important radio- graphic abnormality, especially when the density difference between the two lungs is slight: a subtle discrepancy in density between the two hemithoraces is more readily appreciated by viewing the radio- graph from a distance of at least 1.5 m. The commonest causes of a relatively transradiant hemithorax are shown in Table 18.3.2.2. Close scrutiny of the chest radiograph will usually indicate which one of the categories of causes is responsible for this radiographic sign. If there is any clinical suggestion that the cause of the increased transradiancy is due to an obstructing lesion in a central airway, a chest radiograph taken in full expiration will accentuate the in- creased transradiancy and will show that the lung fails to empty. Once it has been established that the difference in density of the lungs is not due to a technical problem (e.g. rotation of the patient), points to look for are (1) loss of symmetry of the soft tissues of the chest wall, (2) discrepancy in the volumes and vas- cular pattern between the two lungs, and (3) a visceral pleural Fig. 18.3.2.26  Posteroanterior (a) and left lateral (b) radiographs demonstrating left upper lobe collapse due to a central obstruction squamous cell carcinoma. Note the anterior displacement of the oblique fissure (arrow) (b). Fig. 18.3.2.27  Left lower lobe collapse. Table 18.3.2.2  Causes of increased transradiancy of one hemithorax Technical Rotation of the patient Chest wall Loss of soft tissues, most commonly due to a mastectomy Pneumothorax Particularly in supine patients Compensatory overinflation Postlobectomy Overlooked lobar collapse (e.g. left lower lobe) Reduced pulmonary perfusion Hypoxic vasoconstriction due to underventilation caused by an inhaled foreign body or endobronchial tumour Obliterative bronchiolitis following childhood viral infection (MacLeod’s/​Swyer–​James syndrome) Recurrent pulmonary emboli (rarely unilateral)

18.3.2  Thoracic imaging 3987 edge (denoting a pneumothorax). The identification of a pneumo- thorax on an erect chest radiograph is usually straightforward because of the appearance of the collapsed lung which is clearly demarcated by the fine edge of the visceral pleura. However, in the supine patient, such an edge is often not seen because air in the pleural space drifts anteriorly to the least dependent part of the chest. In this situation, a pneumothorax is only seen as a vague area of increased transradiancy over the lower zone of the chest. It is vital to recognize when the pressure of the air trapped in the pleural space exceeds alveolar pressure—​a so-​called tension pneumothorax. The typical signs are of contralateral mediastinal shift with straightening and flattening of the ipsilateral dome of the diaphragm (Fig. 18.3.2.28). The pulmonary nodule/​mass Many pulmonary nodules or masses are discovered incidentally on a chest radiograph. Whenever possible, previous films should be obtained so that the growth rate of the lesion can be estimated. The growth rate is a more reliable indicator of the likely nature of a pulmonary mass than any one of its radiographic features: if a lesion doubles in volume (increases in diameter by approximately 25% on serial chest radiographs) in less than 1 week, it is very unlikely to be malignant. The doubling time of most malignant lesions is between 1 and 6 months, but some neoplasms in the adenocarcinoma spectrum may be more indolent. Over the years much importance has been attached to the radio- logical characteristics of a solitary pulmonary mass in an attempt to make the crucial distinction between benign and malignant le- sions. With the possible exception of heavy calcification within the lesion (most commonly seen in ancient granulomas), no radio- logical appearance will reliably differentiate a benign from a ma- lignant mass. Although generalizations can be made, for example, that bronchial carcinomas have irregular and spiculated margins whereas benign lesions are more likely to have smooth outlines, in the individual patient it is not safe to rely on these radiographic features alone to make the distinction between a benign and ma- lignant lesion. After the discovery of a pulmonary nodule or mass on chest radi- ography, further imaging with CT is usually required. CT is valu- able in evaluating extension of a central mass into the mediastinum (Fig. 18.3.2.29), for demonstrating the presence or absence of en- larged mediastinal lymph nodes which may, but do not invariably, indicate local tumour spread, and for the detection of distant me- tastases, such as to the contralateral lung, adrenal glands, and liver. When surgical resection is a potential option, additional imaging of the brain (CT and/​or MRI) and CT/​PET is usually obtained. If required, mediastinal node sampling may be performed with mediastinoscopy, endobronchial or endoscopic ultrasound (EBUS/​ EUS). Ultrasound-​guided sampling of supraclavicular lymph nodes may be an important tool to both confirm nodal involvement and obtain a diagnosis, particularly in patients who are unable to tolerate percutaneous lung biopsy due to poor pulmonary reserve. Local invasion of mediastinal structures, chest wall, and brachial plexus by an adjacent lung cancer may not always be demonstrated by CT, and MRI may be useful in specific circumstances. When surgery is not indicated and a histological diagnosis is needed, percutaneous needle biopsy of central lesions can be safely performed under CT guidance. Similarly, smaller peripheral lesions that are not access- ible by bronchoscopy may be biopsied, under CT or, if abutting the pleura, ultrasound guidance. Lung cancer screening with CT has been evaluated in several large multicentre studies, and there have been promising results from one large trial in the United States. However, the applicability to other populations (including the developing world and areas with a high incidence of tuberculosis) and comparison of mortality reduction with smoking cessation still need to be addressed to determine if CT screening is an optimal use of resources in any given country. However, with the increased use of multidetector CT scanning in a range of conditions, many small (<1 cm) nodules are now detected ‘incidentally’. Practical guidelines have been produced regarding the follow-​up and management of such findings in both low-​risk and high-​risk individuals and continue to evolve. Assessment of nodule Fig. 18.3.2.28  Chest radiograph demonstrating a left tension pneumothorax with mediastinal shift to the right and depression of the left hemidiaphragm, which is a medical emergency. Fig. 18.3.2.29  An intravenous contrast-​enhanced image of a patient with non-​small cell lung cancer demonstrating involvement of the left main pulmonary artery which is significantly narrowed (arrow).

section 18  Respiratory disorders 3988 volume with CT has been a useful adjunct to assessment of growth (Fig. 18.3.2.30) and allows calculation of volume doubling time. Some nodules (e.g. juxtapleural nodules) cannot be assessed using this method as the computer cannot segment the abnormal soft tissue from normal adjacent pleura. Automatic pulmonary nodule detection using specially designed software packages may aid as- sessment of increasingly larger image data sets in the future, but at present these techniques are time-​consuming and throw up large numbers of false positives. Cavitating pulmonary lesions The radiological definition of cavitation is a lucency, representing air, within a mass or area of consolidation. The cavity may or may not contain a fluid level or an intracavitary body, and is surrounded by a wall of variable thickness. The two most likely diagnoses in an adult presenting with a cavitating pulmonary mass on chest radiog- raphy are lung cancer (central, large, and often squamous in type) (Fig. 18.3.2.31) or a lung abscess (usually peripheral and sometimes multiple). Cavitation is recognized in a variety of bacterial pneumo- nias, particularly those due to tuberculosis, staphylococcus, anaer- obes, klebsiella, and chronic aspergillosis. Less commonly, cavitation is seen within pulmonary infarcts and in areas of pulmonary contu- sion due to trauma. Long-​standing cavities in lungs scarred by pre- vious tuberculosis predispose to the formation of mycetomas; once these fungus balls occupy most of the cavity, a characteristic trans- lucent ‘air-​crescent sign’ may be seen between the upper surface of Fig. 18.3.2.30  Examples of pulmonary nodule volumetry software. Initial volume measurements (a) and (b) and subsequent increase in nodule size six months later (c) and (d). The nodule was resected and adenocarcinoma confirmed on histopathology.

18.3.2  Thoracic imaging 3989 the fungus ball and the margin of the cavity on chest radiography (Fig. 18.3.2.32). Multiple pulmonary nodules Many conditions are characterized by multiple small pulmonary nodules. Only by combining the relevant clinical information with a precise description of the size and distribution of the nodules can the differential diagnosis be narrowed. In the United Kingdom, metastatic deposits are by far the commonest cause of multiple pul- monary nodules of varying sizes in an adult. In some parts of the southern United States of America, histoplasmosis is endemic and multiple granulomatous nodules are commoner than those due to disseminated malignancy. In the absence of a known malignancy and when clinical findings and laboratory investigations are in- conclusive, biopsy of one of the nodules may be the only means of establishing a diagnosis. A myriad of small nodules, less than 5 mm in diameter, produces a pattern that is often described as miliary (Fig. 18.3.2.33). A list of causes of miliary shadowing is given in Box 18.3.2.2. An important diagnosis to consider in any patient with this radiographic pattern is miliary tuberculosis. Other differential diagnoses in an asymptom- atic patient with numerous pulmonary nodules include sarcoidosis, metastatic disease or, if there is a relevant occupational history, a pneumoconiosis. As always, comparison with previous radiographs will give invaluable information about the rate of progression and thus the likely nature of the pulmonary nodules. To a lesser extent the distribution of nodules is a consideration in refining the dif- ferential diagnosis of multiple pulmonary nodules; for example, the small nodules of pulmonary sarcoidosis tend to be mid-​zone and perihilar, whereas haematogenous metastases are generally of varying sizes and have a predilection for the lower lobes (probably because of increased blood flow to these regions). The density of nodules sometimes provides conclusive evidence that the nodules are of benign aetiology—​such as the heavily calci- fied nodules which are seen following histoplasmosis or chickenpox (varicella) pneumonia. Most multiple pulmonary nodules are of soft tissue density, and it may be extremely difficult to judge whether small Fig. 18.3.2.31  Chest radiograph of a large cavitating squamous cell bronchial carcinoma adjacent to the right hilum. The right hemidiaphragm is raised because of phrenic nerve invasion by the tumour. Fig. 18.3.2.32  An air crescent (arrow) around a fungus ball at the left apex. This had developed in a tuberculous fibrotic cavity. Fig. 18.3.2.33  Multiple small pulmonary nodules in a patient with miliary tuberculosis.

section 18  Respiratory disorders 3990 nodules are of calcific or soft tissue density because their apparent density depends so critically on the radiographic technique used. Numerous poorly defined, low-​density nodules approximately 8 mm in diameter may be seen around areas of pulmonary con- solidation. In other areas they may be confluent and so make up a larger poorly defined opacity; occasionally these nodules will be uniformly distributed throughout the lungs. At a pathological level these nodules correspond to individual acini which are full of the products of disease, such as pulmonary oedema, inflammatory ex- udates, or haemorrhage. Radiological features of specific diseases Pleural and chest wall disease Because of the two-​dimensional nature of a PA chest radiograph, abnormalities arising from the pleura or chest wall are often difficult to assess. The appearance of a pleural mass on chest radiography depends on whether it is face on or tangential to the X-​ray beam. Generally, a pleural mass will produce a rounded opacity with a sharp medial border and a less well-​defined lateral margin, and an obtuse angle with the pleura. Although abnormality of an adjacent rib will usually indicate that an apparent ‘pleural’ mass is of chest wall origin (Fig. 18.3.2.34), the distinction between a pleural and chest wall mass often cannot be made from a chest radiograph alone. With extensive pleural pathology it may be difficult to distinguish between a pleural effusion, chronic pleural thickening, or even a neoplasm of the pleura such as a mesothelioma. In such cases, a lat- eral decubitus film will distinguish between pleural fluid or thick- ening by demonstrating redistribution of the shadowing if it is due to an effusion. Ultrasonography is also useful in identifying pleural fluid. CT will show even more precisely the site and extent of an abnormality which is apparently ‘pleural’ on a chest radiograph. Furthermore, CT will reveal subtle abnormalities not shown on a plain chest radiograph, such as flecks of calcification within the wall of a chronic empyema, or underlying rib abnormalities in the case of a neoplastic tumour. Similarly, masses arising from the chest wall that give the appearance of a ‘pleural’ mass, such as an intercostal neurofibroma or lipoma, are most accurately assessed by CT. Chronic obstructive pulmonary disease Most patients with chronic obstructive pulmonary disease show remarkably little radiographic abnormality despite often consider- able symptoms. Of the two principal components falling under this disease, emphysema can be detected on chest radiography when it is severe, whereas chronic bronchitis is a clinical diagnosis with no specific radiographic features. Although emphysema is correctly regarded as a pathological diag- nosis, the destruction of alveolar walls distal to the terminal bron- chiole results in certain radiographic features in more advanced cases: overinflation of the lungs causes flattening of the domes of the diaphragm, which may have a scalloped appearance; a lateral chest radiograph may show striking translucency of the enlarged retrosternal and retrocardiac regions. The pattern of the pulmonary vasculature is deranged, with the smooth tapering of the vessels re- placed by an abrupt change in calibre from the larger proximal pul- monary arteries to spindly and attenuated peripheral vessels, giving a so-​called pruned appearance. Depending on the aetiology of the emphysema, there may be an upper zone (e.g. smokers) or lower zone (e.g. α1-​antitrypsin deficiency) predominance; the relatively spared lung often shows a prominent vascular pattern due to blood diversion to these areas. Bullous emphysema is characterized by cystic air spaces bound by extremely thin walls. They may become extremely large and occupy a large part of the lung (Figs. 18.3.2.35a, b). A fluid level within a bulla represents either infection or haemorrhage. Another compli- cation is a pneumothorax, which may be chronic and is sometimes difficult to distinguish from a large bulla. CT is far more sensitive than chest radiography in the detection of emphysema and in some early cases will show evidence of emphy- sema before lung function tests become abnormal. Bronchiectasis Bronchiectasis, whatever the aetiology, is defined as damage to the bronchial wall causing irreversible dilatation of the bronchi. The diagnosis of bronchiectasis is rarely made with certainty from the chest radiograph alone, unless the disease is extensive and severe. Box 18.3.2.2  Differential diagnosis of widespread nodular (0.5–​ 3 mm diameter) shadowing • Miliary tuberculosis • Fungal diseases • Metastatic disease • Pneumoconiosis • Sarcoidosis • Subacute hypersensitivity pneumonitis • Idiopathic pulmonary haemosiderosis Fig. 18.3.2.34  A malignant chest wall lesion resulting in rib destruction. Note the obtuse angle between the lesion and the pleural surface superiorly and inferiorly.

18.3.2  Thoracic imaging 3991 On a chest radiograph the abnormal bronchi may be visible as ei- ther ring shadows and curvilinear shadows that represent thickened bronchial wall seen end-​on, or as parallel thin lines or ‘tramlines’, particularly in the lower lobes; this latter sign can be very subtle and may be more obvious on the lateral chest radiograph. Other radiographic signs of bronchiectasis include round or oval nodular opacities, and sometimes band shadows representing grossly dilated fluid-​filled bronchi. High-​resolution CT is the imaging technique of choice in investi- gation of patients with suspected bronchiectasis. Abnormally dilated and thickened bronchi are readily identified on high-​resolution CT (Fig. 18.3.2.36); a normal bronchus is of approximately the same diameter as its accompanying pulmonary artery. In addition to al- lowing a confident diagnosis of bronchiectasis to be made, often in the face of a normal chest radiograph, high-​resolution CT will show how many lobes are involved—​a consideration in deciding on op- timal medical or surgical management. Chronic diffuse lung disease Many conditions are characterized by diffuse shadowing of the lungs on a chest radiograph. The lung has few ways of responding to in- jury (capillary leak, cellular infiltration, or interstitial fibrosis) and the resulting spectrum of radiographic patterns is correspondingly limited. It is important that reproducible terms are used in the de- scription of widespread pulmonary shadowing. Vague terms that may convey a pathological meaning (which in fact cannot be in- ferred from the gross signs of disease on a chest radiograph, e.g. ‘in- flammatory shadowing’) should not be used. Instead, descriptions of the radiographic pattern should be limited to strictly morpho- logical terms such as ‘reticular’—​a fine network, ‘nodular’—​small dots of a specified size, ‘linear’—​fine lines which are not vessels, ‘ground glass’—​a greying-​out of the lungs that makes the vascular markings indistinct, and finally ‘air-​space shadowing’ or ‘consolida- tion’—​opacification of the lungs in which an air bronchogram may be visible. These descriptors are more reproducible and are prefer- able to the wide range of imprecise and whimsical terms that have been coined in the past. An analysis of the distribution of the disease is often at least as important as defining the radiographic pattern in reaching a dif- ferential diagnosis. This involves an assessment of whether the disease involves all parts of the lung uniformly, or whether there is a zonal predominance (upper, mid, or lower; central or per- ipheral). The perihilar, mid-​ and upper-​zone distribution of the reticulonodular pattern in sarcoidosis is quite different from the lower-​zone peripheral distribution of idiopathic pulmonary fi- brosis; these differences in distribution are even more obvious on the cross-​sectional images of CT. The differential diagnosis can be Fig. 18.3.2.35  The chest radiograph (a) and an axial CT section (b) in a patient with severe bullous emphysema. The absence of lung markings within the right upper zone makes it difficult to exclude a pneumothorax, however the CT demonstrates the multiple thin-​walled bullae. Fig. 18.3.2.36  Axial high-​resolution CT section of a patient with allergic bronchopulmonary aspergillosis showing bilateral varicose and cystic bronchiectasis.

18.3.3 Bronchoscopy, thoracoscopy, and tissue biop

18.3.3 Bronchoscopy, thoracoscopy, and tissue biopsy 3992 Pallav L. Shah

section 18  Respiratory disorders 3992 further refined by assimilating other radiographic abnormalities, such as the presence of pleural disease in the case of asbestosis, or enlarged hilar lymph nodes in the case of sarcoidosis or lymphan- gitis carcinomatosa. Only when the radiographic findings of a patient with diffuse lung disease are taken in conjunction with the clinical features should a working diagnosis be attempted. Many pieces of informa- tion contribute to final diagnosis. In the context of diffuse lung dis- ease, the chest radiograph should be considered as only one part of the clinical jigsaw since a specific diagnosis can rarely be achieved with complete confidence from the radiographic findings alone. In addition to the nonspecific appearances of many diffuse lung dis- eases, the sensitivity of chest radiography is less than ideal, with up to 15% of patients with biopsy-​proven diffuse lung disease having a normal chest radiograph. Conversely, a less than ideally exposed chest radiograph, especially of an obese patient, may misleadingly raise the spectre of diffuse lung disease. In the last few decades the development of high-​resolution CT has changed the radiological approach to the diagnosis of diffuse lung disease, providing valuable prognostic insights that have substantially aided management of patients with diffuse intersti- tial lung disease. As stated previously, high-​resolution CT images of the lung correlate closely with the macroscopic appearances of pathological specimens; can precisely estimate the extent of diffuse lung disease; and are less prone than biopsy to errors of sampling (although open lung biopsy is still required to achieve a definitive histological diagnosis in difficult cases). In addition, when a bi- opsy is indicated, the distribution of disease will indicate whether a transbronchial biopsy or an open lung biopsy is more likely to obtain a representative specimen. Future developments include computer-​ aided quantification of individual CT patterns to monitor response to therapy (Fig. 18.3.2.37), which is particularly relevant to the de- velopment of new treatments for fibrosing lung diseases. FURTHER READING Adam A, Dixon AK, Gillard JH, Schaefer-​Prokop CM (eds) (2015). Grainger and Allison’s diagnostic imaging, 6th edition. Churchill Livingstone Elsevier, Philadelphia. Bradley YC (2013). PET/​CT. Radiologic clinics of North America. Elsevier, Philadelphia. Callister MEJ, et al. (2015). British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax, 70, ii1–​54. Desai SR, Copley SJ, Aziz ZA, Hansell DM (2012). Thoracic imaging (Oxford specialist handbooks in radiology). Oxford University Press, Oxford. Goodman LR (2014). Felson’s principles of chest roentgenology, 4th edi- tion. W. B. Saunders, Philadelphia. Hansell DM, et al. (2008). Fleischner Society: glossary of terms for thoracic imaging. Radiology, 246, 697–​722. Hansell DM, Lynch DA, McAdams HP, Bankier AA (2010). Imaging of diseases of the chest, 5th edition. Mosby Elsevier, Philadelphia. Heitzmann ER (1988). The mediastinum: radiologic correlations with anatomy and pathology, 2nd edition. Springer-​Verlag, Berlin. MacMahon H, et al. (2017). Guidelines for management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017. Radiology, 284, 228–43. McLoud T, Boiselle P (2010). Thoracic imaging: the requisites, 2nd edition. Mosby Elsevier, Philadelphia. Naidich DP, et  al. (2007). Computed tomography and magnetic res- onance of the thorax, 4th edition. Lippincott Williams & Wilkins, Philadelphia. Proto AV, Speckman, JM (1979). The left lateral radiograph of the chest. Medical radiography and photography. Eastman Kodak Company, Rochester, NY. Raghu G, et al. (2018). Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT Clinical practice guideline. Am J Respir Crit Care Med, 198, e44–e68. Rémy-​Jardin M, Rémy J (2010). Integrated cardiothoracic imaging with MDCT. Springer-​Verlag, Berlin. The National Lung Cancer Screening Team (2011). Reduced lung-​ cancer mortality with low-​dose computed tomographic screening. N Engl J Med, 365, 395–​409. Webb RW, Müller NL, Naidich DP (2014). High-​resolution CT of the lung, 5th edition. Wolters Kluwer, Lippincott Williams & Wilkins, Philadelphia. 18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy Pallav L. Shah ESSENTIALS Bronchoscopy, thoracoscopy, and radiologically guided biopsy techniques provide different methods for visualizing and sam- pling thoracic lesions, the approach chosen in any particular case Fig. 18.3.2.37  Volume rendered 3D image of the lungs in a patient with idiopathic fibrosis. Colour coding has been used to depict the extent of low attenuation, ground glass density, reticular pattern, and honeycombing. Image provided courtesy of Brian Bartholmai MD.

18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy 3993 being based on several factors, including the anatomical loca- tion of abnormal areas, presence of coexisting pulmonary dis- ease, presence of comorbidities, and local expertise. CT is useful in both selection and planning of the most appropriate sampling method. Bronchoscopy Bronchoscopy can be used for sampling central lesions, mediastinal lymph nodes, hilar lymph nodes, and—​where magnetic navigation technology or radial ultrasound is available—​peripheral nodules. Suspected lung cancer is the commonest indication. Lung cancer—​bronchoscopy is an essential tool in diagnosis and staging, when a combination of techniques such as bron- chial washings, brushings, and biopsy improves diagnostic yield, as does review of CT imaging before the procedure. Any abnormal mediastinal lymph nodes should be sampled in the first instance by either transbronchial fine needle aspiration or endobronchial ultrasound-​guided fine needle aspiration. In the active palliation of lung cancer in patients with primary tumour or metastases involving the trachea or main bronchi, a variety of bronchoscopic techniques can be used to restore airway patency, including stenting in selected cases. Diffuse lung disease and focal parenchymal infiltrates—​ bronchoalveolar lavage provides information on cellular processes involved, transbronchial lung biopsy on the pathological charac- teristics, and segmental lavage is a useful tool in patients with sus- pected respiratory infection. Other indications—​the role of therapeutic bronchoscopy is increasing with the development of new endoscopic treatments for respiratory diseases such as emphysema and asthma. Thoracoscopy Thoracoscopy allows visual inspection and direct sampling of pleural abnormalities, the commonest indications being (1) evalu- ation of an exudative pleural effusion when cytological analysis of aspirated fluid does not provide a conclusive diagnosis; and (2) in the treatment of a malignant pleural effusion, when a sclerosing agent such as talc can be evenly applied to the pleural surface, a technique which also has a role in the management of recurrent spontaneous pneumothorax. Percutaneous biopsy The role of ‘blind’ (unguided) pleural biopsy is diminishing as it has been superseded by either thoracoscopic or image-​guided biopsy. Radiologically guided percutaneous biopsy is usually considered where cancer is suspected and there is no clear indication to pro- ceed to surgical resection. Introduction Direct visualization of the airways by bronchoscopy has become an important tool in the diagnosis of respiratory disease since its introduction in Japan in 1966. The ability to visualize specific areas significantly improves diagnostic yield in comparison to blind pro- cedures. Similarly, the diagnosis and treatment of pleural disease has improved significantly with the introduction of thoracoscopy, which allows the direct inspection of the pleural cavity. Tissue biopsy has also evolved, with more procedures now being per- formed with some form of image guidance. Bronchoscopy Bronchoscopy is an essential basic investigation for the respira- tory physician. The first bronchoscopes were rigid instruments that were adapted from oesophagoscopes. The development of optical fibres enabled flexible bronchoscopes to be constructed, which significantly improved the utility of bronchoscopy, and today videobronchoscopes that provide high-​quality images are used routinely. Flexible bronchoscopy permits the visual inspection of the air- ways from the vocal cords, trachea, and endobronchial tree down to the subsegmental level. It also allows for a variety of samples to be easily obtained from the airways. The procedure is very safe and is performed as a day-​case procedure, with local anaesthesia with or without short-​acting intravenous sedation. Rigid bronchoscopy is still performed, primarily by thoracic surgeons and by some phys- icians for interventional procedures: the equipment has a greater intraluminal diameter than do flexible bronchoscopes and hence allows easier instrumentation, but at the expense of a more re- stricted field of view, limited manoeuvrability, and the requirement for general anaesthesia. Indications The main indications for flexible bronchoscopy are listed in Table 18.3.3.1: suspected lung cancer is the commonest, followed by the assessment of pulmonary infiltrates for microbiological sampling. The role of therapeutic bronchoscopy is increasing with the development of new endoscopic treatments for respiratory diseases. Contraindications Informed consent from the patient or their representative is a pre- requisite. The main contraindications for bronchoscopy are hypoxia that cannot be adequately corrected by oxygen supplementation, and a bleeding diathesis. However, even in these circumstances firm ‘cut-​offs’ cannot be given—​the risk-​benefit must be evaluated on an individual patient basis. The procedure should only be per- formed by an individual with an appropriate level of experience, or under supervision by an experienced bronchoscopist. Adequate facilities for resuscitation, and the skills and equipment to deal with any potential complication, should be immediately available. Bronchoscopy staff should be trained and competent in dealing with problems such as respiratory failure, cardiac arrhythmias, haemor- rhage, pneumothoraces, and the requirement for intercostal drain insertion. Equipment The flexible bronchoscope is a flexible tube containing bundles of optical fibres that carry light to the distal end to illuminate the airways, and a further bundle to transmit the image back to the eyepiece. The distal end of the bronchoscope can be angled through 160° by a lever at the head of the scope. This, in combin- ation with rotation of the scope, allows it to be manipulated during the examination of the airways. There is an instrument channel

section 18  Respiratory disorders 3994 that allows procedures such as biopsies to be performed and which also functions as a suction channel. A variety of instruments are available, with the specification of the bronchoscope influencing its use; those with larger instrument channels are more suitable for interventional procedures, whereas smaller instruments allow more distal airways to be examined. The latest generation of video bronchoscopes have improved angulation and also the ability to rotate the distal insertion portion of the bronchoscope through 150°, facilitating improved access for diagnostic and therapeutic purposes. Modern videobronchoscopes have a charge-​coupled device (CCD) chip at the distal end, which allows the image to be pro- jected on to a monitor. The latest systems utilize high-​definition TV technology and produce high-​quality full-​screen images, which significantly enhance diagnosis. There are also several hybrid devices that use fibreoptic bundles to carry light down and images back up towards the proximal portion of the bronchoscope. A CCD chip in the head of the scope allows the image to be trans- mitted onto a monitor, the image quality being determined by the number of optical fibres and the size of the CCD chip. These hybrid scopes have the advantage of having either a smaller ex- ternal diameter or a much larger instrument channel than conven- tional videobronchoscopes. The most important development in the last decade has been the development of an integrated bronchoscope with a linear array ultrasound probe at the distal end. This endobronchial ultrasound bronchoscope (EBUS), with real-​time transbronchial fine needle as- piration (EBUS-​TBNA), has transformed the diagnosis and staging of lung cancer, and its role in other diseases such as sarcoidosis and tuberculosis is also expanding. Disinfection Bronchoscopes are cleaned and disinfected before and after the procedure. Particular care should be taken to clean the in- strument channel and suction ports manually with a brush, as well as flushing the channel with sterile water. The instrument is then placed in a disinfection solution such as 2% alkaline glutaraldehyde (the commonest used), or phenyl or isopropyl al- cohol, and automatic disinfection with 0.2% peracetic acid can also be used. In all cases the instruments should be soaked in the disinfectant solution for at least 20 min. Cross-​infection has been observed with organisms such as environmental mycobacteria and pseudomonas species; processes must therefore be in place to document disinfection before use in each patient, and the serial number of the bronchoscope(s) used in individual patients should be recorded for tracing in the event of suspected cross-​infection. In most cases of cross-​infection, inadequate manual cleaning of bronchoscopes has been a factor. Biopsy forceps and needles are more invasive and hence need to be sterilized rather than simply disinfected. The potential risk of infections with viruses and prions has driven the development of single-​use disposable instruments. The development of instruments that can be sterilized rather than dis- infected is an alternative option, but would incur significant capital investment. Because there is a significant time delay for instru- ments that require sterilization (days, rather than the short time required for disinfection), more than 10 bronchoscopes would be required to maintain a clinical service. Patient preparation Patients need to provide informed consent before the procedure and should ideally be provided with written information in advance, with key aspects such as risks of the procedure and alternative ap- proaches discussed prior to giving final consent. Bronchoscopy is usually performed as an outpatient procedure with conscious sed- ation, and patients should be advised not to eat or drink for at least 4 h beforehand. Box 18.3.3.1 provides a simple checklist for patient preparation. All available imaging should be reviewed prior to bronchos- copy. Ideally, a recent CT scan should be available, as there is good evidence that review of such images before flexible bronchoscopy significantly improves the yield from the procedure. In one study, 171 patients being evaluated for suspected lung cancer were ran- domized: all had a CT scan performed before bronchoscopy, but in one group the scans were reviewed before the procedure, whereas in another (control) group they were not. The diagnostic yield of bronchoscopy was 73% in the former group compared to 54% in the latter and fewer investigations were required in the group where Table 18.3.3.1  Indications for bronchoscopy Investigation
of symptoms Haemoptysis Persistent cough Recurrent infection Suspected neoplasia Unexplained paralysis of vocal cords Stridor Localized monophonic wheeze Segmental or lobar collapse Unexplained paralysis of hemidiaphragm Suspicious sputum cytology Unexplained pleural effusion Mediastinal tissue—​diagnosis and staging Assessing suitability for surgery Staging of lung cancer Infection Assessment of pulmonary infiltrates Identification of organisms Evaluation of airways if recurrent or persistent infection Interstitial lung disease Differential cell counts and cytology Transbronchial lung biopsy Transbronchial cryobiopsy Therapeutic Clearance of airway secretions Recurrent plugging of patient on ventilators following lobar collapse Foreign body removal Palliation of neoplasm Endobronchial ablation of tumour Dilatation of bronchial strictures Insertion of stents Bronchoscopic lung volume reduction for Emphysema Insertion of one-​way endobronchial valves for bronchopleural fistula Bronchial thermoplasty for asthma

18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy 3995 the CT scans were reviewed before bronchoscopy. This approach is therefore more cost-​effective and this author advocates it for all patients undergoing assessment for possible lung cancer. It also al- lows additional staging procedures such as transbronchial needle aspiration to be performed at the same time as the initial diagnostic bronchoscopy. A short-​acting intravenous benzodiazepine such as intravenous midazolam or an opiate such as fentanyl or alfentanil may be used for sedation. Midazolam has the advantage of amnesic properties, whereas fentanyl and alfentanil have good antitussive properties. In some institutions a low-​dose propofol infusion is used to induce and maintain sedation. Patients who have been given sedation should be advised not to drive or handle any machinery for at least 24 h after the procedure. The procedure can be performed without any sed- ation, which should be considered in some individuals who become aggressive and uncontrollable following intravenous benzodiazep- ines. It is also an option in patients who cannot be accompanied for 24 h after the procedure. Patients are monitored by continuous oximetry throughout the procedure. Those with pre-​existing cardiac disease, or where hyp- oxia is not fully controlled by oxygen therapy, should also have elec- trocardiographic (ECG) monitoring and regular blood pressure measurements. Basic procedure Bronchoscopy can be performed with the patient semi-​recumbent and approached from the front, or alternatively the patient can be lying flat and approached from behind. The choice is determined by local practice and also the procedure that is being performed. Intubation can be performed through either the nose or the oro- pharynx. Again, local practice seems to influence the approach, but the external diameter of the bronchoscope and the procedure being undertaken should also be taken into account. The oral pharynx is first anaesthetized with 4% lignocaine (lido- caine) for all procedures. The nasal passage is then anaesthetized with 2% lignocaine gel if a transnasal approach is used. With the nasal route, the bronchoscope is passed through the nares and naso- pharynx under direct vision until the epiglottis is visualized. With the oral route, the patient is asked to gently bite onto a mouthguard and the bronchoscope is then placed through this mouthguard into the oropharynx to the level of the epiglottis. The vocal cords should be visible from this level and their move- ment assessed, after which they are anaesthetized with 2 ml aliquots of 2% lignocaine. When any coughing subsides, the scope is ad- vanced through the widest part of the glottis, with care taken not to touch the vocal cords. The subglottic area of the trachea is very sen- sitive and patients initially feel as if they are choking. Further 2 ml aliquots of 2% lignocaine are administered in the trachea, carina, right main bronchus, and left main bronchus. The trachea and endobronchial tree can be inspected down to the segmental areas (Fig. 18.3.3.1), the limiting factor being the size of the bronchoscope. The average bronchoscope with a 5 mm external diameter can reach the second or third generation subsegments. The following can be assessed at bronchoscopy: • Dynamic and fixed changes in airway calibre, including areas of ex- trinsic compression from enlarged lymph nodes or extrabronchial tumour masses • Distortion of the airways due to traction from fibrotic or collapsed areas of lung • The general appearance of the mucosa, with changes ranging from subtle abnormalities such as increased vascularity (Fig. 18.3.3.1d) and oedema through to gross tumour infiltration Polypoid tumours involving the first or second generation subseg­ ments should be easily identified at bronchoscopy (Fig. 18.3.3.1c). However, submucosal disease can be easily missed, and can range from subtle thickening of the airways through to small pearly nodules (may be present in tuberculosis or sarcoidosis). Small ulcers are also occasionally seen with tuberculosis or Wegener’s granulomatosis. In Kaposi’s sarcoma, cherry-​red-​like lesions are visible. Basic techniques and sampling Bronchial washings Obtaining bronchial washings involves the instillation of 10–​20 ml aliquots of 0.9% saline into a subsegment, as close as possible to the site of abnormality. The sensitivity is variable, being 48% (range 21–​ 76%) in a recent review that evaluated 30 studies where the yield from the different bronchoscopic techniques was evaluated in at least 50 patients with suspected lung cancer. Bronchial biopsies Biopsy forceps can be inserted through the instrument channel of the bronchoscope and pinch biopsies obtained under direct vision, with several biopsies obtained to ensure that adequate tissue has been obtained for diagnosis. A higher yield can be obtained from endobronchial biopsies, with an overall sensitivity for lung cancer of 74% (range 48–​97%), but where an exophytic tumour is visible the diagnostic yield should be at least 90%. The technique is generally very safe and the main complication is that of bleeding, particularly where vascular lesions are sampled, but this is rarely significant and can usually be controlled with conservative measures. Bronchial brushings A cytology brush can be used to scrape cells from the surface of any abnormal areas seen at bronchoscopy. These can then be either smeared onto a slide or rinsed in saline, according to local prefer- ence. In the meta-​analysis described in the previously section, the yield from bronchial brushings was 59% (range 23–​93%). The main Box 18.3.3.1  Preparation for bronchoscopy • Patient information—​verbal and written information • Informed consent • Full blood count and clotting prior to transbronchial lung biopsy • Baseline ECG if history of cardiac disease • Spirometry if arterial oxygen saturation is less than 95% • Arterial blood gases if oxygen saturation is less than 92% • If the patient is to have any sedation, ensure that someone is going to accompany them home after the procedure • Remind the patient that if they are sedated they will be unable to drive or operate machinery for at least 24 h • Intravenous access • Consider bronchodilators if evidence of bronchospasm • Prophylactic antibiotics if asplenia, mechanical heart valve prosthesis, or history of endocarditis

section 18  Respiratory disorders 3996 complication is minor bleeding, but there is a risk of a pneumo- thorax where a brush is advanced blindly beyond a subsegmental bronchus. Transbronchial fine needle aspiration In this technique a transbronchial fine needle is inserted through the mucosa and into a submucosal lesion beyond the endobronchial surface and a few cells are aspirated for cytological analysis. It has a sensitivity of around 56% (range 23–​90%). Transbronchial fine needle aspiration can also be used to sample lymph nodes and is particularly useful in the diagnosis and sta- ging of lung cancer, with a recent CT scan of the thorax required for planning of the procedure. The needle is inserted through the instrument channel of the bronchoscope and then through the tra- cheal or bronchial surface at the position determined, as perpen- dicularly as possible (at least 45° angle) to the airway wall, with a jabbing motion, and with suction applied with a 20 ml syringe at the other end. The cells that are aspirated are sent off for cytological ana- lysis. Occasionally a small piece of tissue is also obtained with this technique. The sensitivity of this technique in lung cancer is around 68% (range 45–​85%). It provides both diagnostic and staging infor- mation, and is often the sole mode of diagnosis (25% of patients). The availability of rapid on-​site cytological analysis significantly improves the diagnostic yield. However, a negative result does not Fig. 18.3.3.1  The videobronchoscopic appearance of (a) the trachea and main bronchi; (b) segmental bronchi in the right lower lobe; (c) polypoid tumour arising from a bronchial segment; and (d) submucosal disease.

18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy 3997 exclude neoplastic disease and should be followed up by further in- vestigations such as mediastinoscopy in appropriate cases. Although it is possible to diagnose lymphoma with transbronchial fine needle aspiration, the samples obtained are predominantly cyto- logical and do not provide the architectural information required to classify lymphomas. It is also a useful technique in the diagnosis of nonmalignant disease such as sarcoidosis and tuberculosis, but the sensitivity is lower. Overall, transbronchial fine needle aspiration is a very safe and effective technique: complications are rare, consisting of pneumo- thorax, pneumomediastinum, and bleeding (<0.01%). However, the growth and development of endobronchial ultrasound-​guided transbronchial fine needle aspiration has almost completely dis- placed blind TBNA, except where local submucosal disease is found. Bronchoalveolar lavage Bronchoalveolar lavage is a useful diagnostic test in the assessment of parenchymal lung disease. It enables sampling of the distal air- ways and alveolar spaces, and is particularly useful in the assessment of (1) diffuse drug-​induced interstitial lung disease, (2) parenchymal infiltrates, (3) pulmonary infiltrates in immunocompromised pa- tients, and (4) assessment of occupational dust exposure. The samples obtained provide information on the cellular com- position of pulmonary infiltrates, types of infective organisms, and presence of particulate and acellular matter in the alveolar spaces (Table 18.3.3.2). Identification of specific bacteria, fungi, and acid-​ fast bacilli are diagnostic. Malignant cells may be identified in the lavage in patients with bronchoalveolar cell cancer, lymphangitis carcinomatosus, or diffuse metastatic disease. A milky lavage laden with amorphous periodic acid–​Schiff positive staining cellular debris is diagnostic of pulmonary alveolar prognosis. Bronchoalveolar lavage is performed by wedging the broncho- scope in the desired subsegment. In diffuse lung disease, the right mid-​lobe is the segment of choice as it drains well and hence pro- vides the best yield; otherwise the optimal segment is selected on the basis of radiological findings. Once the bronchoscope is wedged, 30-​ to 60-​ml aliquots of normal saline are instilled and aspirated back into a collecting bottle, either by gentle hand suction or with low-​ pressure suction. The total fluid instilled ranges from 100 to 250 ml, depending on the exact indication and local circumstances. The main adverse effects of bronchoalveolar lavage are usually dyspnoea, wheezing, and transient fever. Many patients are hypoxic due to their underlying condition, and installation of significant volumes of saline can precipitate hypoxia and, in some cases, pul- monary oedema. Transbronchial lung biopsy Transbronchial lung biopsy is invaluable in the assessment of diffuse lung disease and in patients where there is localized parenchymal shadowing (at least of segmental distribution). It has a high diag- nostic yield (>80%) in bronchocentric conditions such as sarcoid- osis and has an important role in the diagnosis of lymphangitis carcinomatosis, disseminated malignancy, interstitial pneumonitis, and extrinsic allergic alveolitis. The two main complications of transbronchial lung biopsy are haemorrhage and pneumothorax. The risk of the latter is 5–​10%, but a clinically significant pneumothorax requiring intervention occurs in about 1% of cases. The degree of bleeding is very variable, but blood loss of more than 250 ml is infrequent, and usually managed with aggressive suctioning of any blood combined with instillation of ice-​cold saline and dilute adrenaline (1:100 000). Blocking bal- loons that occlude a lobar bronchus may be used to tamponade the bleeding, and blood transfusion may be required on rare occasions. Fluorescence bronchoscopy Fluorescence bronchoscopy, currently a research tool, is directed to the early detection of lung cancer. It utilizes the finding that normal tissue emits a green fluorescence when illuminated by a light of blue wavelength, whereas dysplastic or cancerous tissue absorbs this fluorescence and appears reddish brown in colour. These changes are not visible to the unaided eye, but can be visualized with the use of appropriate filters and image enhancement. Fluorescence bron- choscopy is significantly more sensitive at detecting severe dysplasia and carcinoma in situ than conventional white light bronchoscopy, but inflammatory lesions and metaplastic changes also appear ab- normal; hence specificity is low and false-​positive results are a limiting factor. Narrow band imaging The new video bronchoscopes have a mode that accentuates the signal from blood vessels and highlights the superficial micro- vascular pattern. Patterns of neovascularization are associated with neoplasia, early changes of increased vessel growth, and networks of tortuous vessels progressing to small spiral or cork screw type vessels in microinvasive carcinoma. Combination of conventional Table 18.3.3.2  Cellular composition of bronchoalveolar lavage according to disease aetiology Lymphocytic cell composition Sarcoidosis Extrinsic allergic alveolitis Hypersensitivity pneumonitis Connective tissue disease Tuberculosis Viral pneumonia Neutrophilic cell composition Idiopathic pulmonary fibrosis/​usual interstitial pneumonia Desquamative interstitial pneumonitis Acute interstitial pneumonitis Acute respiratory distress syndrome Pneumonia Connective tissue disease Wegener’s granulomatosis Cryptogenic organizing pneumonia/​obliterative bronchiolitis Eosinophilic cell infiltrate Eosinophilic pneumonia Churg–​Strauss syndrome Allergic bronchopulmonary aspergillosis Drug-​induced pneumonitis Mixed picture Cryptogenic organizing/​obliterative bronchiolitis Connective tissue disease Nonspecific interstitial pneumonitis

section 18  Respiratory disorders 3998 video bronchoscopy and narrow band imaging has a greater sensi- tivity for the detection of early neoplasia Endobronchial ultrasound-​guided transbronchial
needle aspiration The development of a linear array ultrasound probe integrated into a videobronchoscope, which allows simultaneous ultrasound and conventional bronchoscopic imaging, has significantly im- proved the utility of ultrasound in bronchoscopy (Fig. 18.3.3.2). Endobronchial ultrasound mediastinoscopy has transformed the diagnosis and staging of suspected lung cancer. The linear probe can be applied against the tracheal wall and the mediastinum assessed for abnormal lymph nodes or any adjacent masses, which are vis- ible as hypoechoic lesions. Blood vessels can be identified as very hypoechoic structures, with identification enhanced by the use of the Doppler mode. A  dedicated needle can be inserted through the instrument channel of the bronchoscope and transbronchial needle aspiration performed with real-​time ultrasound imaging (Fig. 18.3.3.2). Abnormal lymph nodes as small as 5 mm in diam- eter can be sampled. This elegant technique, which allows sampling of lymph nodes and masses adjacent to the airway, has a diagnostic yield of 85–​90% and has superseded mediastinoscopy as the first-​ line investigation for staging the mediastinum in lung cancer. It also has an important role in the diagnosis of other metastatic disease, as well as in sarcoidosis and tuberculosis. Radial ultrasound Endobronchial ultrasound was originally performed using a 20 MHz radial vascular mini-​ultrasound probe enclosed in a water-​filled balloon sheath. These ultrasound probes produce ex- cellent images of the mediastinum and hilar structures, and can provide information on vascular invasion. They are able to identify the different bronchial layers from submucosa to adventitia, and have the potential of determining if the mucosa has been breached by cancer and hence distinguish between carcinoma in situ and invasive carcinoma. The procedure has been adapted by the use of a guide sheath which facilitates sampling of peripheral nodules. The yield is improved in conjunction with fluoroscopy, when the radial ultrasound probe is inserted with a guide sheath through the instrument channel of a video bronchoscope and directed into the appropriate segment. When the radial probe approaches the peripheral mass, the ultrasound signal changes to reveal an ir- regular mass. The guide sheath is secured in this position and the radial probe exchanged for sampling tools such as biopsy forceps, cytology brushes, and peripheral fine needle. Multiple samples should be obtained with fluoroscopic guidance to ensure that the guide sheath has not moved. Magnetic navigation Magnetic positional tip technology can be integrated with CT scan- ning data to create a virtual CT scanner in the bronchoscopy suite. A spiral CT with reconstructions of 1 mm slices is required, the data from which is used to create a virtual bronchoscopy model. Specific landmarks such as the primary and lobar carina are marked. At bronchoscopy, a catheter with a magnetic tracking device is inserted through the instrument channel and the catheter tip is positioned and calibrated with the CT data by systematically examining the bronchial segments. The system then integrates the CT data with the bronchoscopy data and can be used to guide the catheter with the magnetic tracking device to the target lesion (Fig. 18.3.3.3). Once the target is reached, the tracking device is removed, the biopsy for- ceps or needle is inserted through the catheter, and appropriate sam- ples are obtained for diagnosis. The main benefit from this system is that it facilitates the biopsy of peripheral pulmonary lesions which measure more than 20 mm in size. The bronchoscopic route tends to be safer, with a lower in- cidence of complications such as pneumothoraces than percutan- eous approaches. It may also improve the accuracy of transbronchial needle aspiration of mediastinal lymph nodes. Diagnostic role of bronchoscopy in lung diseases Lung cancer Suspected lung cancer is one of the main indications for bronchos- copy, the value of which in the diagnosis of central lesions is self-​ evident. Although the diagnostic rate is much lower in peripheral lesions, a variety of techniques such as bronchoalveolar lavage, fluoroscopic biopsy, radial ultrasound, and magnetic navigation-​ guided biopsy can improve this. Where there is mediastinal adenopathy, consideration should be given to sampling of these lymph nodes by transbronchial needle aspiration, ideally with endo- scopic ultrasound guidance (EBUS-​TBNA) Diagnosis and staging should be evaluated simultaneously, with every effort made to sample mediastinal lymph nodes where they are enlarged (>10 mm in short axis on CT) or where there is increased uptake on a 18F-​fluorodeoxyglucose positron emission tomography (FDG-​PET) scan. Diffuse lung disease Bronchoalveolar lavage and transbronchial lung biopsies in conjunc- tion with high-​resolution CT form the basis of diagnosis for diffuse lung disease. The cell morphology of the lavage fluid is useful in the diagnosis of specific conditions (see Table 18.3.3.2): in sarcoidosis Fig. 18.3.3.2  An ultrasound image demonstrating a needle in a hypolucent ovoid lymph node during endobronchial ultrasound-​guided transbronchial fine needle aspiration.

18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy 3999 there is a lymphocytic infiltrate which may demonstrate a high CD4/​ CD8 ratio; a mixed lymphocytosis with CD8 predominance in the presence of foamy macrophages and plasma cells is suggestive of extrinsic allergic alveolitis; haemosiderin-​laden macrophages are found in alveolar haemorrhage. A novel technique of cryobiopsy is currently being evaluated for the diagnosis of interstitial lung disease. A cryoprobe is inserted through the instrument under fluoroscopic guidance. The probe is directed to the area of interest and, following a freeze cycle of about 6–​8 seconds, the probe and bronchoscope are both removed as one unit. Tissue adherent to the probe is then thawed and sent for histology. This technique provides relatively large biopsy specimens without crush artefact (as is seen with forceps biopsy) for the diag- nosis and characterization of diffuse lung disease. Respiratory infection Bronchial lavage is useful in the diagnosis of respiratory infection when sputum cannot be obtained. It is usually reserved for patients who are failing to respond to empirical treatment, but has a vital role in the diagnosis of pulmonary infiltrates in those who are immuno- compromised. Bronchial lavage allows optimal specimens to be col- lected for microscopy and culture before starting antituberculous Fig. 18.3.3.3  Magnetic navigation-​guided bronchoscopy: (a) screen shot during planning stage with virtual bronchoscopy and CT images; (b) screen shot of procedure stage which demonstrates the location of the magnetic tracker in relation to the target lesion.

section 18  Respiratory disorders 4000 chemotherapy in patients with suspected tuberculosis who are not smear positive on sputum samples. Therapeutic role of bronchoscopy in lung diseases Lung cancer About 30% of patients with lung cancer present with advanced disease that involves the trachea or main bronchi. They develop symptoms such as breathlessness, cough, and haemoptysis, and are prone to recurrent pneumonia. Progressive symptoms of respiratory failure and recurrent endobronchial sepsis lead to death. Endobronchial metastases from other tumour sites have a similar effect. Bronchoscopy can have an important palliative role in the treat- ment of tumours that are accessible via the bronchoscope. Several techniques allow tumour debulking and restoration of airway patency, but these are generally underutilized and most patients only receive external beam radiation or chemotherapy. Tumours can be debulked by flexible bronchoscopy using electrocautery, argon plasma coagulation, neodymium yttrium aluminium garnet (YAG) laser, photodynamic therapy, and cryotherapy, most of which can be performed on a day-​case basis in the endoscopy suite under conscious sedation. Improving access to these tech- niques in the palliation of endobronchial malignancy should im- prove survival. In selected patients debulking may need to be combined with the insertion of self-​expanding metal stents, the key indication being where there is significant airway narrowing due to extrinsic com- pression by tumour, or where the airway structure has been des- troyed by the cancer. In both situations a stent attempts to improve airway patency by exerting an outward radial force. Covered stents can also be used to seal off airway fistulas and also prevent tumour ingress into the airway. However, the use of airway stents is asso- ciated with important complications including displacement and endoluminal wall damage, mucus impaction, granuloma formation, reobstruction, infection, halitosis due to biofouling, haemoptysis, pain, cough, and stent fracture. Emphysema Dynamic airway collapse in emphysema in conjunction with bullous lung disease leads to significant air trapping, flattened diaphragms, impaired respiratory muscle dynamics, and breath- lessness. Lung volume reduction surgery has been shown to be effective in patients with upper lobe emphysema and poor base- line exercise tolerance. In selected patients bronchoscopic lung volume reduction can be performed with much lower morbidity and mortality than are associated with open surgical procedures. Two main devices are available: one is a valve that is placed in a segmental bronchus and allows air and secretions to drain, but pre- vents air from entering into that lung segment, thus causing lobar atelectasis (Fig. 18.3.3.4b); the other is an umbrella-​like device (intrabronchial valve) that acts in a similar manner by blocking air from entering and allowing the drainage of secretions. Clinical trials have demonstrated that patients with heterogenous emphy- sema (greater damage in one lobe with better lung tissue in the ipsilateral lobe) and intact fissures, or those where the absence of collateral ventilation is proven, derive the greatest benefits. In this selected group improvements in exercise capacity and quality of life are observed in over two-​thirds, but there is a greater risk of pneumothoraces in this population (20%). Other techniques that show promise in clinical trials are endobronchial coils, which restore the elastic recoil of the lung. Approximately 10 coils are inserted by bronchoscopy with fluoro- scopic guidance into one of the lobes in each lung, a therapy which suitable for patients with both heterogenous and homogenous em- physema, irrespective of the presence of collateral ventilation, but not in those with severe bullous disease. Experience thus far dem- onstrates appreciable improvements in quality of life, walking dis- tances, and pulmonary function. Thermal ablation with vapour, which causes fibrosis and contracture in the treated area of the lung, Fig. 18.3.3.4  (a) A catheter delivering thermal energy during bronchoscopy in an asthmatic patient; (b) image of a valve in situ in a patient undergoing bronchoscopic lung volume reduction.

18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy 4001 and a biofilm sealant, which induces localized inflammation and fi- brosis, are also under clinical investigation. A different approach, in which artificial airways are created be- tween pockets of trapped gas and the segmental airways, has been developed for patients with homogenous emphysema. The tech- nique identifies avascular areas in the airway with the use of Doppler ultrasound and employs a needle to create a hole measuring up to 5 mm in diameter, which is then maintained with a drug-​eluting stent. These new airway passages allow trapped gas to escape and hence reduce lung volume. Preliminary reports suggest physio- logical improvements in lung volumes, exercise capacity, and quality of life. Although proof of principle of efficacy has been established, the airways occlude over time and the benefit diminishes. Asthma Bronchial thermoplasty is a promising bronchoscopic treatment for asthma (Fig. 18.3.3.4a). The technique involves the application of thermal energy under direct vision to the wall of airways more than 3 mm in size, leading to a reduction in smooth muscle. Randomized control trials have demonstrated improvements in asthma-​related quality of life measures, and reductions in exacerbations, hospital- ization rates, and days lost due to ill health. Thoracoscopy Thoracoscopy is a simple invasive procedure which can safely be performed under local anaesthesia, with or without conscious sed- ation. It provides excellent direct visualization of the pleural cavity. Indications The commonest indication for medical thoracoscopy is evaluation of an exudative pleural effusion when cytological analysis of aspir- ated fluid does not provide a conclusive diagnosis. It allows direct visualization of the pleura and targeted biopsies of any abnormal areas, and in experienced hands has a diagnostic sensitivity of 90–​ 95%. It is also a key investigation in the assessment of patients with repeated pneumothoraces or a persistent air leak, and it is also used in some centres for the assessment of interstitial lung disease. Contraindications The main contraindication to thoracoscopy is absence of an ad- equate pleural space due to adhesions or previous surgery. Relative contraindications are a bleeding diathesis (INR >1.4), pulmonary hypertension, severe cardiac disease, or hypoxia. An uncontrolled cough or inability to lie still makes the procedure difficult and is an- other relative contraindication. However, as with bronchoscopy, the risk and benefits of the procedure should be evaluated for the indi- vidual patient. Equipment The basic equipment comprises of a rigid thoracoscope with a 9 or 11 mm diameter. These instruments have a variety of optics that allow straight and angled examination, and there are also integrated biopsy forceps with optics that allow accurate biopsy under direct vision. Other essential pieces of equipment include special nee- dles (Verres or Deneke) for inducing an artificial pneumothorax in the absence of a pleural effusion. A gas insufflator is used to fill the pleural space with carbon dioxide or another gas to create a large enough space to facilitate inspection of the pleural cavity. The key precaution is to avoid inducing an artificial tension pneumothorax. Sterilization As thoracoscopy is an invasive procedure, it is not adequate to simply disinfect equipment as in bronchoscopy—​all of the equipment used has to be sterilized by autoclaving. Patient preparation and basic procedure Patient preparation is as for flexible bronchoscopy. The procedure can be performed with local anaesthesia, with or without con- scious sedation. Patients are fasted for at least 4–​6 h beforehand, and oxygen saturation, ECG, and blood pressure are monitored during thoracoscopy. Aseptic conditions are required:  operators should wash their hands thoroughly and use sterile gloves and gowns. The patient is usually placed in the lateral decubitus position and the entry site is cleaned with chlorohexidine, with appropriate sterile drapes placed around. The access site is usually the fourth or fifth intercostal space in the midaxillary line, the exact entry port being influenced by the indi- cation for the procedure and also guided by imaging such as CT or ultrasonography. The pleura is visualized and appears as a delicate, transparent, light-​reflecting surface with a fine network of blood vessels within it. Any changes in its surface are recorded, varying from areas of increased vascularity or localized thickening to diffuse changes, and there may be obvious nodules or tumour deposits. An angle telescope is often used to inspect the far reaches of the thoracic cavity such as the apex, interlobar space, paravertebral gutter, and mediastinal surfaces. Any fluid present can be sampled and sent for appropriate investi- gations, including cytology, and any areas of localized diffuse thick- ening may be biopsied. Whatever the visual findings, the parietal pleura should usually be biopsied, with care taken to obtain samples from the upper border of the ribs to avoid the neurovascular bundle that runs along the lower margin. It is possible to obtain visceral pleural biopsies and lung biopsies during thoracoscopy, but they carry a greater risk of bleeding and/​or inducing a persistent air leak. The main complications of thoracoscopy are bleeding and pro- longed air leaks. Bleeding can usually be controlled by coagulation with either electrocautery or argon plasma photocoagulation. An intercostal drain should be placed whenever biopsy of the visceral pleura or lung has been performed. Serious but less common com- plications include secondary infection, mediastinal or subcutaneous emphysema, and air embolism. Re-​expansion oedema is a theoret- ical risk, particularly in patients with long-​standing effusions: this can be minimized with slow intercostal tube drainage and carefully managed re-​expansion of the lung. Therapeutic role of thoracoscopy The most common therapeutic indication for thoracoscopy is in the treatment of a malignant pleural effusion. The procedure allows the even application of sclerosing agents such as talc on the pleural surface and is very successful in combination with tube drainage. Thoracoscopy also has a role in the management of spontaneous pneumothorax: small blebs may be identified and obliterated with

section 18  Respiratory disorders 4002 argon plasma photocoagulation or electrocautery, usually combined with pleurodesis. It also has a therapeutic role in empyema and tu- berculous pleuritis, where it can be used to break up adhesions and facilitate drainage of effusion. Video-​assisted thoracic surgery Video-​assisted thoracic surgery is increasingly used in the manage- ment of patients with pleural disease (see Chapter 18.17) and also allows lung biopsy or resection in some patients in whom an open procedure would be high risk because of poor lung function. Under general anaesthesia the ipsilateral lung is collapsed with the use of a double lumen endotracheal tube, and a stab incision with adjacent instrument ports is made in the sixth or seventh intercostal space in the midaxillary line (Fig. 18.3.3.5). In other respects, the tech- nique is similar to standard thoracoscopy. Pulmonary tube drainage is required after the procedure, but hospital stay is shorter than after standard surgical thoracotomy. Single port video-​assisted thoracic surgery is being utilized increasingly for lobar resections and nodal dissection in patients with lung cancer. Percutaneous biopsy Pleural biopsy The use of ‘blind’ (unguided) pleural biopsy is diminishing: wher- ever possible, pleural biopsies should be performed with image guidance. Traditionally, pleural biopsy was performed using an Abrams needle, which has three components: an outer trochar with a notch on its side near the distal tip, an inner cutting cannula that interlocks with the trochar, and a central stylette. A 5 mm incision is made in the skin surface and the whole unit is inserted carefully through the intercostal space just above a rib. The central stylette is withdrawn and the inner cannula is rotated anticlockwise and withdrawn slightly. Aspiration of pleural fluid confirms position in the pleural space. The Abrams needle is then angulated and slowly withdrawn to catch a small piece of pleura within the notch of the trochar, at which point the inner cannula is rotated and moved forwards to cut off and retain the specimen. There are several variants of the Abrams needle, such as the Cope needle and the Radja needle, but they all obtain a biopsy by tearing or shearing a piece of pleura. The blind nature of the procedure and the shearing technique for obtaining a biopsy specimen result in a variable diagnostic yield and a complication rate of 15%, with more serious consequences in about 0.1% of procedures. These range from haemorrhage and pneumothorax to laceration of adjacent organs such as the liver, spleen, and kidneys. Blind pleural biopsy has largely been superseded by CT or ultrasound-​guided procedures, and wherever possible by thoracoscopy. The Tru-​cut needle is favoured by many radiologists and comprises an outer cutting column and an inner trochar that has a notch within which the biopsy material is collected. Percutaneous lung biopsy Percutaneous biopsies are primarily performed in the assessment of pulmonary nodules for suspected malignancy. They are a par- ticularly important tool in the assessment of patients who are bor- derline candidates for surgery due to comorbidity or disease extent, but are less appropriate where a patient is operable and the nodule is considered highly likely to be cancer. Large masses may be more safely sampled with bronchoscopic techniques. Sampling of en- larged hilar or mediastinal lymph nodes by endoscopic ultrasound guidance should be considered as alternative sites for tissue biopsy and have the advantage of providing staging as well as diagnostic information. The main contraindications to percutaneous lung biopsy are poor respiratory reserve (FEV1 <1 litre) and bleeding diathesis (INR

1.4). Relative contraindications are extensive bullous emphysema, intractable cough, patients who are unable to lie still, pulmonary hypertension, and contralateral pneumonectomy. Fine needle aspirates can be used to diagnose malignancy but are very poor at firmly diagnosing benign conditions. The use of cut- ting needles, which obtain a core of tissue, provides greater diag- nostic confidence. Under CT guidance, the needle is placed so that when the needle tip is fired its distal position remains within the mass being sampled (Fig. 18.3.3.6), care being taken to avoid blood vessels, pulmonary fissures, bullae, and adjacent organs. The outer sheath is held in position after initial biopsy so that the procedure can be repeated and further samples obtained without the need to perform repeated needle punctures. Pneumothoraces and haemorrhage are the two main compli- cations of percutaneous biopsy, the frequency of which is influ- enced by the size, depth, and position of the mass. The presence of parenchymal lung disease, particularly emphysema, also influ- ences the incidence of pneumothoraces. Air embolism is a rare but serious complication and can occur if the needle lies within the pulmonary vein. Retractor Camera Grasper 180° 0° Fig. 18.3.3.5  The arrangement of ports for video-​assisted thoracic surgery. The principal access is in the midaxillary line.

18.3.3  Bronchoscopy, thoracoscopy, and tissue biopsy 4003 FURTHER READING Annema JT, et  al. (2010). Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA, 304, 2245–​52. Baaklini WA, et  al. (2000). Diagnostic yield of fiberoptic bron- choscopy in evaluating solitary pulmonary nodules. Chest, 117, 1049–​54. Castro M, et  al. (2010). Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma. A multicentre, ran- domized, double blind, sham controlled clinical trial. Am J Respir Crit Care Med, 181 Suppl 1, 116–​24. Davey C, et  al. (2015). Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (The BeLieVeR-​HiFi study): a random- ised controlled study. Lancet, 386, 1066–​73. Du Rand IA, et  al. (2011). BTS Interventional Bronchoscopy Guideline Group. British Thoracic Society Guidelines for advanced diagnostic and therapeutic flexible bronchoscopy in adults. Thorax, 66, iii1–​iii21. Du Rand IA, et  al. (2013). British Thoracic Society Bronchoscopy Guideline Group. British Thoracic Society guideline for diagnostic flexible bronchoscopy in adults:  accredited by NICE. Thorax, 68 Suppl 1, i1–​i44. Hartman JE, et al. (2019). Endobronchial valves for severe emphysema. Eur Resp Rev, 28(152), pii: 180121. doi: 10.1183/16000617.0121-2018. Herth FJ, Eberhardt R, Ernst A (2006). The future of bronchoscopy in diagnosing, staging and treatment of lung cancer. Respiration, 73, 399–​409. Kurimoto N, et  al. (2004). Endobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically. Chest, 126, 959–​65. Lam S, et al. (1998). Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest, 113, 696–​702. Lam WK, et al. (1983). Fibreoptic bronchoscopy in the diagnosis of bronchial cancer: comparison of washings, brushings and biopsies in central and peripheral tumours. Clin Oncol, 9, 35–​42. Laroche C, et al. (2000). Role of computed tomographic scanning of the thorax prior to bronchoscopy in the investigation of suspected lung cancer. Thorax, 55, 359–​63. Manhire A, et al. (2003). Guidelines for radiologically guided lung bi- opsy. Thorax, 58, 920–​36. Prakash UB, Offord KP, Stubbs SE (1991). Bronchoscopy in North America: the ACCP Survey. Chest, 100, 1668–​75. Reichenberger F, et al. (1999). The value of transbronchial needle as- piration in the diagnosis of peripheral pulmonary lesions. Chest, 116, 704–​8. Schreiber G, McCrory DC (2003). Performance characteristics of dif- ferent modalities for diagnosis of suspected lung cancer: summary of published evidence. Chest, 123 Suppl 1, 115S–​128S. Shah PL (2011). Atlas of bronchoscopy. Hodder Arnold, London. Shah PL, et al. (2011). Bronchoscopic lung volume reduction with ex- hale airway stents for emphysema (EASE trial): randomized, sham-​ controlled multicentre trial. Lancet, 378, 997–​1005. Shah PL, et al. (2013). Endobronchial coils for the treatment of severe emphysema with hyperinflation (RESET): a randomised controlled trial. Lancet Respir Med, 1, 233–​40. Tassi GF, Davies RJ, Noppen M (2006). Advanced techniques in med- ical thoracoscopy. Eur Respir J, 28, 1051–​9. Vergnon JM, Huber RM, Moghissi K (2006). Place of cryotherapy, brachytherapy and photodynamic therapy in therapeutic bronchos- copy of lung cancers. Eur Respir J, 28, 200–​18. von Bartheld MB, et  al. (2013). Endosonography vs. conventional bronchoscopy for the diagnosis of sarcoidosis: the GRANULOMA randomized clinical trial. JAMA, 309, 2457–​64. Fig. 18.3.3.6  CT-​guided Tru-​cut needle biopsy of a left upper lobe mass.

18.4 Respiratory infection 4004 18.4.1 Upper respi

18.4 Respiratory infection 4004 18.4.1 Upper respiratory tract infections 4004 P. Little

CONTENTS 18.4.1 Upper respiratory tract infections  4004 P. Little 18.4.2 Pneumonia in the normal host  4008 Wei Shen Lim 18.4.3 Nosocomial pneumonia  4022 Wei Shen Lim 18.4.4 Mycobacteria  4026 Hannah Jarvis and Onn Min Kon 18.4.5 Pulmonary complications of HIV infection  4031 Julia Choy and Anton Pozniak 18.4.1  Upper respiratory
tract infections P. Little ESSENTIALS Acute upper respiratory tract infections are one of the commonest reason for patients to seek medical advice in the United Kingdom. Pharyngitis/​tonsillitis—​this is caused by both bacterial and viral or- ganisms, with sore throat often accompanied by fever, headache, and other symptoms. Investigations are not generally performed or required. Antibiotics have modest benefit, so for patients who are not unwell systemically the physician should either not prescribe, or use a delayed prescribing approach which is likely to have similar bene- fits to an immediate antibiotic prescription, advising the patient to wait for several days before collecting or using their prescription. If an antibiotic is considered, the antibiotic of choice is probably penicillin V, with a short-​acting macrolide the second-​line agent. The benefits of tonsillectomy in preventing recurrent sore throat are modest. Acute rhinitis—​causes nasal congestion and rhinorrhoea, mild malaise, sneezing, sore throat, variable loss of taste and smell, and usually recovers within two weeks. Oral and topical decongestants may help symptoms but have significant side effects, and antibiotics provide limited benefit. Acute sinusitis—​usually defined as an infection that lasts for less than three weeks, is an uncommon complication of coryzal illness and pharyngitis. Diagnosis based on a clinical risk score is reasonably sensitive and specific, but the effectiveness of antibiotics or other treatments is questionable. Introduction Acute upper respiratory tract infections (URTIs) include acute pha- ryngitis/​tonsillitis and acute rhinitis. Acute sinusitis, acute otitis media, and influenza also come under the umbrella of infections of the upper respiratory tract. Otitis media and influenza will be dis- cussed elsewhere: this chapter concentrates on acute pharyngitis/​ tonsillitis, acute rhinitis, and acute sinusitis. Acute URTIs are one of the commonest reason for patients to seek medical advice in the United Kingdom, and nearly all cases are man- aged in primary care. Respiratory tract infections are also the com- monest reason for antibiotics to be prescribed, leading to serious concern that the inappropriate use of antibiotics for predominantly self-​limiting conditions will foster the development of antibiotic resistance, with the danger that serious infections will become un- treatable. Thus it is currently an international priority to discourage the use of antibiotics where there is poor evidence of their efficacy. The evidence for the effectiveness of treatments for URTI in this chapter comes from a search of the Cochrane Library databases of systematic reviews and randomized controlled trials. Pharyngitis/​tonsillitis Clinical presentation Pharyngitis is caused by both bacterial and viral organisms, and has been somewhat arbitrarily divided into nasopharyngitis (with 18.4 Respiratory infection

18.4.1  Upper respiratory tract infections 4005 nasal symptoms, i.e. rhinitis), and pharyngitis or tonsillopharyngitis (without nasal symptoms). Causal organisms include:  group A  β-​haemolytic streptococcus; adenoviruses; influenza A  and B; parainfluenza 1, 2, 3; Epstein–​Barr virus (EBV); enteroviruses; Mycoplasma pneumoniae; and Chlamydia pneumoniae. In addition to a sore throat, pharyngitis is often accompanied by fever, headache, nausea, vomiting, anorexia, and sometimes abdom- inal pain, with or without enlarged and tender cervical lymph nodes, tonsillar erythema, and exudate. Scarlet fever has a characteristic ‘scarlatiniform’ rash caused by group A β-​haemolytic streptococcal exotoxins. Infectious mononucleosis due to EBV may present with or without exudative tonsillitis, cervical or general lymphadenop- athy, palatal petechiae, splenomegaly, rhinitis, and cough. Throat swabs, rapid tests, and clinical algorithms Antibiotics can be targeted to those patients who have positive throat swabs for group A streptococcus; those who have group A, C, or G streptococci; or those who have a positive rapid antigen detec- tion test (RADT designed to detect group A). However, the results of throat swabs take days to return to the clinic, and they signifi- cantly increase the costs of managing what is mostly a self-​limiting condition. Alternatively antibiotics can be targeted to individuals with clin- ical characteristics associated with a positive throat swab for patho- genic streptococci. Various systems have been devised to try and do this. The Centor criteria—​designed to predict the presence of group A streptococci—​awards one point for each of high temperature; pus; nodes; the absence of cough. Patients with scores of 3–​4 are typically offered antibiotic treatment. The FeverPAIN score—​designed to pre- dict the presence of A, C, or G streptococci—​awards one point each for Fever; Pus; rapid Attendance (<=3 days); very Inflamed tonsils; No cough or coryza. The likelihood of streptococcal infection is as follows: score 0–​1, 13–​18% (no antibiotic strategy recommended); score 2–​3, 34–​40% (back-​up antibiotic prescription strategy recom- mended); score 4 or more, 62–​65% (immediate antibiotic strategy recommended if severe). A small Canadian trial compared using the Centor criteria or an RADT and demonstrated reduction in antibiotic use when the RADT was used, but not with the Centor criteria. A larger UK trial of the FeverPAIN score demonstrated both a reduction in antibiotic use and better symptom control when using FeverPAIN, but no add- itional benefit of additionally using an RADT for those with high FeverPAIN scores. Treatment Antibiotics for symptoms The Cochrane review of the efficacy of antibiotics for the treatment of sore throat indicates that antibiotics have modest benefit in redu- cing the symptoms. At day 3, where the maximal benefit was found, 49% of the antibiotic group compared to 66% of the placebo group still had sore throat (i.e. the number needed to treat for benefit (NNTB) was 6, and the estimated NNTB at one week was 21). This marginal benefit of antibiotics in resolving symptoms suggests that, for patients who are not unwell systemically, the physician should either not prescribe, or use a delayed prescribing approach, ad- vising the patient to wait for several days before collecting or using their prescription. Both these approaches have been shown in a large randomized controlled trial to be acceptable, to change atti- tudes and behaviour, and not to delay symptom resolution appre- ciably (Fig. 18.4.1.1). Antibiotics to prevent complications The Cochrane review of antibiotics for treating a sore throat sup- ports the use of antibiotics to prevent complications, but the evi- dence is limited by both clinical importance and generalizability. For the commoner complications (e.g. otitis media), more than 50 people would have to be treated to prevent one case of a self-​limiting illness, and from more recent trials nearer 200 people would need to be treated: in other words, it is not important clinically. For the rarer complications—​rheumatic fever and glomerulonephritis—​the evidence is not generalizable; for instance, evidence of efficacy in rheumatic fever is based largely on trials where intramuscular peni- cillin was used in barracked military personnel after the Second World War. This evidence cannot be sensibly applied to modern set- tings where the attack rate is much lower and oral antibiotics are used. However, the benefits of antibiotics are likely to be greater in settings where complications are much more common. The commonest complication of practical importance to health services is quinsy (peritonsillar abscess), but this is still relatively uncommon—​about 1 in 200 to 1 in 400 following presentation in primary care with sore throat. The Cochrane systematic review, which demonstrates that antibiotics prevent quinsy, relies on data from patients with tonsillitis who were systemically unwell enough to be admitted to hospital shortly after the Second World War, when the prevalence of quinsy in untreated patients was very high (1 in 18). Clearly, this data cannot be extrapolated to patients pre- senting from modern populations who are not systemically unwell, 100 80 60 40 20 0 Days with sore throat Cumulative percentage 0 1 2 3 4 5 6 7 8 9 ≥10 Group 1 Immediate antibiotics Group 2 No antibiotics Group 3 Offer of delayed antibiotics Fig. 18.4.1.1  A trial of three pragmatic antibiotic prescribing strategies: the graphs show the percentage of patients cured in the days following seeing the doctor. Reproduced from BMJ, Little et al., 314, 722–​7, copyright 1997 with permission from BMJ Publishing Group Ltd.

section 18  Respiratory disorders 4006 treated with oral antibiotics, and where the prevalence of quinsy is much lower. Quinsy following sore throat is possibly slightly more common (1 in 60) in those who are unwell, with three out of four Centor criteria, most of whom have fever. Rigorously con- ducted placebo-​controlled trials in patients with these criteria suggest quinsy may be prevented by oral penicillin, but in routine clinical practice, where compliance is not assessed, the preventive benefit of penicillin is not likely to correspond to trials where com- pliance is more tightly controlled. The lesser effect of antibiotic in preventing complications in routine practice compared with trial data has been confirmed in the recent large DESCARTE pro- spective observational study. There has been no increase in admissions with quinsy since the uptake of the delayed prescribing strategy in the United Kingdom. In the DESCARTE cohort study it was not possible to predict accurately which individuals developed complications, and al- though immediate antibiotic or delayed antibiotics both reduced complications effectively, complications of acute sore throat were uncommon (1%) and mostly not serious (otitis media or sinus- itis). Delayed antibiotics and immediate antibiotics both reduced reconsultations, but delayed antibiotic prescription was associated with a larger reduction in reconsultations than immediate anti- biotics. This suggests that most people do not need any antibiotic for acute sore throat, but that if a clinician is concerned and an antibiotic is being considered, a delayed antibiotic prescription is preferable. Lemierre syndrome—​a rare complication This syndrome, caused by fusobacterium—​an anaerobe that is part of normal throat flora—​has been highlighted recently following a rise in reports between 1990 and 2000 to about 20 per year in the United Kingdom. A  patient with pharyngitis does not improve, remains pyrexial, and develops pharyngeal swelling due to a local abscess. Internal jugular thrombosis or embolism to the lungs com- monly occurs or is suspected, and in such cases prompt referral to hospital is needed. The condition responds to metronidazole, but—​ since the differential diagnosis is incipient quinsy—​high-​dose peni- cillin should also probably be given. Isolates in case series have been sensitive to metronidazole, with a small minority resistant to peni- cillin or erythromycin. However, to encourage increased prescribing of antibiotics on the basis of an increase in Lemierre’s syndrome is unwarranted: it would increase the dangers of both resistance and anaphylaxis—​and anaphylaxis, although rare, is still commoner than Lemierre’s syndrome. Which antibiotic and for how long? A Cochrane systematic review has concluded that cephalosporins may provide minimal additional benefit to penicillin in acute sore throats. There was no significant difference in symptom resolution between cephalosporins and penicillin (odds ratio for absence of resolution of symptoms (OR) 0.79), but clinical relapse was lower with cephalosporins (OR 0.55), although the absolute effect was very small (overall NNTB 50, and found only in adults, OR 0.42, NNTB 33). Hence, if an oral antibiotic is to be prescribed, then it is probably preferable to give a narrow-​spectrum antibiotic (penicillin V) to minimize side effects and the risk of resistance developing. If penicillin V is used, there are arguments for using a large dose given the variable absorption (e.g. 2 g/​day adults and 1 g/​day children). A 10-​day course will better eradicate streptococcus, but the clinical significance of this is unclear. Longer courses have the disadvantage of poorer compliance, and greater likelihood of antibiotic resistance developing in the long term. Twice-​daily dosing of penicillin V com- pared with the same total dose of more than four doses per day may result in better compliance and better clinical/​microbiological out- comes. Intramuscular injection of penicillin can be used, although in practice is rarely employed in the United Kingdom. Ampicillin will cause a rash in patients with infectious mononucleosis, so erythromycin is a suitable second-​line agent among patients with penicillin allergy. Treatment of patients with rheumatic fever Patients who have had one attack of rheumatic fever are at a higher risk from new infections since they are likely to develop recurrent attacks of rheumatic fever and complications. Although most of the evidence for the prevention of rheumatic fever comes from old trials in unusual settings, it seems reasonable to treat patients with a past history who are at a high risk of recurrence and secondary com- plications, since what evidence there is suggests penicillin prevents rheumatic fever. (See Chapter 16.9.1 for further discussion of the issues involved.) Other medical treatments Treatment with aspirin in children is contraindicated because of the small but avoidable risk of Reye’s syndrome. There are sev- eral trials of the use of nonsteroidal anti-​inflammatory drugs (NSAIDs) in providing effective relief of pain and fever in tonsil- litis and pharyngitis, but a Cochrane review suggests very limited benefit among participants with the common cold. Furthermore, the limited trial evidence comparing them with standard treat- ment (paracetamol) does not clearly demonstrate their superiority. A recent pragmatic trial documented some harm in advising the regular use of ibuprofen compared with the use of paracetamol, resulting in more reconsultations with a nonresolution of illness and also increased complications, presumably due to suppressing the inflammatory component of the immune response. Limited trial data suggest that other useful analgesic adjuncts may in- clude caffeine, and benzydamine hydrochloride gargle. There is also evidence from a systematic review that patients with more severe presentations who are receiving antibiotics may benefit from steroids, but there is no evidence as yet from a more typ- ical primary care sample, nor among those where no antibiotic are prescribed. Recurrent attacks Surgery A Cochrane review of nine trials assessed the role of surgery for chronic/​recurrent sore throat. For episodes of moderate/​severe sore throat, children had on average 1.1 episodes of sore throat in the first postoperative year, compared with 1.2 episodes in the control group of less severely affected children had more episodes of moderate/​severe sore throat after surgery (1.2 episodes) than in the control group (0.4 episodes), and as with the more severe episodes, one episode was the predictable postoperative episode. When discussing options with parents, the modest benefits of surgery must be weighed against its disadvantages: tonsillectomy

18.4.1  Upper respiratory tract infections 4007 has complications (4–​7% requiring operative surgery for haemor- rhage, or other significant symptoms such as severe nausea and dehydration). Other treatments There is preliminary trial evidence for the use of α-​streptococci spray, immune stimulants, and pneumococcal vaccination, but fur- ther confirmation is required. Nasal congestion and rhinorrhoea Nasal symptoms are a common reason for attending the doctor. They may be due to a variety of causes—​commonly acute viral in- fection (common cold), allergic rhinitis and sinusitis, vasomotor rhinitis and rhinitis medicamentosa, and less commonly atrophic rhinitis, hormonal rhinitis, and mechanical/​obstructive rhinitis. Colds are responsible for significant morbidity: on average there are 0.4 episodes and 1.2 days of restricted activity per person per year for the common cold. Acute rhinitis Symptoms are acute nasal congestion and rhinorrhoea, mild mal- aise, sneezing, sore throat, variable loss of taste and smell, and usu- ally last from 1 to 2 weeks unless sinusitis is present. Examination reveals a hyperaemic and oedematous mucosa, with or without purulent secretions. Treatment Symptomatic Trial evidence supports the use of both oral and topical decongestants for the symptoms of rhinitis. Intranasal ipratropium bromide is also effective symptomatic treatment, but only available (in the United Kingdom) on prescription. However, topical decongestants should probably not be used for more than a maximum of 7 days: rhinitis medicamentosa starts to develop at 10 days. A Cochrane review of oral antihistamines, with or without decongestants and analgesics, suggests they do help, but side effects such as drowsiness, dry mouth, insomnia, and dizziness are common. Because of their moderate systemic effects, care should be taken with oral decongestants in pa- tients with heart disease and hypertension. Saline drops are com- monly advocated, but saline or medicated nose drops have been shown to be ineffective in trials in both children and adults. A recent trial of steam inhalation for respiratory infections demonstrated no benefit and some harm (mild thermal injury). Antibiotics The use of antibiotics for the common cold has been assessed in a Cochrane systematic review and shown to provide modest benefit. Other Reviews of trials indicate little benefit from antihistamines or zinc lozenges. A Cochrane review of the herb echinacea demonstrated very modest results in most studies, and there was not enough evi- dence to recommend the use of a specific product. Acute sinusitis Diagnosis Acute sinusitis, usually defined as an infection that lasts for less than 3 weeks, is an uncommon complication of coryzal illness and pha- ryngitis. There is no absolute standard against which symptoms and signs can be compared for accuracy of diagnosis: aspiration by sinus puncture is probably the definitive investigation, since it indicates the presence of infecting organisms, but for obvious reasons this is rarely performed, and contamination by commensal organisms can occur. A four-​item clinical risk score developed to predict bacterial infections—​of purulent rhinorrhoea with unilateral predomin- ance, local pain with unilateral predominance, bilateral purulent rhinorrhoea, and presence of pus in the nasal cavity—​is as sensitive and specific as any other method in predicting the results of antral sinus puncture. Thus, for acute sinusitis, diagnostic tests are not cur- rently indicated, and until valid near-​patient tests are available, clin- ical targeting probably performs as well as any other method. Treatment Antibiotics A Cochrane review of all controlled trials in a primary care setting, where the vast majority of sinusitis is managed, suggests that the absolute benefit for symptom resolution is moderate and must be balanced against the disadvantages of prescribing antibiotics. An in- dividual patient data meta-​analysis of trials using a clinical diagnosis documented a number needed to treat of 15 for all patients and 8 for those with purulence, and no greater benefit for those with symp- toms for longer than a week. Thus both the effectiveness and cost-​ effectiveness of antibiotic treatment of acute sinusitis in primary care is questionable for most patients. Other There is limited evidence that antihistamines may be helpful for pa- tients with a history of allergic rhinitis who develop sinusitis, and very limited evidence that some proteolytics (e.g. bromelain) and mucolytics may help. There is mixed trial evidence for the benefit of topical steroids. Although trials of NSAIDs suggest they are helpful, they may not be significantly more effective than paracetamol. FURTHER READING Little PS, et al. (1997). An open randomised trial of prescribing strat- egies for sore throat. BMJ, 314, 722–​7. Little PS, et al. (1997). Reattendance and complications in a random- ised trial of prescribing strategies for sore throat: the medicalising effect of prescribing antibiotics. BMJ, 315, 350–​2. Little P, et al. (2013). Ibuprofen, paracetamol, and steam for patients with respiratory tract infections in primary care:  pragmatic ran- domised factorial trial. BMJ, 347, f6041. Little P, et al. (2014). Antibiotic prescription strategies for acute sore throat:a prospective observational cohort study. Lancet Infect Dis, 14, 213–​9. Little P, et al. (2014). PRImary care Streptococcal Management (PRISM) study: in vitro study, diagnostic cohorts and a pragmatic adaptive

18.4.2 Pneumonia in the normal host 4008 Wei Shen

18.4.2 Pneumonia in the normal host 4008 Wei Shen Lim

section 18  Respiratory disorders 4008 randomised controlled trial with nested qualitative study and cost-​ effectiveness study. Health Technol Assess, 18, vii–​xxv, 1–​101. Mehta N, et al. (2017). Antibiotic prescribing in patients with self- reported sore throat. J Antimicrob Chemother, 72, 914–22. Young J, et al. (2008). Antibiotics for adults with clinically diagnosed acute rhinosinusitis:  a meta-​analysis of individual patient data. Lancet, 371, 908–​14. The Cochrane Library—​trials and Cochrane reviews can be accessed online at http://​www.cochrane.org 18.4.2  Pneumonia in the normal host Wei Shen Lim ESSENTIALS Pneumonia is an acute or chronic infection involving the pulmonary parenchyma. Aetiology—​most cases are caused by microbial pathogens, the commonest being Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, le- gionella, anaerobic bacteria, and viruses (influenza, parainfluenza, and respiratory syncytial virus). Staphylococcus aureus is an important superinfecting pathogen in influenza, and the most common form of embolic pulmonary infection with injected drug use and tricuspid valve endocarditis. Prevention—​the main preventive measures are smoking cessation, and vaccination against influenza and S. pneumoniae. Clinical features—​classic presentation is with cough and fever, with variable sputum production, dyspnoea, and pleurisy. Most patients have constitutional symptoms and many also have gastrointestinal symptoms. Clinical examination may reveal features indicative of the severity of respiratory compromise and (in some cases) of consoli- dation. The ‘CURB-​65’ score—​based on compromised consciousness, elevated blood urea nitrogen, increased respiratory rate, reduced blood pressure, and age over 65 years—​is a useful predictor of mor- tality from pneumonia. Diagnosis—​the key test is the chest radiograph, showing an in- filtrate consistent with infection. The use of laboratory studies for identifying pulmonary pathogens in pneumonia is evolving: even with extensive use of current diagnostic resources a likely aetio- logical agent is only detected in 40–​60% of cases. For outpatients, microbiological tests are not routinely performed; empirical therapy is generally advocated. For inpatients, blood cultures (preferably taken before the initiation of antibiotic treatment) and Gram stain and culture of expectorated sputum (if any) are recom- mended. Rapid urinary antigen tests for legionella (which detects L.  pneumophila serogroup 1; responsible for 80% of cases) and S. pneumoniae are available. Pleural effusions should be sampled to exclude empyema. Management—​supportive treatment includes (as appro- priate) intravenous fluids, supplementary oxygenation, and ven- tilatory support. Antibiotics are the mainstay of therapy, with recommendations for empirical treatment of community-​acquired
pneumonia typically as follows (but local hospital protocols and pol- icies may vary): (1) outpatients—​amoxicillin, doxycycline, macrolide (erythromycin, clarithromycin, azithromycin), or fluoroquinolone (levofloxacin, moxifloxacin, or other fluoroquinolone with enhanced activity against S.  pneumoniae); (2)  hospital inpatients, moderate severity—​β-​lactam (amoxicillin) plus macrolide, or fluoroquinolone alone; (3) hospital inpatients high severity/​intensive care unit—​β-​ lactamase stable β-​lactam (coamoxiclav, cefotaxime, ceftriaxone) plus macrolide, or β-​lactam plus fluoroquinolone; (4) special cir- cumstances:  aspiration pneumonia—​clindamycin, or β-​lactamase stable β-​lactam. Introduction History Pneumonia has been recognized since Hippocrates described ‘peripneumonia’ in the fourth century BC. Up to the early nine- teenth century, the nature of pneumonia was poorly understood, although it was regarded as some sort of inflammation of the lungs. In 1834, Laennec described three stages of consolidation that are still recognized today. These are associated with classical ausculta- tory findings heard with the stethoscope which he invented in 1816 (Table 18.4.2.1). Towards the end of the nineteenth century, infectious agents as the cause of pneumonia began to be recognized. Between 1881 and 1884, Friedlander first found bacteria in the lungs of fatal cases of pneumonia using the newly described staining methods of his colleague Gram. In 1884, Fraenkel isolated an organism which he called ‘pneumoniemikroccus’ (pneumococcus) from a 30-​year-​old man dying of pneumonia. In 1892, Haemophilus influenzae was dis- covered and initially thought to be the cause of influenza. The in- fluenza virus was not identified as the causative agent of influenza until 1933 at the Medical Research Council laboratories in Mill Hill, England, many years after the 1918 pandemic. Advances in microbiological techniques have since enabled a range of pathogens to be identified in association with pneu- monia (Table 18.4.2.2). The importance of viruses is increasingly recognized. Definition of pneumonia Pneumonia may be defined as an acute inflammatory condition of the lung characterized by consolidation due to the presence of Table 18.4.2.1  Laennec’s three stages of consolidation in pneumonia Stage Pathological findings Auscultatory findings 1st stage Engorgement: the lung is wet,
oedematous, and congested. Crepitus rattle (crepitations) 2nd stage Red hepatization: the lung is dry, red, friable, and solid like liver. Bronchial breathing 3rd stage Grey hepatization: the lung is softer
and exudes yellow purulent material indicative of resolution. Rhonchus crepitus redux (return of crepitations)

18.4.2  Pneumonia in the normal host 4009 exudate in the alveolar spaces and caused by an infectious agent. In clinical practice, a definite diagnosis of pneumonia relies on a com- plex of symptoms and signs, together with relevant radiological findings. This may be summarized as the combination of: • Symptoms of an acute lower respiratory tract infection (e.g. cough, sputum production, dyspnoea) • Systemic features of infection (e.g. fever, chills) • Signs of consolidation on clinical examination (e.g. focal lung crepitations) • Radiological features consistent with pneumonia • No other alternative explanation for the illness In situations where access to radiological tests is not available, a pre- sumptive clinical diagnosis of pneumonia may be made based on the presence of clinical features alone. This is generally the case for patients diagnosed outside a hospital setting. Classification Pneumonia may be classified according to: • Source of infection (e.g. community acquired, hospital acquired) • Radiographic features (e.g. bronchopneumonia, lobar pneumonia) • Severity of infection (e.g. severe, nonsevere) • Microbiology (e.g. pneumococcal pneumonia, legionella pneumonia) These classifications are useful in identifying patient groups with common features that inform patient management. Rather confus- ingly, the term ‘pneumonia’ is also adopted in some conditions that are noninfectious in nature, such as eosinophilic pneumonia and usual interstitial pneumonia. Further discussion in this chapter is restricted to community-​acquired pneumonia (CAP) in the adult immunocompetent host. Aetiology The relative frequencies of different pathogens causing community-​ acquired pneumonia differ according to geography and setting. Results from studies conducted in Europe and Asia are summar- ized in Table 18.4.2.3. Important limitations of these studies are that most were conducted in large urban hospitals; diagnostic tests performed after antibiotic treatment mask the relative frequency of antibiotic-​susceptible pathogens; no pathogens were identified in 30–​85% of cases, even with the use of multiple diagnostic tests; and there are seasonal variations in the frequency of infection by specific pathogens. These limitations make a direct comparison of studies conducted in different regions difficult. Some important differences in the microbial aetiology of CAP in Asia, compared to the West are that Mycobacterium tuberculosis is a relatively common pathogen in some areas; Burkholderia pseudo­ mallei is the commonest pathogen identified in northeast Thailand and is an important pathogen in neighbouring countries including Malaysia and Singapore; and Klebsiella pneumoniae (a Gram-​ negative enteric bacilli) is a common pathogen in Asia, particularly in patients with severe disease. More sophisticated diagnostic tests are being developed that may fill the gaps in our current knowledge and provide more rapid pathogen-​specific diagnoses at the time of clinical presentation. In severe pneumonia, the most frequently encountered pathogens are (Table 18.4.2.4): • Streptococcus pneumoniae • Legionella sp. • Staphylococcus aureus • Gram-​negative enteric bacilli (such as Klebsiella pneumoniae) • Burkholderia pseudomallei—​in endemic countries (restricted to East Asia) Table 18.4.2.2  Important events in the history of pneumonia Date Discovery/​ event 1834 3 stages of lobar pneumonia described by Laennec 1881 Pneumococcus first isolated by Pasteur and Sternberg 1884 Pneumococcus in pneumonia described by Fraenkel 1892 Haemophilus influenzae discovered by Pfeiffer 1928 Penicillin discovered by Alexander Fleming 1933 Influenza virus discovered by Wilson Smith, Christopher Andrewes, and Patrick Laidlaw 1938 Coxiella burnetii (Q fever) named after discoverers Macfarlane Burnet and Herald Rea Cox 1944 Mycoplasma pneumoniae discovered by Monroe Eaton 1969 First report of penicillin-​resistant pneumococcus 1974 Pneumococcus named Streptococcus pneumoniae 1976 Legionella pneumonia (legionnaires’ disease) described following Philadelphia outbreak 1977 Emergence of multidrug resistant pneumococcus 1986 Chlamydophila pneumoniae identified 2003 Severe acute respiratory syndrome (SARS)-​coronavirus identified following international outbreak 2012 Middle East respiratory syndrome (MERS)-​coronavirus identified following first case in the Kingdom of Saudi Arabia Table 18.4.2.3  Frequency of pathogens in patients with CAP: from one British study and summary figures from two large reviews of studies conducted in Europe (46 studies) and Asia (48 studies) Pathogen British study Europe Asia % Range (%) Unweighted average (range, %) Streptococcus pneumonaie 48 12–​68 13 (0–​39) Mycoplasma pneumoniae 13 0–​32 8 (0–​30) Legionella sp. 3 0–​13 3 (0–​17) Chlamydophila pneumoniae 2 0–​27 7 (0–​37) Haemophilus influenzae 7 3–​45 7 (9–​19) Staphylococcus aureus 1.5 0–​12 4 (0–​13) Gram-​negative enteric bacilli 1.4 0–​41 9 (0–​22) Viruses 23 1–​19 10 (1–​22) Mycobacterium tuberculosis not reported not reported 10 (0–​21)

section 18  Respiratory disorders 4010 ‘Atypical’ pathogens? During the first half of the twentieth century, the concept of an ‘atypical pneumonia syndrome’ was described; this comprised fever without shaking chills, a nonproductive cough, headache, and myalgia. The ‘atypical pneumonia syndrome’ was thought to be associated with infections by pathogens such Mycoplasma pneumoniae. In contrast, ‘typical pneumonia’, which comprised an abrupt onset of high fever, shaking chills, pleuritic pain, and purulent sputum, was associated with Streptococcus pneumoniae infection. However, more recent studies have shown that spe- cific pathogens are not associated with distinctive clinical pres- entations, hence the term ‘atypical pneumonia’ is now mostly abandoned. The concept of an ‘atypical pathogen’ has been retained as useful in denoting those commonly encountered respiratory patho- gens, which (a) replicate intracellularly, and (b) are therefore not susceptible to β-​lactam antibiotics (such as penicillins and ceph- alosporins). While there is no global consensus as regards which pathogens fall into this group of atypical pathogens, this descrip- tive term is widely used in relation to Mycoplasma pneumoniae, Legionella sp., Chlamydophila pneumoniae, Coxiella burnetti, and Chlamydophila psittaci. Specific pathogens Streptococcus pneumoniae Streptococcus pneumoniae is both a human commensal and pathogen, and widely recognized as the commonest pathogen asso- ciated with CAP. About 10–​40% of children aged less than 7 years are asymptomatic carriers of Streptococcus pneumoniae in their naso- pharynx. The carriage rate peaks around 2–​3 years of age and di- minishes thereafter to less than 10% in many adult populations. In adults, aerosol transmission of S. pneumoniae to the nasopharynx most commonly results in clearance. Clinical disease occurs when there is spread to the lungs or blood. Epidemiological factors associated with an increased frequency of infection with this pathogen include close contact with children; winter months in temperate climates, rainy season in tropical cli- mates; aged more than 65 years; and HIV infection (particularly bacteraemic pneumococcal infection) There are at least 94 serologically distinct pneumococcal sero- types. In countries where the pneumococcal conjugate vaccine has been introduced into childhood immunization programmes, rates of pneumococcal pneumonia associated with vaccine serotypes have decreased in both children and adults. Mycoplasma pneumoniae Historically associated with atypical pneumonia, cold agglutinin pneumonia, and Eaton-​agent pneumonia, this organism is one of the commonest causes of lower airways infection. It is more fre- quent in young adults and patients in a community setting with low severity pneumonia. Mycoplasma pneumoniae displays 4-​yearly cycles of infection. The typical patient is a young adult who experiences a respira- tory tract infection accompanied by headache, myalgia, cough, and fever. The cough is often nonproductive, but when sputum is obtained it is mucoid, shows predominantly mononuclear cells, and no dominant organism. A characteristic feature is the relatively high frequency of extrapulmonary complications such as rash, neurological syndromes (aseptic meningitis, enceph- alitis, neuropathies), myocarditis, pericarditis, and haemolytic anaemia. Legionella Legionnaires’ disease was originally described during the American Legion Convention in Philadelphia in 1976, with the putative agent reported the following year. Legionella causes two very dif- ferent clinical syndromes:  a self-​limiting influenza-​like illness—​ called ‘Pontiac fever’ in reference to an outbreak in 1967 in Pontiac, Michigan; and severe pneumonia—​called legionnaires’ disease. Legionnaires’ disease is defined as pneumonia caused by any spe- cies of the genera legionella, but most cases are caused by Legionella pneumophila. The disease may be epidemic or sporadic. Outbreaks are usually related to legionella contamination of potable water or the cooling systems of air conditioners, and have been recorded to occur at flower shows, in hotels, and on cruise ships. Patient-​to-​ patient transmission does not occur. Features of legionnaires’ disease to consider at presentation: • The incubation period from exposure to presentation is 10 days. In the United Kingdom, roughly half of cases of legionnaires’ dis- ease report travel outside the United Kingdom within the incuba- tion period. • There is a seasonal pattern with peak activity in late summer and autumn • Most patients are severely ill and supportive management on a critical care unit may be required. • Extrapulmonary features, such as diarrhoea and mental confu- sion, may predominate. • A rapid diagnosis is possible using a urinary antigen assay for the detection of L. pneumophila serogroup 1 (which accounts for 70–​80% of cases in Europe and the United States). A negative legionella urinary antigen assay does not exclude a diag- nosis of legionella pneumonia, which may be caused by another legionella species. In Australia, Legionella longbeachae causes half of all cases of legionella pneumonia and is related to exposure to potting compost. If legionella pneumonia is suspected, the micro- biology laboratory should be alerted to set up legionella culture of respiratory secretions on selective media. Table 18.4.2.4  Frequency of pathogens in CAP in Europe according to clinical setting (summary of 46 studies) Pathogen Outpatient Hospital Intensive care S pneumonaie 38 27 28 M pneumoniae 8 5 2 Legionella sp 0 5 12 C pneumoniae 21 11 4 H influenzae 13 6 7 Staphylococcus aureus 1.5 3 9 Gram-​negative enteric bacilli 0 4 9 Viruses 17 12 3 Figures are percentage means from 46 studies.

18.4.2  Pneumonia in the normal host 4011 Chlamydophila pneumoniae Although frequently identified in patients with pneumonia, the role of this pathogen in pneumonia has not been settled. It is often found in association with another pathogen (commonly Streptococcus pneumoniae) and resolution of pneumonia without appropriate antibiotic therapy is recognized. On the other hand, outbreaks of pneumonia due to this pathogen are well described. Consequently, its role in pneumonia may be as a primary pathogen, copathogen, or bystander. When implicated, it is generally associated with a non-​ severe pneumonia. Haemophilus influenzae When Haemophilus influenzae is identified in respiratory specimens, distinguishing between colonization and infection can be difficult. H.  influenzae commonly colonizes the upper respiratory airways, leading to contamination of expectorated specimens, and in patients with chronic obstructive pulmonary disease (COPD) it is commonly found in the lower airways, even when patients are clinically stable. H.  influenzae strains causing pneumonia in adults are usually nontypable. In contrast, type B H. influenzae is a well-​established pathogen, primarily in infants and young children, but is a relatively rare cause of disease in areas where there is widespread H. influen­ zae (Hib) immunization. Bacteraemia with H. influenzae in adults is very uncommon. Staphylococcus aureus Staphylococcus aureus is associated with different patterns of pneumonia: • secondary pneumonia following influenza infection; • bilateral (embolic) pneumonia in intravenous drugs users with tricuspid valve endocarditis; and • cavitating pneumonia. Staphylococcal pneumonia is often a fulminant infection. Cavitation occurs in up to 25% of cases and may be associated with Panton–​ Valentine Leukocidin (PVL)-​producing strains. The PVL toxin cre- ates pores on neutrophil membranes leading to neutrophil lysis. Overall, PVL-​producing Staphylococcus aureus is relatively rare (about 10% of all staphylococcal pneumonias), but should be sus- pected in patients with frequent skin and soft tissue infections. When suspected, toxin gene profiling confirms the diagnosis, and anti- biotic sensitivity testing is important because some PVL-​producing strains are associated with methicillin resistance. Klebsiella pneumoniae Klebsiella pneumoniae was originally described in 1882 by Friedlander, who believed it was the cause of pneumococcal pneu- monia. It has increasingly been implicated as a cause of severe community-​acquired pneumonia, accounting for 5–​10% of cases that require ICU support. The classic description of ‘Friedlander’s pneumonia’ was of: • a severe pneumonia • occurrence in men with chronic alcoholism • sputum that resembled ‘redcurrant jelly’ • involvement of the right upper lobe • bulging interlobar fissures and cavitation on chest X-​ray It is uncommon for patients with klebsiella pneumonia to have all these features at presentation. Viral pathogens With the use of advanced microbiological tests, a viral pathogen is identified in about 30% of adults with CAP (Table 18.4.2.5). The role of viruses in the pathogenesis of pneumonia is complex and may differ for different viruses. In up to a third of cases, a bac- terial copathogen is identified. In cases of coinfection, the viral in- fection usually predates the bacterial infection. Influenza Influenza virus usually causes a self-​limiting respiratory tract infec- tion. It is also associated with secondary bacterial pneumonia and, less commonly, a severe primary viral pneumonia. The latter is es- pecially prominent during influenza pandemics when there is little host immunity to the new circulating strain of virus. Typical features of influenza-​related secondary bacterial pneu- monia are a biphasic illness, with a typical influenza-​like illness which initially improves, followed by acute clinical deterioration; alveolar infiltrates on chest X-​ray; and Streptococcus pneumoniae or Staphylococcus aureus infection. Typical features of primary influenzal pneumonia are a rapidly progressive illness with severe pneumonia and bilateral consolida- tion on chest X-​ray. During the 2009 H1N1 influenza pandemic, patients with influenza-​related pneumonia were typically found to have a normal white cell count on hospital admission and only a marginally raised C-​reactive protein level, even if severely unwell. Mental confusion was unusual. The median time from hospital pres- entation to intensive care admission was one day. Acute respiratory distress syndrome and multiorgan failure are recognized compli- cations of primary influenzal pneumonia. Similar clinical presen- tations are described for human cases of avian influenza infection, such as with H5N1 and H7N9 influenza viruses. Epidemiology The incidence of CAP varies by country and increases with patient age. Estimates also vary according to clinical setting (Table 18.4.2.6). The proportion of patients with CAP who are managed in hospital varies by country and depends on the structure of the healthcare system; estimates range from 10 to 50%. Of those Table 18.4.2.5  Viruses most commonly identified in hospitalized adults with CAP Viral pathogen Frequency (%) Influenza virus 4–​12 Respiratory syncytial virus 2–​7 Rhinovirus (most as coinfections) 2–​17 Parainfluenza 0–​8 Human coronavirus 2–​13 Human metapneumovirus 0–​4 Adenovirus 0–​4 Summary of six studies from Review Inf Dis Clinic N Am, 2013.

section 18  Respiratory disorders 4012 admitted to hospital, 5 to 15% receive treatment on an intensive care unit. The average length of hospital stay for an episode of CAP is 7 to 10 days. Mortality from CAP treated in the community is generally low (<1%). For patients treated in hospital, studies report a range of mortality rates from 4% to over 20%. For critically ill patients treated in ICUs, mortality rates generally exceed 25%. Mortality increases sharply with increasing age (Fig. 18.4.2.1). The economic burden associated with CAP is substantial. In the United States, it is estimated at over US$17 billion annually. Direct healthcare-​associated costs related to CAP are mostly driven by the cost of hospital-​based care (87–​95% of total costs). Future increases in population size together with relative in- creases in the proportion of older persons mean the overall number of episodes of pneumonia and hospitalizations for pneumonia are expected to increase. In a US model, total direct costs (in 2007 dol- lars) for pneumococcal pneumonia alone are predicted to double from US$2.5 billion in 2004 to US$5.0 billion in 2040, with the lar- gest proportional increase in costs taking place between 2020 and 2030 (25% increase from US $3.3 billion to US$4.2 billion). Pathogenesis Risk factors for pneumonia The common risk factors for pneumonia (Table 18.4.2.7) are broadly those that increase a person’s vulnerability to pneumonia, either through affecting the risk of exposure to pathogens or the host im- mune response. In adults, increasing age is strongly associated with an increasing incidence of pneumonia and increasing rates of hospi- talization for pneumonia. Cigarette smoking is a strong modifiable risk factor for the devel- opment of pneumonia, including specifically invasive pneumococcal disease and legionella pneumonia. A dose-​response relationship has been described, particularly for invasive pneumococcal disease; the greater the cigarette smoke exposure, the higher the risk. Possible mechanisms of action include suppression of the immune system, impairment of wound healing, disruption of the respiratory epithe- lium or impairment of mucociliary clearance. Sustained smoking cessation decreases the risk of pneumonia. Impairment of the host’s immune response may occur because of coexisting disease (e.g. HIV), or medication (e.g. immunosuppres- sive agents), including corticosteroids. Patients with chronic lung disease are particularly at risk of pneumonia, and in patients with COPD the use of inhaled corticosteroids further increases the risk of pneumonia. Obesity (body mass index (BMI) 30 to 39 kg/​m2) and morbid obesity (BMI ≥40 kg/​m2) are both associated with an increased risk of influenza-​related pneumonia but (surprisingly) the association with CAP is less strong. Children are efficient carriers of the pneumococcus in their naso- pharynx. In contrast, adults tend to either clear the pneumococcus or develop disease when challenged. Regular contact with children is associated with an increased risk of pneumonia, probably as a re- sult of transmission of the pneumococcus or other pathogens from child to adult. Table 18.4.2.6  Incidence of CAP in Europe Clinical setting Incidence per 1000 population CAP diagnosed in the community 1.6 to 11 CAP requiring hospital admission 1.1 to 4 16–24 0 200 400 600 Number of patients 800 25–34 35–44 45–54 55–64 Age (years) 65–74 75–84 85–94 >=95 Died Survived Fig. 18.4.2.1  Hospital admissions for CAP and 30-​day mortality according to age: data from a single British centre (n = 2764). Table 18.4.2.7  Risk factors for the development of pneumonia Risk factors for pneumonia Crude odds ratios for pneumonia (based on case-​control studies) Patient factors Smoking 1.4–​1.8 High alcohol intake (>41 g/​day) 1.6–​2.4 Being underweight (BMI <18.5 kg/​m2) 1.04–​2.2 Regular contact with children 1.5–​3.4 Previous pneumonia 2.4–​6.3 Hospitalization in the last 5 years 1.6 Comorbid diseases Chronic lung disease, including COPD 2.2–​3.9 Chronic cardiovascular disease 1.4–​3.2 Cerebrovascular disease/​stroke 1.9–​2.4 Dementia 2.1–​2.4 Diabetes mellitus 1.4–​1.5 Cancer 1.4–​1.7 Chronic liver disease 1.7–​2.2 Chronic renal disease 1.7–​2.1 Rheumatoid arthritis 1.5–​2.0 Asplenia 2.6a HIV 2.5a–​5.9a a adjusted ORs

18.4.2  Pneumonia in the normal host 4013 Clinical features The medical history in a patient with suspected pneumonia is dir- ected at establishing the diagnosis, risk factors for the development (and future prevention) of pneumonia, prognostic factors related to clinical outcome, and epidemiological factors associated with spe- cific pathogens. Clinical history Symptoms The average duration from symptom onset to presentation is 2–​5 days. However, the timing of onset of illness can be difficult to determine, especially in older persons. There may be a preceding his- tory of an upper respiratory tract illness, particularly with viral and mycoplasma infections. Systemic symptoms common to any febrile illness are usually present—​fever, malaise, anorexia, sweating, myalgia, and headache. • Chills (the sensation of cold accompanied by shivering) are more frequently experienced in younger patients compared to older patients • Rigors are reported in up to 62% of patients with pneumococcal pneumonia • New onset confusion is a relatively common symptom in the older patient (c.10%) and in patients who are severely ill Respiratory symptoms commonly experienced include: • Cough c.75% • Dyspnoea c.65% • Sputum production c.50%—​when produced, this is purulent in about 50%. Bloodstained sputum which is described as ‘rust col- oured’ is classically associated with pneumococcal pneumonia, while in klebsiella pneumonia it is classically described as resem- bling redcurrent jelly • Pleuritic chest pain c.30%—​more commonly reported by younger patients Extrapulmonary manifestations of pneumonia may be present (Table 18.4.2.8). Although an association of some of these symp- toms with specific pathogens is recognized, they should not be con- sidered diagnostic in the absence of microbiological confirmation. Other concomitant causes for these symptoms may be more likely and should also be sought, for instance, recent antibiotic therapy causing diarrhoea or a skin rash. Unusual presentations Approximately 10% of patients with CAP present to hospital with atypical, or extrapulmonary symptoms alone. Older patients may present with a fall, acute confusion, or simply with generalized weakness (commonly described as being ‘off legs’). Occasionally, pa- tients with lower lobe pneumonia present with features suggestive of an acute abdomen—​acute abdominal pain, rigidity, and ileus. In older patients presenting with nonspecific symptoms, a chest X-​ray is usually necessitated, even if the chest examination is normal as clinical signs may be subtle. The diagnosis of pneumonia is fre- quently delayed in patients who present with atypical symptoms with consequent delay in the institution of appropriate therapy and a poorer outcome. Social, travel, and immunization history Relevant factors to consider in the history are: • occupation • recent travel • recent contact with other persons with pneumonia • recent contact with animals, wild, and domestic • smoking habits • alcohol consumption • recreational drug use • pneumococcal immunization • influenza immunization Occupational, travel, and contact histories are helpful in determining likely causative pathogens and for the early identification of disease outbreaks (Table 18.4.2.9). Table 18.4.2.8  Extrapulmonary symptoms of pneumonia and associated pathogens Presentation Possible pathogen Myringitis Mycoplasma pneumoniae Cerebellar dysfunction Legionella sp., Mycoplasma pneumoniae Meningitis Legionella sp., Mycoplasma pneumoniae, Streptococcus pneumoniae Encephalitis Coxiella burnetii, Mycoplasma pneumoniae, Legionella sp. Acute flaccid paralysis
(in children) Enterovirus-​D68 Diarrhoea Legionella sp., severe pneumococcal pneumonia Polyarthropathy Legionella sp., Mycoplasma pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae Skin rash Chlamydophila pneumoniae, Chlamydophila psittacii, Mycoplasma pneumonaie, Pseudomonas aeruginosa Herpes labialis Streptococcus pneumoniae Table 18.4.2.9  Social, travel, and occupational features associated with specific pathogens History/​exposure to Possible pathogen Contaminated water source (hotel shower, sauna, jacuzzi, water fountain) Legionella sp. Farm animal around birthing time (cattle, sheep, goats, rabbits) Coxiella burnetii Poultry and birds Chlamydophila psittaci Bat droppings in endemic area (e.g. Midwest, United States) Histoplama capsulatum Rabbits in endemic area (e.g. Finland) Francisella tularensis Camels in endemic area (e.g. Middle East) MERS-​CoV Recent influenza infection Staphylococcus aureus Intravenous drug use Staphylococcus aureus, anaerobes Travel to: South Mediterranean countries Legionella sp. Southeast Asia, Thailand, northern Australia Burkholderia pseudomallei Desert areas in south-​western United States Coccidioides immitis

section 18  Respiratory disorders 4014 Physical signs The patient usually looks flushed and unwell. Fever is present in about 85% of cases. The absence of fever is commoner in older pa- tients and may detract from an early diagnosis. Tachycardia and a raised respiratory rate may be the only signs indicating a pneu- monia. A low blood pressure is usually associated with severe illness and raises concerns of septic shock. Examination of the chest will reveal reduced movement on the affected side, particularly if pleuritic pain is prominent. A pleural rub may be heard even in the absence of pleural pain. The classic signs of lobar consolidation are dullness to percussion, bronchial breathing, and egophony, but these are uncommon, occurring in only 10–​30% of patients. More commonly, in 60–​80% of patients, focal crepitations or coarse crackles are heard. Occasionally, the chest examination appears normal and consolidation is only evident on radiological imaging. Clinical signs outside the chest may be present even if the patient does not report any extrapulmonary symptoms. Tenderness in the upper abdomen may be a feature of lower lobe pneumonia. Differential diagnosis In the absence of a chest X-​ray, the main alternative diagnoses to consider in a patient presenting with symptoms suggestive of a respiratory infection are acute bronchitis and nonpneumonic exacerbation of underlying lung disease (asthma, COPD). A bac- terial pathogen is implicated in only about 50% of exacerbations of COPD and up to 20% of exacerbations of asthma and acute bronchitis. Some noninfectious conditions may mimic the radiographic fea- tures of pneumonia and lead to diagnostic confusion (Fig. 18.4.2.2a and b). Patient and clinical factors are important in arriving at the correct diagnosis (Table 18.4.2.10). In patients with multiple comorbid illnesses, it can sometimes be very difficult to differentiate between cardiac failure, pulmonary infarction, and pneumonia. Immediate treatment for more than one condition may be appro- priate until the diagnosis becomes clearer. Clinical investigations Radiology Chest X-​ray is considered the ‘gold standard’ investigation for the diagnosis of pneumonia. The three commonest radiographic pat- terns associated with a diagnosis of pneumonia are: a) Lobar or segmental alveolar consolidation (lobar pneumonia) b) Patchy alveolar consolidation (bronchopneumonia) c) Interstitial shadowing (nodular and reticular patterns) Although some earlier studies suggested that certain radiographic patterns are associated with specific pathogens, it is now widely accepted that these radiographic patterns do not reliably discrim- inate the causative pathogen. For instance, although an interstitial pattern has been more frequently described in association with Mycoplasma pneumoniae infection, all three radiographic pat- terns can be caused by S. pneumoniae, Legionella sp., Mycoplasma pneumoniae, and influenza virus infections. Pleural effusions are noted in 20–​40% of cases at presentation. They are usually small to (a) (b) (c) Fig. 18.4.2.2  CT appearances of (a) cryptogenic organizing pneumonia, (b) lung adenocarcinoma, (c) lobar pneumonia. Table 18.4.2.10  Noninfectious conditions mimicking pneumonia radiologically Condition Distinguishing features from pneumonia Pulmonary infarction Sudden onset dyspnoea Risk factors for pulmonary emboli Pulmonary oedema Other features of cardiac failure Cryptogenic organizing pneumonia Subacute clinical course Adenocarcinoma of the lung, lepidic pattern Not acutely unwell with relative lack of systemic inflammatory response Eosinophilic pneumonia Blood eosinophilia Allergic bronchopulmonary aspergillosis Flitting shadows over time Background of asthma Pulmonary haemorrhage Haemoptysis, usually fresh blood

18.4.2  Pneumonia in the normal host 4015 moderate in size and are commonly associated with pneumococcal pneumonia. Less common radiographic abnormalities noted on the chest X-​ray in pneumonia include lung cavitation and lymphadenopathy. The range of pathogens associated with these abnormalities is dif- ferent. The commonest pathogens associated with lung cavities are: • Staphylococcus aureus • Mycobacterium tuberculosis • Gram-​negative bacteria (e.g. Klebsiella pneumoniae) • Anaerobes (e.g. Peptostreptococcus) The presence of prominent lymphadenopathy in pneumonia is asso- ciated with infection with: • Mycoplasma pneumoniae • Coxiella burnetti • Mycobacterium tuberculosis Greater detail can be obtained with CT scanning, which has a higher sensitivity than the chest X-​ray for the diagnosis of pneumonia. Ground-​glass opacities are best appreciated on CT scanning and are another pattern associated with pneumonia (see Fig. 18.4.2.3). The pathogens most commonly associated with this finding are Mycoplasma pneumoniae, Pneumocystis jirovecii, and viruses. However, even with CT scanning, the pattern of radiographic ab- normality cannot reliably discriminate between viral and bacterial pathogens, nor between specific pathogens. General investigations General investigations are performed to establish the diagnosis, as- sess the severity of illness, evaluate the impact on comorbid diseases, and to identify complications (Table 18.4.2.11). For many patients with mild pneumonia, blood investigations do not contribute to clinical management and are not necessary. C-​reactive protein (CRP) is an acute phase protein synthesized by the liver in response to infection and inflammation. CRP levels are almost always raised (>50 mg/​litre) in immunocompetent patients with pneumonia, and levels of CRP are higher in bacterial compared to viral infections. In the primary care setting, when the diagnosis of pneumonia is uncertain on clinical grounds alone, a very low CRP level (<20 mg/​litre) may be used to exclude the need for antibiotic therapy. A CRP level of more than 100 mg/​litre usually indicates that antibiotic therapy is warranted. Intermediate levels of CRP are less helpful in guiding treatment decisions. Microbiological investigations Microbiological investigations are used to identify the aetiological agent and hence direct antimicrobial therapy. However, results from microbiological tests are not usually available immediately, hence their use in the community setting is limited. For hospitalized patients, the recommended depth of microbio- logical investigations is partly dependent on the severity of illness. Fig. 18.4.2.3  CT appearance of acute TB pneumonia demonstrating ground-​glass opacities. Table 18.4.2.11  Purpose of general investigations in patients with pneumonia Investigation Purpose and interpretation Chest X-​ray To establish the diagnosis. Oxygen saturation or
arterial blood gases To inform severity assessment and identify respiratory failure. Full blood count High white cell count (WCC) supports a diagnosis of pneumonia. WCC of >15 × 109/​litre is associated with pneumococcal pneumonia. Very high (>20 × 109/​litre) and low (<4 × 109/​litre) WCCs indicate a poorer prognosis. Haemolytic anaemia is associated with infection by Mycoplasma pneumoniaea and (more rarely) Coxiella burnetii. Urea and electrolytes Raised urea (>7 mmol/​litre) is a poor prognostic factor. Low sodium (<130 mmol/​litre) is associated with legionella pneumonia and severe pneumococcal pneumonia. Liver function tests Commonly deranged in one-​third of pneumococcal pneumonia and half of legionella pneumonia. Hepatitis seen in infection with atypical pathogens. Low albumin (<30 g/​litre) is a poor prognostic factor. C-​reactive protein (CRP) Aids diagnosis of pneumonia. Most patients with pneumonia have a CRP >50 mg/​litre at presentation. A bacterial infection is unlikely if CRP <20 mg/​litre. A fall of less than 50% in the level of CRP after 3 days of treatment is associated with a poorer prognosis. Procalcitonin A bacterial infection is unlikely if procalcitonin <0.1 ug/​litre. HIV serology (in at-​risk patients) Identify altered host immune status. a This is due to the presence of cold agglutinins which are present in up to 50% of cases of mycoplasma pneumonias. A bedside test for cold agglutinins involves mixing a few drops of fresh blood with the same volume of sodium citrate (as found in a prothrombin tube) and leaving this in a refrigerator for 2–​3 minutes to reach about 4°C. Coarse agglutination of the blood, seen as the cooled tube is rotated, is usually associated with cold agglutinin titres greater than 1:64.

section 18  Respiratory disorders 4016 In patients with low severity illness, the diagnostic rate from micro- biological tests is lower and a positive test result leads to an alter- nation in antimicrobial management in only a small proportion of patients. Considerations of cost-​effectiveness mean that micro- biological tests are most warranted in patients with moderate and severe disease (Table 18.4.2.12); patients where there is clinical suspicion of less common pathogens that may not be covered by standard empirical therapy; and in outbreaks of pneumonia. In areas where Mycobacterium tuberculosis is a relatively frequent cause of CAP, microbiological investigations for M. tuberculosis should al- ways be considered. Specific investigations Viral pathogens, including influenza virus Viral polymerase chain reaction (PCR) is increasingly the diag- nostic test of choice for the detection of respiratory viral pathogens. Respiratory samples for viral PCR are ideally lower respiratory tract samples such as an induced sputum, bronchoalveolar lavage, or endotracheal aspirate. Where this is not possible, a nose or throat swab is acceptable. Multiplex viral PCR assays enable the detection of: • respiratory syncytial virus • influenza A and B viruses • parainfluenza virus • adenovirus • rhinovirus • human metapneumovirus • coronaviruses Mycoplasma pnemoniae and Chlamydophila species The serological investigation of M. pneumoniae and Chlamydophila species is increasingly being replaced by PCR detection in respira- tory samples. Serological tests may be unreliable in patients who are immunocompromised and may not provide a definitive result until the convalescent phase of the illness. Lower respiratory tract sam- ples or throat swabs are the preferred samples for PCR of M. pneu­ moniae and Chlamydophila species. Legionella species The use of serological tests to diagnose Legionella pneumophila in- fection is unreliable and is no longer offered in many places. Urinary antigen detection is the main method of diagnosis: this has a sensi- tivity of 80–​90% for the diagnosis of community-​acquired legionella pneumonia caused by L pneumophila serogroup 1, but less than 50% sensitivity for other L. pneumophila strains. Culture and isolation of legionellae from clinical specimens (blood, respiratory samples) is the diagnostic gold standard, al- lows detection of non-​L. pneumophila strains, and has a sensitivity of 50–​80%. However, reliable isolation of legionellae is not simple and requires the use of selective agars and pretreatments with heat or acid. These microbiology cultural techniques are not routinely performed in most laboratories and may need to be specifically requested when clinically indicated. Crucially, isolation of the infecting strain allows epidemiological typing to be done, which is important for the control and prevention of further cases, hence culture from appropriate specimens should always be pursued in patients where urinary antigen detection was the initial means of diagnosis. PCR allows detection of any L.  pneumophila serogroup with a higher sensitivity than culture (around 15% increased yield). However, the specificity of PCR remains unclear and respiratory samples for PCR are not always available as (typically) patients with legionella pneumonia have a dry cough. Pleural fluid In patients with para-​pneumonic effusions, a sample of pleural fluid should be sent for Gram stain and bacterial culture. Inoculating pleural fluid into a blood culture bottle, in addition to standard cul- ture of pleural fluid, increases the microbiological yield by about 20% (from 38% to 58% in one study). Pneumococcal urinary antigen de- tection from pleural fluid is not a licensed indication for most com- mercial assays but has a sensitivity and specificity of about 88% and 70%, respectively. Treatment Severity assessment at presentation Patients with CAP present with a wild spectrum of illness ranging from mild and self-​limiting to fulminant and life-​threatening. An accurate assessment of disease severity at the outset informs deci- sions regarding site of care (community, hospital), extent of micro- biological testing, choice of empirical antimicrobial therapy, route of administration, and duration of treatment. Prognostic studies using mortality as the main outcome measure have been the most widely studied. A number of clinical features, investigations, and radiographic features are independently asso- ciated with mortality at 30 days. Many of these factors have been combined in the form of a prediction tool called the pneumonia severity index (PSI) (Fig. 18.4.2.4), which enables patients to be stratified on admission to hospital into five categories based on the risk of mortality at 30 days. In clinical practice, a limitation of the PSI is the requirement for numerous test results and complex calculations. An alternative mortality prediction tool is the CURB65 score which relies on five factors and enables patients to be stratified into three groups (Fig. 18.4.2.5). Both PSI and CURB65 prediction tools have been internation- ally validated and are the two most widely recommended tools for severity assessment in national CAP guidelines. In comparative studies, both tools perform equally well. However, and most im- portantly, when using any prediction tool, it must be acknowledged Table 18.4.2.12  Recommended microbiological tests in hospitalized patients with moderate and high severity CAP Sample Microbiological test Blood (minimum 20 ml) Bacterial culture and sensitivities Sputum Gram stain, bacterial culture and sensitivities PCR for respiratory viruses and atypical pathogens Urine Pneumococcal urinary antigen Legionella urinary antigen

18.4.2  Pneumonia in the normal host 4017 that no prediction tool is perfect (miscategorization does occur); prediction tools are adjuncts to, not replacements for, clinical judgement; and regular reassessment during the course of treat- ment is required. A variation of the CURB65 score is the CRB65 score, which does not require any test result for its calculation. It can therefore be applied in the community where access to tests is limited. Interpretation of the CRB65 score: • Score 0: less than 1% mortality risk • Score 1 or 2: 1–​10% mortality risk • Score 3 or 4: more than 10% mortality risk The 2014 UK National Institute for Clinical Effectiveness (NICE) Pneumonia Guideline recommends the following for patients with CAP assessed in a: Community setting—​clinical judgement in conjunction with the CRB65 score is used to inform decisions about whether patients need hos- pital assessment as follows: consider home-​based care for patients with a CRB65 score of 0; consider hospital assessment for all other patients, particularly those with a CRB65 score of 2 or more. Hospital setting—​clinical judgement in conjunction with the CURB65 score is used to guide the management of community-​acquired pneumonia, as follows:  consider home-​based care for patients with a CURB65 score of 0 or 1; consider hospital-​based care for patients with a CURB65 score of 2; consider intensive care assess- ment for patients with a CURB65 score of 3 or mores. Aside from disease severity assessment, other factors that should be taken into account when considering management decisions are stability of comorbid illnesses; the social circumstances of the pa- tient, especially for community treatment; and the patient’s wishes. Up to 40% of patients who are hospitalized with CAP have low Step 1: Age ≤ 50 years, and No adverse clinical factors (given in red) NO: go to Step 2 (calculate points) Prognostic factor Male (Female) adverse clinical factors Nursing home resident Age (Age –10) +10 +30 Neoplastic disease Chronic liver disease Cerebrovascular disease Chronic renal disease Altered mental status Respiratory rate ≥30/min Systolic BP <90 mmHg Temperature <35°C or ≥40°C Pulse ≥125/min Pleural effusion Step 3: Stratify to Risk Class Total points Risk Class Risk of mortality (%) <70 71–90 91–130

130 PaO2 <60mm Hg Arterial pH<7.35 Urea >11mmol/l Sodium <130mmol/l Haematocrit <30% Glucose ≥14mmol/l Congestive heart failure +20 +10 +10 +10 +20 +20 +20 +15 +10 +30 +20 +20 +10 +10 +10 +10 Points Yes Risk class I Risk of mortality: 0.4% II 0.7 2.8 8.5 31.1 III IV V Fig. 18.4.2.4  Pneumonia severity index: calculation and interpretation. Step 1: Determine if risk class I or risk classes II–​V. Step 2: If not risk class I, calculate total points. Step 3: Stratify to risk classes II–​V. After Fine MJ, et al. (1997). A prediction rule to identify low-​risk patients with community-​acquired pneumonia. New Engl J Med, 336, 243–​50. CURB65 score Score 1 point for each feature present: Confusion Urea >7 mmol/litre Respiratory rate ≥ 30/min Blood pressure, SBP <90 or DBP ≤60 mm Hg Age ≥ 65 years Score 30–day risk of mortality (SBP = systolic blood pressure. DBP = diastolic blood pressure) 0–1 2 3–15% 15% 3–5 <3% Fig. 18.4.2.5  CURB65 score: calculation and interpretation.

section 18  Respiratory disorders 4018 severity pneumonia reflecting the importance of other factors in determining their need for hospital care. Biomarkers Biomarkers that can characterize underlying mechanisms of dis- ease in CAP may, theoretically, provide additional prognostic in- formation. Inflammatory biomarkers such as CRP, procalcitonin, and cytokines (e.g. interleukin-​6, tumour necrosis factor-​α) are associated with disease severity and mortality. Cardiovascular biomarkers include N-​terminal B-​type natriuretic peptide (NT-​ proBNP), proendothelin-​1 (proET-​1), midregional proatrial natri- uretic peptide (MR-​proANP), proarginin-​vasopressin (copeptin), and midregional proadrenomedullin (MR-​proADM). Coagulation biomarkers such as D-​dimers have been studied in CAP but the overlap with its established use in venous thromboembolic disease is troublesome clinically. Stress response biomarkers such as cor- tisol and copeptin are associated with disease severity and early clinical instability. Cortisol levels may be affected by the timing of sampling and concurrent use of corticosteroids. Overall, bio- markers are best considered as complementary to clinical prog- nostic tools, but in the future they may be employed selectively to assess different aspects of patient management at different phases of illness. General management The components of initial management include appropriate: • fluid administration • oxygen supplementation • antipyretics (e.g. paracetamol) • prophylaxis for venous thromboembolism Mechanical ventilatory support may be indicated in critically ill pa- tients. Expectorants and cough suppressants have not been shown to be of proven value and chest physiotherapy is not routinely advised. In patients with large pleural effusions, drainage may be beneficial. Antimicrobial therapy Antimicrobial agents are the mainstay of therapy. A  definitive microbiological diagnosis is rarely established at the point of ini- tial diagnosis, hence most initial prescribing is empirical and based around the most likely pathogens expected in the clinical context. Invariably, a tension arises between providing sufficiently broad antimicrobial cover for a range of pathogens versus inappropriate overuse of antimicrobials with associated risks of adverse effects in both the short and long terms. There are no robust placebo-​controlled trials of antimicrobial therapy in CAP. Drug-​drug comparative trials have been mainly de- signed to demonstrate noninferiority and most compare new agents against older agents which are commonly used as the standard of care, meaning that considerable debate continues regarding the most appropriate treatment regimens for patients. Most studies indicate that in low severity CAP, most patients can be adequately treated with a single antibiotic. In moderate and high severity CAP, most data suggest that a combination of a β-​lactam plus a macrolide is superior to a β-​lactam alone in terms of mor- tality and treatment failure, although newer studies are challenging this view. In general, most guideline recommendations for empirical anti- microbial therapy in CAP reflect the following principles: • Streptococcus pneumoniae should always be covered initially. • Broader coverage is offered for patients who are severely ill, in whom the consequences of treatment failure can be life-​threatening. • Therapy should be directed by microbiological test results as soon as possible. • The oral route of administration should be used as soon as appropriate. The 2014 UK NICE Pneumonia Guideline recommendations are based around β-​lactams and macrolides (Table 18.4.2.13). Other guidelines offer alternative recommendations that include respira- tory fluoroquinolones (mostly in place of macrolides). Antibiotic therapy should be given as soon as possible once a diag- nosis is made. For patients referred to hospital, delay in antibiotic therapy beyond 4 to 6 hours from presentation has been associated with a poorer prognosis. However, efforts to achieve early antibiotic therapy should not disregard the need to also establish a diagnosis of pneumonia. Suggestions for specific agents according to microbial pathogen are summarized in Table 18.4.2.14; these suggestions do not repre- sent an exhaustive list of all possible antimicrobial agents. Antimicrobial resistance Streptococcus pneumoniae Antimicrobial resistance in relation to the leading pathogen in CAP, Streptococcus pneumoniae, is of greatest concern. Rates of pneumo- coccal drug-​resistance vary greatly across the world. In the United States, resistance to one or more antibiotics is found in about 30% of invasive pneumococcal infections. Resistance to penicillin and other β-​lactams in Streptococcus pneumoniae is mediated by modifications in penicillin binding pro- teins, and most β-​lactam resistance arises from mutations in three of six such proteins. Fortunately, high-​doses of β-​lactams can often still be used to successfully treat infections caused by penicillin non-​ susceptible S pneumoniae. Macrolide resistance is mediated by two different mechan- isms: the efflux mechanism (mef gene), which confers low level resistance and is common in the United States; and ribosomal target site mutations (erm gene), which confer high level resistance Table 18.4.2.13  Summary of the 2014 UK NICE Pneumonia Guideline antimicrobial recommendations for adults presenting with CAP Severity of pneumonia Antimicrobial choice Duration of therapy Low severity Amoxicillin Alternatives: macrolide, or a tetracycline 5 days Moderate severity Amoxicillin plus a macrolide 7–​10 days High severity β-​lactamase stable β-​lactam plus a macrolide 7–​10 days Examples (nonexhaustive list) of: • macrolides: clarithromycin, erythromycin, azithromycin. • β-​lactamase stable β-​lactams: coamoxiclav, 2nd or 3rd generation cephalosporins.

18.4.2  Pneumonia in the normal host 4019 and are common worldwide, and increasingly common in the United States. Fluoroquinolone resistance arises from the alteration of the fluoroquinolone binding site through the gradual accumulation of spontaneous mutations in the quinolone resistance determinant re- gion of gyrA and/​or parC. Monotherapy of pneumococcal CAP with macrolides or fluoroquinolones in the presence of corresponding drug-​resistance is usually associated with treatment failure. Haemophilus influenzae Resistance of H.  influenzae to penicillin is mediated predomin- antly by β-​lactamase resistance. β-​lactamase-​positive nontypeable H influenzae strains account for 10–​25% of strains in most regions (South Africa, Europe, United States, Canada, Central America, South America), but up to 55% of strains in other regions (Taiwan, Vietnam, Japan, South Korea). Of some concern is the emergence of H. influenzae strains with higher levels of β-​lactam resistance, including new mechanisms of resistance. Adjuvant therapy The goal of adjuvant therapy (given alongside antimicrobial therapy) is to suppress overexuberant pathogen-​activated inflammation, thereby attenuating unwanted pulmonary damage. Macrolides have anti-​inflammatory properties as well as anti- microbial properties. This may partly explain the benefits of combin- ation therapy with a β-​lactam plus macrolide over β-​lactam therapy alone observed in some studies of patients with severe pneumonia, and also in penicillin-​sensitive pneumococcal pneumonia. Further studies are required to better define the role of macrolides as adju- vant therapy in CAP. Corticosteroids are currently the most promising anti-​ inflammatory agents in pneumonia. Placebo-​controlled random- ized trials in hospitalized patients, excluding those with severe pneumonia, suggest corticosteroids reduce the time to clinical stability and length of hospital stay, but have no impact on mor- tality. At the same time, other trials conducted in patients with se- vere pneumonia, including those admitted to the intensive care, suggest corticosteroids reduce treatment failure and mortality. Further results from larger trials of corticosteroids in pneumonia are awaited. Several other candidates have been tested over the years but have not been found to be beneficial; this list includes granulo- cyte colony stimulating factor (G-​CSF), recombinant human ac- tivated protein C (drotrecogin alfa) and recombinant tissue factor pathway inhibitor (tifacogin). Critical care support Patients with high severity CAP who are at high risk of mortality should be considered for supportive care in a critical care setting. Indications for such transfer include: • persisting hypoxia (PaO2 <8 kPa) despite oxygen supplementation • progressive hypercapnia Table 18.4.2.14  Antimicrobial therapy of pneumonia by specific pathogens Pathogen Preferred Alternative S pneumoniae Amoxicillin Macrolide, respiratory fluoroquinolone, doxycycline, cephalosporins M pneumoniae Doxycycline Macrolide Fluoroquinolone C pneumoniae Doxycycline Macrolide Fluoroquinolone Legionella sp. Fluoroquinolone Macrolide C psittaci Doxycycline Macrolide, fluoroquinolone C burnetii Doxycycline Macrolide, fluoroquinolone H influenza Amoxicillin (if non-​β-​lactamase producing) β-​lactamase stable β-​lactam Macrolide, fluoroquinolone Staphylococcus aureus i) non-​MRSA Flucloxacillin +/​–​ rifampicin Cefazolin, cefuroxime, Teicoplanin, Vancomycin, clindamycin, TMP–​SMX, fluoroquinolone ii) MRSA Vancomycin Linezolid Teicoplanin +\–​ rifampicin Requires in vitro testing P aeruginosa Aminoglycoside + antipseudomonal β-​lactam: ceftazidime, imipenem, meropenem, doripenem, piperacillin/​ticarcillin, cefepime or aztreonam Aminoglycoside + ciprofloxacin Ciprofloxacin + antipseudomonal β-​lactam GNEB Cephalosporin—​3rd generation ± aminoglycoside Carbapenem Aztreonam, β-​lactamase stable β-​lactam, Fluoroquinolone Influenza Neuraminidase inhibitor -​ Examples of: macrolides: erythromycin, clarithromycin, azithromycin, dirithromycin respiratory fluoroquinolones: levofloxacin, moxifloxacin—​has enhanced activity against S. pneumoniae nonrespiratory fluoroquinolone: ciprofloxacin—​has activity against legionella spp., C. pneumoniae, M. pneumoniae, fluoroquinolone-​sensitive Staphylococcus aureus, and most Gram-​negative bacilli neuramidase inhibitors: oseltamivir, zanamivir, peramivir

section 18  Respiratory disorders 4020 • severe acidosis (pH <7.26) • depressed consciousness The use of continuous positive airway pressure (CPAP) or non-​in- vasive ventilation (NIV) for the treatment of respiratory failure in CAP has not been adequately tested in clinical trials. Neither mode of treatment is routinely indicated. If the use of CPAP or NIV is attempted, this should ideally be conducted in a setting that per- mits a rapid transition to invasive mechanical ventilation as soon as it becomes evident that the patient is failing to respond to CPAP or NIV. The value of extracorporeal membrane oxygenation (ECMO) in the management of acute respiratory failure due to CAP is also un- clear. During the 2009 H1N1 pandemic, ECMO was used with some reported success. Prognosis/​outcome Response to treatment Following appropriate initial treatment, including antibiotics, most patients with pneumonia will begin to improve. The median time to return to normal levels for heart rate and blood pressure is 2 days; and for temperature, respiratory rate, and oxygen saturation is 3 days. In up to 30% of patients, a lack of response is evident after 3 days. Blood cultures in bacteraemic patients are usually negative within 24–​48 hours. Cultures of sputum will usually show eradication of bacterial pathogens within 24 to 48 hours. Patients with nonbacteraemic infection who are initially treated with intravenous antibiotics can usually be switched to receive oral agents after 2–​3 days when the following features are met: evidence of clinical improvement; there is resolution of fever for more than 24 hours; the patient can take oral fluids and there are no concerns over gastrointestinal absorption. Following a switch to oral antibiotics, no benefit has been found with keeping a patient in hospital for a further 24 hours of observation if otherwise clinically fit for hospital discharge Chest X-​ray response Radiographic improvement lags behind clinical improvement. In patients who are clinically improving, repeat chest radiographs are generally unnecessary except for patients in whom there are con- cerns that the pneumonia was a complication of an underlying con- dition such as lung cancer. The recommended time to arrange such chest X-​rays is about 6 weeks after treatment. Failure to respond It is important to differentiate between a true failure to respond and an adequate response that is slower than expected. The CRP level is useful as a prognostic marker in this respect. A fall in CRP level from day 1 to day 4 of less than 50% is associated with a poorer clin- ical outcome and suggests an inadequate response. Careful clin- ical evaluation for the cause of an inadequate response is necessary (Table 18.4.2.15). Investigations to consider include repeat blood and sputum cultures, chest imaging and bronchoscopy. A more protracted clinical course of recovery is often seen in older people and in severe legionella pneumonia. In such instances, no alteration to therapy may be required, but close observation is mandatory. Special circumstances/​complications Parapneumonic effusion A pleural effusion is found in 20–​40% of patients hospitalized with CAP. Many of these are small parapneumonic effusions that re- solve with appropriate antibiotic therapy alone. In some patients, a parapneumonic effusion may be the cause of a persisting fever des- pite appropriate antibiotic therapy. Drainage of the pleural space is usually indicated if the pleural fluid pH is less than 7.2 (even if the fluid looks clear) or there is pus or microbiologically confirmed in- fection in the pleural space (an empyema). Further details on the management of complicated parapneumonic effusions are given in Chapter 18.17. Lung abscess and cavitating pneumonia The development of a lung abscess during the course of pneumonia is uncommon. Patients may appear surprisingly well despite the presence of a lung abscess; a persistence of fever or high inflamma- tory markers may be the only manifestations. The diagnosis is usu- ally evident on chest X-​ray. Presence of a lung abscess should prompt consideration of less common bacterial pathogens such as Staphylococcus aureus, anaer- obes (including Streptococcus milleri), and Gram-​negative bacilli (e.g. Klebsiella pneumoniae). Poor dentition and aspiration are risk factors associated with anaerobic and Gram-​negative infections. Prolonged antibiotic therapy (2–​6 weeks), initially with intra- venous antibiotics, is typically given in patients with lung abscesses. Response to treatment is the best guide to the total duration of therapy. Complete resolution of even large abscesses (>4 cm size) is possible with antibiotic therapy alone. In the uncommon instance when drainage of a lung abscess may be considered, an individual- ized assessment is required, taking into account the size, location, and number of abscesses, response to antibiotics, host fitness, and pathogen involved. Table 18.4.2.15  Causes of failure to respond to treatment (acronym CHAOS) Cause Example Complication of pneumonia Parapneumonic effusion or empyema Lung abscess Metastatic infection Septicaemia Host susceptibility Immunocompromised state (e.g. HIV, corticosteroid use) Impaired local defences (e.g. endobronchial obstruction, bronchiectasis) Antibiotic Inappropriate antibiotic Inadequate dose Inappropriate route of administration
(e.g. oral route in patient with gastrectomy) Antibiotic hypersensitivity Organism Antibiotic-​resistant organism Unexpected organism More than one organism Second diagnosis Antibiotic-​associated diarrhoea Phlebitis at intravenous cannula site Pulmonary embolism Incorrect diagnosis in the first instance (not pneumonia!)

18.4.2  Pneumonia in the normal host 4021 Aspiration pneumonia Aspiration pneumonia generally refers to the development of pneu- monia following the inhalation of material into the lower airways. It is typically associated with a defect in swallow or protective airways defences. However, not all patients with pneumonia and a defective swallow necessarily have aspiration pneumonia. Conversely, silent aspiration is well-​recognized in older patients and aspiration events may be unwitnessed. The lower lobes are usually affected, more commonly on the right. In patients who are recumbent at the time of aspiration, the pos- terior segment of the upper lobes may be affected. Clinical presentations that increase the suspicion for aspir- ation pneumonia include recurrent pneumonias, anaerobic pneumonias, and lung abscesses. The microbiology reflects the organisms usually found in the oropharynx, including Gram-​ negative bacteria and anaerobes. Often, more than one pathogen is involved. Prevention Lifestyle factors, such as smoking and high alcohol intake, are im- portant modifiable risk factors for the development of pneumonia. Exposure to drugs that modulate host immune responses is usually determined by the need for such medication. Whenever appro- priate, the use of such drugs, including oral and inhaled corticoster- oids, should be kept to the minimum. Pneumococcal vaccines Two types of pneumococcal vaccines are available. The most com- monly used of these are: • the pneumococcal polysaccharide vaccine containing polysac- charide from 23 serotypes (PPV23)l; • the pneumococcal conjugate vaccine (PCV), generally containing polysaccharide from 10, 13 or 15 serotypes (PCV10, PCV13, or PCV15). Recommendations for the use of PPV23 in adults have been in place in various countries since the mid-​1980s. The efficacy of PPV23 in preventing invasive pneumococcal disease is still de- bated; some meta-​analyses report efficacy estimates of 50–​70%, while other studies have found no benefit. The value of PPV23 in preventing noninvasive pneumococcal pneumonia is also contested. The poor immunogenicity of polysaccharides in infants less than 2 years of age led to the development of PCVs, which in- volves conjugation of pneumococcal capsular polysaccharides to a carrier protein that is nontoxic and nearly identical to diph- theria toxin (CRM197). A key advantage of PCVs is the activa- tion of a T-​cell dependent antibody response in the setting of mucosal immunity. Hence, PCV use in children is associated with decreased nasopharyngeal carriage of S. pneumoniae which in turn is associated with reductions in adult pneumococcal in- fections through decreased transmission (an effect know as herd protection). A randomized-​controlled trial of PCV13 involving roughly 85 000 adults aged 65 years and older found that PCV13 was associated with 45% fewer episodes of vaccine-​type CAP; 45% fewer episodes of nonbacteraemic vaccine-​type CAP; and 75% fewer episodes of vaccine-​type invasive pneumococcal disease. Following the introduction of PCV13 into the US infant im- munization programme in 2010, a 12–​32% decline in the inci- dence of total adult invasive pneumococcal disease by June 2013 was observed. Recommendations relating to the use of pneumo- coccal vaccines in adults issued by the US Advisory Committee on Immunization Practices (ACIP) are: • Adults aged 19 years or over with immunocompromising condi- tions should receive PCV13 and PPV23 (issued 2012) • All adults aged 65 years or over should receive both PCV13 and PPV23 (issued 2014) New protein-​based vaccines and live, attenuated whole cell vac- cines are under development. If successful, these vaccines should offer broad serotype-​independent protection from pneumococcal infections. Influenza vaccine The benefit of influenza vaccination in the general elderly popu- lation (65 years and older), many of whom have chronic health conditions, has not been adequately assessed in randomized trials. Early cohort studies suggested up to 43% effectiveness in preventing influenza-​related pneumonia. However, more recent analyses suggest the true size of these estimates may not be as large. In the United Kingdom, adult influenza vaccination was recom- mended in 2017/​18 for: • everyone aged 65 and over • everyone aged from 6 months to less than 65 years of age with a serious medical condition • pregnant women, at any stage of pregnancy • all those aged two and three (on 31 August 2017) • all children in reception class and school years 1–​4 (aged 4–​9 years) • everyone living in a residential or nursing home • everyone who cares for an older or disabled person • household contacts of anyone who is immunocompromised • all frontline health and social care workers Controversies/​future developments Research investment in pneumonia is disproportionately low compared to the global burden of disease. The lack of robust evi- dence to support many currently recommended therapies fuels ongoing controversy in these areas: use of macrolides in combin- ation with β-​lactams in empirical antibiotic regimens; use of cor- ticosteroids as adjunctive therapy; optimal duration of antibiotic therapy; role of biomarkers in guiding management decisions; and use of CPAP or NIV in acute respiratory failure secondary to pneumonia. Increased translational research into rapid microbiological diag- nostics and novel antimicrobial agents (not just new antibiotics) is required. The future goal should be to provide individualized therapy which is pathogen-​specific as soon as a diagnosis of pneu- monia is made.

18.4.3 Nosocomial pneumonia 4022 Wei Shen Lim

18.4.3 Nosocomial pneumonia 4022 Wei Shen Lim

section 18  Respiratory disorders 4022 FURTHER READING Briel M, et al. (2018). Corticosteroids in patients hospitalized with community-acquired pneumonia: Systematic review and indi- vidual patient data meta analysis. Clin Infect Dis, 66(3), 346–54. doi: 10.1093/cid/cix801. Kolditz M, Ewig S, Hoffken G (2013). Management-​based risk predic- tion in community-​acquired pneumonia by scores and biomarkers. Eur Respir J, 41, 974–​84. Lee JS, Giesler DL, Gellad WF, Fine MJ. (2016). Antibiotic therapy for adults hospitalized with community-acquired pneumonia: A systematic review. JAMA, 315(6), 593–602. doi: 10.1001/ jama.2016.0115. Lim WS, et al. (2009). BTS guidelines for the management of commu- nity-​acquired pneumonia in adults: update 2009. Thorax, 64 Suppl, iii1–​55. Mandell LA, et  al. (2007). Infectious Diseases Society of America/​ American Thoracic Society consensus guidelines on the manage- ment of community-​acquired pneumonia in adults. Clin Infect Dis, 44 Suppl 2, S27–​72. National Institute for Health and Care Excellence (2014). Pneumonia in adults: diagnosis and management (CG191). https://www.nice.org. uk/guidance/cg191 Tomczyk S, et  al. (2014). Use of 13-​valent pneumococcal conju- gate vaccine and 23-​valent pneumococcal polysaccharide vaccine among adults aged >/​=65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep, 63, 822–​5. Welte T, Torres A, Nathwani D (2012). Clinical and economic burden of community-​acquired pneumonia among adults in Europe. Thorax, 67, 71–​9. Wunderink RG, Waterer G (2017). Advances in the causes and manage- ment of community acquired pneumonia in adults. BMJ, 358, j2471. doi: 10.1136/bmj.j2471. 18.4.3  Nosocomial pneumonia Wei Shen Lim ESSENTIALS Nosocomial pneumonia is generally defined as a new pulmonary infiltrate on chest radiography, combined with evidence of infec- tion expressed as fever, purulent respiratory secretions, and/​or leucocytosis, with onset 48 hours or more after admission. It is the most frequent lethal nosocomial infection (overall mortality 7% in general ward inpatients to over 50% in critically ill patients). Aetiology—​most cases are caused by Gram-​negative bacteria
(50–​70%) or Staphylococcus aureus (15–​30%). Gram-​negative bacteria reach the lung by aspiration of gastric contents or by microaspiration of upper airway secretions; throat cultures reveal that 60–​75% of patients on intensive care units are colonized by these organisms (compared to 2–​6% of healthy people). Prevention—​simple methods of prevention are by nursing the pa- tient in the semi-​upright position to reduce the risk of aspiration, and hand-​washing between patients to prevent transmission of nosocomial pathogens. Diagnosis—​this can be difficult, especially on intensive care units, when pulmonary infection is confirmed in only about 30% of cases of suspected ventilator-​acquired pneumonia. Management—​when empirical decisions are necessary in ser- iously ill patients, the favoured drugs directed against Gram-​negative
bacteria are ceftazidime, cefepime, imipenem/​meropenem, piperacillin/​piperacillin–​tazobactam, ticarcillin/​ticarcillin–​sulbactam, or ciprofloxacin. For methicillin-​resistant S. aureus, vancomycin or linezolid is added. Introduction Definition Hospital-​acquired pneumonia Hospital-​acquired pneumonia (HAP) is defined as an inflam- matory condition of the lung parenchyma caused by infectious agents not present or incubating at the time of hospital admis- sion (i.e. pneumonia that occurs 48 hours or more after hospital admission). Hospital-​acquired pneumonia is further classified into pneu- monias that occur on the intensive care unit (ICU HAP) and those that occur on the ward (non-​ICU HAP) (Fig. 18.4.3.1). Ventilator-​ acquired pneumonia (VAP) is a subset of HAP that includes all pa- tients receiving mechanical ventilation at the time of infection. It is defined as HAP that develops more than 48 hours after endotracheal intubation. Aetiology Although most HAP occurs outside the ICU, knowledge about the microbiology of HAP is dominated by studies conducted HAP in the intensive care unit (ICU) (c.35%) Non-ICU HAP (c.65%) Ventilator-acquired pneumonia (VAP) (c.85%) Non-VAP ICU HAP (c.15%) Hospital-acquired pneumonia (HAP) Subdivisions of hospital-acquired pneumonia Fig. 18.4.3.1  Subdivisions of hospital-​acquired pneumonia. HAP = hospital-​acquired pneumonia. ICU = intensive care unit. VAP = ventilator-​acquired pneumonia.

18.4.3  Nosocomial pneumonia 4023 in ICU settings. The pathogens associated with HAP vary according to ward environment (e.g. ICU vs. non-​ICU, surgical vs. medical), patient factors (e.g. reason for being in hospital, im- mune status), and treatments received (e.g. type of surgery, prior antibiotics). There are considerable local and regional differences in the spectrum of pathogens encountered in HAP, including their in- cidence and antibiotic resistance profile. The spectrum of likely pathogens (Table 18.4.3.1) can be broadly classified according to the absence, or presence, of risk factors for multi-drug resistant (MDR) pathogens. These risk factors include: • Previous antimicrobial therapy • Hospital stay more than 4 days • Invasive ventilation more than 4 days • Malnutrition • Structural lung disease • Known upper airway colonization by MDR pathogens In patients who are immunosuppressed, other less commonly en- countered pathogens may also cause HAP, including Legionella sp., Pneumocystis jiroveci, Nocardia sp., Aspergillus sp., Candida sp., and cytomegalovirus. Epidemiology Hospital-​acquired pneumonia HAP is the second commonest nosocomial infection, after urinary tract infections, with a crude overall rate of about 6 per 1000 dis- charges. The incidence rates of HAP vary depending on the hospital environment and patient groups affected. Most infections occur on non-​ICU wards where reported rates range from 1.6 to 18 per 1000 hospital admissions. Only about 35% of HAP occurs in ICU settings, although the incidence of HAP is greater among patients in the ICU compared to patients on general wards. HAP carries the highest mortality rate of all nosocomial infec- tions, varying from about 7% in patients on general wards to over 60% in patients on bone marrow transplant units. Ventilator-​acquired pneumonia The overall rate of VAP is about 16 per 1000 ventilator days. The rate of contracting VAP has been described as 3% per day during the first week of mechanical ventilation (MV), 2% per day during week 2, and 1% per day thereafter. Rates of VAP are highest in trauma ICUs (Table 18.4.3.2). Between 10% and 20% of patients receiving more than 48 hours of mechanical ventilation will develop VAP. The mean duration of occurrence of VAP is around 5–​7  days, with associated mortality ranging from 25% to 75%. Critically ill patients who develop VAP, compared with patients without VAP are twice as likely to die, have significantly longer ICU lengths of stay (mean = 6 days), and incur more than US$10 000 in additional hospital costs. However, it is less clear whether more patients die with VAP or because of VAP. The at- tributable mortality of VAP is estimated at about 13%, with higher mortality rates in surgical patients and patients with mid-​range illness severity scores (such as the acute physiology and chronic health evalu- ation (APACHE) score). Attributable mortality is lowest (close to 0%) in trauma and medical patients, and in patients with low or high illness severity scores. Pathogenesis In general terms, pneumonia develops when pathogenic organisms gain entry to the lower respiratory tract, overwhelm lung defences, and cause inflammation in the lung parenchyma. Infections causing HAP can be considered to arise from endogenous or exogenous sources. Endogenous infection is the commonest. In health, the oropharynx of individuals is colonized by Gram-​ positive organisms mainly of streptococcal species and secretions from the larynx or pharynx are cleared by mucociliary action or the cough reflex. In patients who are unwell, the usual oropharyngeal colonizers are gradually replaced by Gram-​negative enteric bacteria, Pseudomonas aeruginosa, and Staphylococcus sp. With increasing severity of illness, colonization by Gram-​negative enteric bacteria increases, from about 6% of normal persons to nearly 75% of critic- ally ill patients Microaspiration of oropharyngeal secretions is the predom- inant mechanism by which organisms enter the lower airways. In patients who are mechanically ventilated, colonizing organisms together with oropharyngeal secretions form biofilms along the endotracheal tube cuff or within the tube lumen. From there, or- ganisms may be introduced into the lower airways. Pneumonia Table 18.4.3.1  Pathogens most commonly associated with HAP In patients without risk factors for MDR pathogens In patients with risk factors for MDR pathogens: additional pathogens to consider Enterobacteriaceae • Escherichia coli • Klebsiella sp. • Enterobacter sp. Haemophilus influenzae Staphylococcus aureus Streptococcus pneumoniae Methicillin-​resistance Staphylococcus aureus Extended-​spectrum β-​lactamase forming Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter baumannii Stenotrophomonas maltophilia MDR, multi-drug resistant Table 18.4.3.2  Rates of VAP in different types of ICU—​pooled results from global surveillance study Type of ICU Pooled mean VAP rate
(per 1000 ventilator days) 95% CI Trauma 40.0 37 to 44 Neurologic 28.1 23 to 34 Respiratory 27.7 25 to 30 Neurosurgical 20.9 19 to 23 Medical/​surgical 18.4 18 to 19 Surgical 16.3 16 to 17 Medical cardiac 10.8 10 to 12 Medical 7.7 7 to 8 Overall 15.8 15 to 16

section 18  Respiratory disorders 4024 ensues if these organisms are not then cleared by cellular defence mechanisms. Exogenous infection with nosocomial pathogens acquired from the hospital environment is much less common. Pathogenic organisms found on healthcare workers or medical devices can colonize the upper airways of vulnerable patients or be inhaled into the lower airways. Potential sources of exogenous infec- tion include ventilator circuits, humidifiers, bronchoscopes, and nebulizers. Haematogenous spread of infection from distant sites to the re- spiratory tract occasionally occurs. Intravenous cannulas or urinary catheters are potential sources of such infections. Risk factors Risk factors for the development of HAP are those that: a) increase oropharyngeal or gastric colonization by pathogenic organisms; b) facilitate the entry of organisms into the lower airways; c) impair host lung defences. They can be broadly divided into modifiable or nonmodifiable fac- tors (Table 18.4.3.3). Clinical features Patients with HAP are, by definition, already receiving care within a hospital setting for another medical condition. Symptoms related to HAP are therefore superimposed on any pre-​existing symptoms. In this situation, recognizing the early symptoms of HAP can be very difficult, particularly in patients who are already severely ill, such as those receiving treatment in ICUs. The cardinal symptoms of HAP are: • fever c.80% • cough c.85% • breathlessness c.70% • sputum production c.50% • chest pain c.45% While it is possible for HAP to develop without any specific symp- toms, this is unusual. The clinical signs associated with HAP are similar to those for CAP (see Chapter 18.4.2). These include fever, tachycardia, raised respiratory rate, hypoxia, and hypotension. On examination of the chest, signs of consolidation may be pre- sent. The frequency with which these signs occur is not well studied and vary according to the patient cohort. However, as these signs are not specific for HAP, the main challenge is in differentiating HAP from other causes that might be responsible for, or contributing to, any abnormal findings identified. Differential diagnosis Making a diagnosis of HAP or VAP can be very difficult. Conditions that mimic HAP include pulmonary infarction, adult respiratory distress syndrome, pulmonary oedema (with another infection site), pulmonary haemorrhage, vasculitis, interstitial lung disease, malig- nancy, and drug toxicity. Clinical investigation Making a diagnosis The objective of investigations in HAP is to confirm or refute the diagnosis as soon as possible. A chest X-​ray (CXR) is essential to establishing the diagnosis with a sensitivity of 50–​80%. However, the specificity of CXR changes for HAP is poor, especially for critic- ally ill patients being managed on the ICU. Similarly, general blood investigations and serum biomarkers may be abnormal for many reasons other than HAP. In clinical practice, it is widely accepted that a diagnosis of HAP should be suspected in a patient with new-​onset or progressive in- filtrates on CXR in combination with two or more of the following criteria: • white cell count more than 10 000 or less than 4000/​ul • fever more than 38.3°C • purulent respiratory secretions In these circumstances, isolation of a relevant pathogenic or- ganism from blood or respiratory samples confirms the diagnosis of HAP, but in many instances microbiological confirmation is not attained and the diagnosis of HAP may only be upheld based on the combination of ongoing compatible clinical features, the lack of an alternative diagnosis, and response to antimicrobial therapy. In patients with suspected VAP, a clinical pulmonary infection score has been advocated to improve the specificity of clinical diag- nosis. This combines clinical, radiological, physiological, and micro- biological (culture of tracheal aspirate) data into a single figure. However, it remains an imprecise diagnostic tool and its value is de- bated. Overall, in patients with suspected VAP, a pulmonary infec- tion is confirmed in only about 30%. Microbiological investigations When HAP is suspected, samples from all potential sites of noso- comial infection should be obtained for culture, preferably before antibiotic therapy is started. This includes blood, urine, and respira- tory samples. Table 18.4.3.3  Risk factors associated with HAP and VAP Nonmodifiable risk factors Modifiable risk factors • Advanced age • Male gender • Chronic lung disease • Diabetes • Immunosuppression • Cranial trauma • Neurosurgery • Extensive burns • Coma • Shock • Renal dysfunction • ARDS • Multiorgan failure • Smoking • Malnutrition • Supine positioning • Gastric overdistension • Nasal tubes • Endotracheal intubation • Colonization of ventilation circuits • Patient movement in and out of ICU
for investigations or procedures • Duration of hospital stay

18.4.3  Nosocomial pneumonia 4025 A range of respiratory samples—​sputum, tracheobronchial as- pirate (TBA), bronchoalveolar lavage (BAL)—​may be obtained depending on whether the patient is being managed in ICU and is being mechanically ventilated. A bronchoscopy with BAL provides good-​quality targeted lower re- spiratory airway specimens, but there is no good evidence that use of a BAL specimen for the diagnosis of HAP, compared to a TBA obtained in a sterile manner, results in reduced mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change. The decision to perform bronchoscopy in patients with suspected HAP or VAP should take into account all indications for and against bronchos- copy, not just the potential microbiological diagnostic yield. Measurement of biomarkers such as IL-​1β, IL-​8, procalcitonin, and type 1 soluble triggering receptor expressed on myeloid cells (sTREM-​1) in BAL specimens or serum, may improve the diagnosis of HAP in future. Treatment Some general principles of treatment are widely recognized:

  1. Delay in commencing appropriate antimicrobial therapy is asso- ciated with poorer outcomes.
  2. Empirical combination therapy is mainly indicated when treating patients who are severely ill or at increased risk of infec- tion by MDR pathogens.
  3. There are no clinical trials demonstrating clear superiority of one antimicrobial regimen over another.
  4. Overuse of antimicrobial therapy should be avoided. De-​escalation of antimicrobial therapy should start as soon as possible, even within 2–​3 days of initiation of empirical treatment.
  5. The duration of therapy does not usually need to exceed 8 days. In clinical practice, the combined difficulty in establishing a defini- tive diagnosis of HAP together with the consequences of failing to treat HAP in a timely manner, mean that patients with suspected HAP are usually treated aggressively at the outset, followed by an equally determined de-​escalation plan based on regular clinical and microbiological re-​assessments. Many national guidelines offer recommendations for the empir- ical therapy of HAP (Table 18.4.3.4), but given the large spectrum of possible pathogens and the variation in local resistance patterns, local intelligence of the prevailing microbiology is critical to the choice of empirical antimicrobial therapy. De-​escalation and duration of therapy Following the initiation of antimicrobial therapy in patients with sus- pected HAP, daily review of the diagnosis should enable antibiotics to be discontinued if features of HAP do not evolve and the patient remains stable, and/​or an alternative diagnosis becomes apparent. In patient where a positive microbiological diagnosis is obtained, de-​escalation of therapy from broad spectrum to targeted antibiotics is usually possible and desirable. For patients treated initially with appropriate antibiotics, seven to eight days of antimicrobial therapy is usually suffi- cient, although patients infected with certain pathogens, such as Pseudomonas aeruginosa or methicillin-​resistant Staphylococcus aureus (MRSA), may require longer treatment courses of up to 14 or 21 days. Prevention In hospital, general infection control measures have an important role in reducing cross transmission of pathogens and hence the de- velopment of healthcare-​acquired infections, including HAP. These include simple measures such as universal hand hygiene, and use of personal protective equipment. For patients awaiting elective surgery, smoking cessation and the maintenance of good nutrition during the preoperative period are important preventive measures. Prevention of ventilator-​acquired pneumonia Most of the evidence for preventive strategies relate to HAP occurr­ ing on the ICU and to VAP (Table 18.4.3.5). Nonpharmacological approaches to the prevention of VAP are generally aimed at re- ducing or preventing aspiration of oropharyngeal and gastric secretions. Duration of mechanical ventilation Strategies to reduce the duration of mechanical ventilation in- clude the use of weaning protocols, limiting the use of sedation and avoiding re-​intubation. Noninvasive ventilation (NIV) may be used to both avoid mechanical ventilation in the first instance, or as a means of supporting early extubation. It has been shown to lower the risk of VAP and reduce mortality. Table 18.4.3.4  A guide to empirical antimicrobial therapy in HAP (based on various national guidelines) I. Patients not at risk of MDR pathogens β-​lactamase stable β-​lactam (e.g. coamoxiclav), or 3rd generation cephalosporin (e.g. cefotaxime), or Respiratory fluoroquinolone (e.g. levofloxacin) II. Patients at increased risk of MDR pathogens β-​lactam active against Pseudomonas aeruginosa Piperacillin/​tazobactam, or Anti-​pseudomonal cephalosporin (e.g. cefepine or ceftazidime), or Carbapenem (e.g. meropenem) Plus Fluoroquinolone (e.g. ciprofloxacin), or Aminoglycoside (e.g. amikacin) Plus (if increased risk of MRSA) Vamcomycin, or linezolid Table 18.4.3.5  Prevention of VAP Nonpharmacological approaches Reduce the time of mechanical ventilation • Use of noninvasive ventilation (NIV) • Weaning protocols • Sedation protocols Avoid re-​intubation Reduce endotracheal tube colonisation and microaspiration • Subglottic suctioning • Head of bed elevation above 30 degrees • Antimicrobial-​coated endotracheal tube Pharmacological approaches Selective digestive tract decontamination (SDD) Selective oropharyngeal decontamination (SOD) Oral decontamination

18.4.4 Mycobacteria 4026 Hannah Jarvis and Onn Min

18.4.4 Mycobacteria 4026 Hannah Jarvis and Onn Min Kon

section 18  Respiratory disorders 4026 Colonization and aspiration Secretions in the upper airways of intubated patients often pool above the endotracheal tube. Efforts to reduce the aspiration of these secretions into the lower airways include continuous suc- tion of subglottic secretions through the use of specially designed endotracheal tubes. A meta-​analysis of 13 randomized controlled trials including 2442 patients found that subglottic suctioning was associated with lower rates of VAP but with no reduction in mortality. Aspiration of gastric contents occurs more commonly in patients nursed supine compared to patients nursed in a semi-​recumbent position. In intubated patients, some evidence indicates that eleva- tion of the head of the bed to 45 degrees significantly reduces rates of VAP compared to the supine position, but achieving constant head elevation above 30 degrees is practically challenging. Silver-​coated endotracheal tubes have been shown to reduce rates of VAP but are expensive. Other coating materials such as chlorhexidine are also being evaluated. Decolonisation of the digestive tract Selective digestive tract decontamination and selective oropharyn- geal decontamination are approaches in which antibiotic therapy is used to eradicate potentially pathogenic microorganisms in the oropharynx and gastric tract. In a large study involving 13 ICUs in the Netherlands, 28-​day mortality was reduced by 3.5% with the former and 2.9% with the latter. However, a follow-​up study reported that bacterial resistance had increased in the ICUs that used decontamination. Hence any strategy that embraces wide- spread use of antibiotics must also consider the potential harms from increasing antibiotic resistance rates. Oral decontamination with chlorhexidine is associated with reduced rates of VAP in patients undergoing cardiac surgery; 2% chlorhexidine is more effective than 0.2% or 0.12%. A reduction in mortality as a con- sequence of oral decontamination strategies has not been confirmed. Controversies/​future developments Hospital-​acquired pneumonia occurring in the non-​ICU setting re- mains a vastly understudied subject. Extrapolating treatment strat- egies from data derived from VAP may not be acceptable in future as concerns regarding antibiotic stewardship increase. Hurdles related to the diagnosis of VAP remain significant. The incorporation of bio- markers into diagnostic and prognostic algorithms is being actively pursued and holds promise. FURTHER READING Endimiani A, et al. (2011). Are we ready for novel detection methods to treat respiratory pathogens in hospital-​acquired pneumonia? Clin Infect Dis, 52 Suppl 4, S373–​83. Roquilly A, et al. (2015). Pneumonia prevention to decrease mortality in intensive care unit: a systematic review and meta-​analysis. Clin Infect Dis, 60, 64–​75. Rosenthal VD, et  al. (2012). International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004–​2009. Am J Infect Control, 40, 396–​407. Kalil AC, et al. (2016). Executive Summary: Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis, 63(5), 575-82. doi: 10.1093/cid/ciw504. Erratum in: Clin Infect Dis, (2017) 64(9), 1298. Clin Infect Dis, (2017) 65(7), 1251. Torres A, et al. (2017). International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J, 50(3), pii: 1700582. doi: 10.1183/13993003.00582-2017. Trotter AJ, et al. (2019). Recent and emerging technologies for the rapid diagnosis of infection and antimicrobial resistance. Curr Opin Microbiol, 51, 39–45. Yu VL (2011). Guidelines for hospital-​acquired pneumonia and health-​care-​associated pneumonia: a vulnerability, a pitfall, and a fatal flaw. Lancet Infect Dis, 11, 248–​52. Zilberberg MD, Shorr AF (2010). Ventilator-​associated pneu- monia:  the clinical pulmonary infection score as a surrogate for diagnostics and outcome. Clin Infect Dis, 51 Suppl 1, S131–​5. 18.4.4  Mycobacteria Hannah Jarvis and Onn Min Kon ESSENTIALS Mycobacteria are gram-​negative, rod-​shaped bacilli comprising the Mycobacterium tuberculosis complex (TB) and nontuberculous mycobacteria. Tuberculosis Infection, usually via inhalation, is often asymptomatic but can lead to primary TB or to latent TB infection which can subsequently de- velop into ‘reactivation’ or ‘post-​primary’ active disease. Pulmonary TB is the commonest manifestation, but extrapulmonary disease can affect almost any organ. Definitive diagnosis is by culture. Standard chemotherapy involves the use of rifampicin, isoniazid, pyrazinamide, and ethambutol. Drug resistance is an increasing problem. Around 1.3 million people die from TB each year. Nontuberculous mycobacteria Infection tends to present with a worsening of chronic re- spiratory symptoms in patients with underlying lung diseases. Diagnosis is difficult because these organisms are common in the environment. A long course of treatment with several drugs is required.

18.4.4  Mycobacteria 4027 Introduction The mycobacteria genus are gram-​negative, rod-​shaped bacilli which comprise the Mycobacterium tuberculosis complex (M. tuber­ culosis, M.  africanum, M.  bovis, M.  microti) and nontuberculous mycobacterium species, the most important of which for human disease include M. avium complex, M. kansasii, M. xenopi, M. fortu­ itum, M. abscessus, and M. malmoense. Tuberculosis (TB), the airborne condition caused by infection with the Mycobacterium tuberculosis complex, is responsible for more deaths worldwide than any other airborne respiratory infec- tion, with an estimated 10  million incident cases of tuberculosis worldwide and an estimated 1.3 million deaths in 2017. Most of these cases were found in India, China, and South-East Asia, yet TB remains a global disease with just under 6000 cases diagnosed in England in 2017. It also causes significant extrapulmonary disease. The nontuberculous mycobacteria (or ‘atypical’ mycobacteria) are generally less pathogenic and highly prevalent in the environment, but can cause significant pulmonary, as well as bone or soft tissue disease, in those who are immunocompromised or with existing structural pulmonary conditions. The emergence of drug-​resistant tuberculosis is an increasing concern. Multidrug resistant TB (MDR-​TB) is defined as resistance to rifampicin and isoniazid, whereas extensively drug-​resistant TB (XDR-​TB) is MDR-​TB with additional resistance to a fluoroquino- lone and at least one of three injectable second-​line drugs. Natural history Infection is usually via inhalation of aerosolized droplets containing bacilli to the middle or lower lobes. Here activation of the innate immune system results in either complete clearance of the bacilli or primary infection within the lung and associated mediastinal nodes (the Ghon complex). Primary infection is often asymptom- atic. Possible outcomes following exposure to Mycobacterium tuber­ culosis complex are shown in Fig. 18.4.4.1. Latent TB is a term denoting infection which has been con- tained in a state whereby the bacilli persist in a dormant form, not causing symptoms/​disease, but maintaining the potential to reacti- vate, replicate, and cause pathology at a later stage. Approximately 10–​15% of individuals with latent infection go on to develop ac- tive TB disease. Individuals that develop disease within 2 years of the initial infection have ‘primary’ disease, and those who develop disease later (possibly many decades later) have ‘post-​primary’ or ‘reactivation’ disease. Factors that increase the risk of progression to disease include HIV and immunosuppressive states, including treatments used in transplantation and inflammatory conditions (Table 18.4.4.1). Clinical features Pulmonary tuberculosis The manifestation of primary disease in the chest normally consists of mediastinal lymphadenopathy or effusions, although there may be consolidation or collapse secondary to bronchial compression from nodes. Post-​primary pulmonary disease classically causes cavi- tation and ‘fluffy’ upper zone disease. TB is generally ‘subacute’ and can cause prolonged symptoms of cough, fever, night sweats, weight loss, and fatigue. Although the cough is initially nonproductive, this generally progresses to sputum production and occasionally Exposure to Mtb No infection Primary TB infection established Latent TB infection Development of primary TB disease (within 2 years of infection) Active disease develops: ‘reactivation’ or ‘post- primary’ TB Active disease never develops Fig. 18.4.4.1  Outcomes following Mycobacterium tuberculosis complex (Mtb) exposure. Table 18.4.4.1  Individuals at high risk for the development of active tuberculosis disease from latent infection (based on NICE guidance) High-​risk groups for development of active TB disease HIV positive Injecting drug users Solid organ transplant recipients Patients with a haematological malignancy Patients with chronic renal failure or on haemodialysis Patients with a previous gastrectomy Patients receiving antitumour necrosis factor-α streatment Patients with silicosis

section 18  Respiratory disorders 4028 haemoptysis. There can also be immune-​mediated manifestations including erythema nodosum and uveitis in the absence of obvious clinical disease. Extrapulmonary tuberculosis The symptoms and signs of extrapulmonary disease reflect the site of disease as well as the systemic features of general malaise seen in classical pulmonary disease. Common extrapulmonary TB sites are as follows: • Lymph nodes: The commonest extrapulmonary site is cervical, presenting as fluctuant, tender swellings, often in the supraclavi­ cular or anterior cervical chain. Other common sites include the mediastinum, abdomen, axillary, and inguinal areas. • Bone: The spine is the commonest site of bony infection (Pott’s disease) and destruction at the site of disease can result in pain, deformity, and nerve impingement. • Gastrointestinal: This classically affects the terminal ileum and can be confused with inflammatory bowel disease. Advanced dis- ease involving the peritoneum can present with ascites. • Genitourinary tract: This should be considered in patients with a persistent sterile pyuria. Untreated, there is the potential for fi- brosis, calcification, and stricture formation. • Central nervous system:  Meningeal or cerebral involvement is rare but should be considered in individuals presenting with head- aches, fever, cranial nerve abnormalities, seizures, or behavioural changes. Cerebrospinal fluid obtained from a lumbar puncture may be lymphocytic with high protein and low glucose. • Miliary tuberculosis: This is a state of disseminated disease with multiorgan involvement that results from haematogenous spread, often in in the young and those with immunocompromise. Without treatment there is rapid progression and a significant risk of death. Pulmonary involvement is common with diffuse, small ‘millet-​sized’ tubercles present throughout the lung fields, but other commonly affected organs can include the brain, bone marrow, abdomen, liver, spleen, and renal tract. Nontuberculous (‘atypical’) mycobacteria Infection tends to present with a worsening of chronic respiratory symptoms in patients with underlying lung diseases such as chronic obstructive pulmonary disease or bronchiectasis. It is also an im- portant pathogen in patients with immunocompromise, particu- larly HIV. Patients may have systemic features such as weight loss or night sweats, or a worsening of cough and breathlessness. The respiratory radiology of nontuberculous mycobacteria can include cavities, bronchiectasis, small airway inflammation, nodules, and mediastinal nodes Diagnosis Mycobacterium tuberculosis complex The gold standard for diagnosis remains culture of the organism, allowing not only for certainty of diagnosis but also the identifica- tion of drug susceptibility. Unfortunately, due to the difficulty of accessing tissue or fluid samples in some instances, as well as the fas- tidious nature of the pathogen, this is only achieved in approximately 60% of cases. A diagnosis may therefore have to rely on recognition of a combination of clinical features. Microbiology A range of samples can be sent for microbiological examination. In pulmonary disease at least three sputum samples should be obtained, using hypertonic saline to induce sputum, if needed. In some patients bronchoscopy may be required to obtain re- spiratory samples. Samples should be assessed by an auramine or Ziehl–​Neelsen stain (‘smear’), looking for the presence of acid and alcohol fast bacilli, and also cultured for a minimum of 6 weeks. Molecular techniques such as the polymerase chain reaction are increasingly being used as they can provide a rapid and specific diagnosis. In respiratory samples there is a higher sensitivity than the smear, and molecular testing also allows for the rapid identifi- cation of drug resistance. In extrapulmonary disease samples such as lymph node aspirates, pleural fluid/​biopsies, ascites, and cerebrospinal fluid should be sent as appropriate. Radiology The classical features of TB are upper zone consolidation with cavi- tation (Fig. 18.4.4.2), but a range of appearances can be seen on plain imaging, including consolidation, mediastinal lymphaden- opathy, and effusions, and in some cases no abnormalities are pre- sent. Atypical features are particularly common in older people or immunocompromised and there should be a low threshold for the consideration of CT imaging of the appropriate system in suspected cases. CT allows the identification of intrathoracic abnormalities such as cavities, mediastinal nodes, effusions, and small airway in- flammation (Fig. 18.4.4.3), but also importantly in extrapulmonary Fig. 18.4.4.2  Chest X-​ray showing right upper zone cavitation and consolidation.

18.4.4  Mycobacteria 4029 disease, can help target subsequent investigations to increase the likelihood of successful microbiological sampling. MRI is particu- larly useful in central nervous system disease. PET/​CT scanning may also have a role in identifying occult sites of disease. Histology/​cytology When tissue has been collected operatively or endoscopically, histo- logical or cytological examination may reveal granulomas. The pres- ence of granulomas, while not specific to mycobacteria, can add significant support to a diagnosis and is useful in excluding other conditions such as malignancy (Fig. 18.4.4.4). Tuberculin skin test The intradermal injection of tuberculin, an extract from the filtrate of attenuated Mycobacterium tuberculosis complex, causes a de- layed hypersensitivity reaction in individuals previously exposed to mycobacteria. This reaction has been used as a surrogate marker for TB infection (latent or active) for over 100 years. A measure- ment of skin induration is made at 48–​72 hours (Fig. 18.4.4.5), but it must be recognized that the skin test can be affected by immunosuppression and patients with advanced disease can even be anergic. Interferon-γ release assays Interferon-γ release assays (IGRAs) are peripheral blood assays of prior TB exposure and measure ex-​vivo interferon-γ release on stimulation by two specific Mycobacterium tuberculosis complex antigens (ESAT-​6 and CFP-​10). These are relatively specific for Mycobacterium tuberculosis complex and avoid any cross reaction with Bacille Calmette–​Guérin (BCG) vaccinated individuals (as can be seen in the tuberculin skin test). Although they are likely to be more sensitive than the skin test in immunocompromised indi- viduals, they can still be attenuated in these circumstances. They have the additional advantage of requiring only one patient attend- ance compared to the two needed for the skin test. Nontuberculous (‘atypical’) mycobacterial infection The diagnosis of clinically significant nontuberculous mycobacterial infection is complex. The environmental prevalence of these patho- gens means that repeated culture or a single culture from a sterile site alongside appropriate symptomatology and radiological find- ings is necessary to make a diagnosis. This is particularly an issue in individuals with chronic lung disease, although in immunocom- promised individuals mycobacteria avium complex can also cause significant extrapulmonary disease. The decision to initiate complex and prolonged therapy is often complicated by patient frailty and comorbidities and can have a poor outcome. Latent tuberculosis The diagnosis of latent infection (versus active disease) relies on the presence of a positive IGRA or skin test, in the absence of clinical and radiological evidence of active disease. Fig. 18.4.4.3  CT chest showing consolidation with cavitation and bronchiolar (‘tree-​in-​bud’) changes. Fig. 18.4.4.4  Granuloma in a lung biopsy specimen. Fig. 18.4.4.5  Positive tuberculin skin test with blistering reaction.

section 18  Respiratory disorders 4030 Management/​treatment General management Those with significant pulmonary disease who are productive of sputum, and especially those with confirmed smear positive pul- monary tuberculosis, pose an infectivity risk. These patients should be nursed in respiratory isolation if admitted to hospital, or alterna- tively self-​isolate at home. Repeated sputum smears can guide clin- icians in assessing infectivity and response to treatment. As HIV is a major risk factor for progression from latent infec- tion to disease, and given that treatment of known HIV disease is an important factor in response to treatment, it is important to test for HIV in all cases of active TB. An assessment should be made of the ability of each patient to comply with their medication regime and directly observed therapy offered for those who may find this difficult (e.g. those who are homeless or engage in substance abuse). The medication regimen can be adjusted so treatment is given on an intermittent basis to as- sist with this but is not recommended for pulmonary disease as as- sociated with poorer outcomes. Identification and screening of close contacts should also be undertaken, and preventative treatment offered where appropriate. Drug treatment Tuberculosis Standard antituberculosis chemotherapy involves the use of rifam- picin, isoniazid, pyrazinamide, and ethambutol for 2 months, fol- lowed by rifampicin and isoniazid for a further four months. The use of multiple agents aims to prevent drug resistance. By two months most cultures should be complete and drug susceptibility available to guide ongoing therapy. Extrapulmonary tuberculosis is treated with the same regime, al- though CNS disease requires more prolonged treatment. The use of adjuvant corticosteroids should be considered when starting treat- ment for CNS or pericardial disease. Second-​ and third-​line drugs are reserved for cases of drug resist- ance or intolerance due to their reduced potency and increased tox- icity. These drugs include fluoroquinolones such as moxifloxacin or levofloxacin, linezolid, clofazimine and injectable drugs (amikacin/​ kanamycin or capreomycin). Novel agents such as bedaquiline and delamanid are now available for and notably bedaquiline is recom- mended as an integral part of the first line therapy in MDR TB. Latent TB preventative treatment (Table 18.4.4.2) is generally offered to individuals with history of recent exposure and to those who are immunosuppressed, including people about to start treat- ment with biological agents such as anti-​TNF therapy or transplant- ation candidates. Atypical mycobacteria These require treatment with at least two to three agents for 12–​24 months depending on the species and clinical presentation (Table 18.4.4.3). Monitoring Careful monitoring of patients receiving treatment for TB or atyp- ical mycobacteria is needed to identify the development of poten- tial side effects. The most common of these is drug induced liver damage, which can be severe and, in rare cases, life-​threatening. In addition, visual acuity and colour vision testing should be per- formed due to the potential of ocular complications with eth- ambutol. Neuropathy from isoniazid can be prevented with the concomitant use of pyridoxine. Drug interactions are common with rifampicin. Table 18.4.4.2  Treatment regimen for latent TB Drug Dose and frequency Duration Comment Isoniazid 300 mg OD (5 mg/​kg for adults or 10 mg/​kg for children) 6 months NICE WHO Isoniazid 300 mg OD (5 mg/​kg for adults or 10 mg/​kg for children) or 900 mg twice weekly (DOT) 9 months WHO ATS/​CDC Rifampicin 600 mg OD (10 mg/​kg) 3–​4 months ATS/​CDC WHO Rifampicin + Isoniazid 600 mg (10 mg/​kg) + 300 mg (5 mg/​kg adults and 10 mg/​kg children) OD 3 months NICE WHO Rifapentine + Isoniazid By body weight + 900 mg (15 mg/​kg) once weekly 3 months ATS/​CDC WHO Not in pregnancy or children <2 years ATS, American Thoracic Society; CDC, Centers for Communicable Disease (USA); DOT, directly observed therapy; WHO, World Health Organization; NICE, National Institute for Clinical Excellence (UK). Table 18.4.4.3  Suggested treatment regimen for atypical mycobacterial pulmonary infections in HIV negative patients
(based on American and British Thoracic Societies’ guidance) Pathogen Drug regime Duration M. avium complex Clarithromycin or azithromycin + rifampicin + ethambutol
(+/​-​ streptomycin/​amikacin if advanced disease or cavities) Until 12 months of negative sputa M. kansasii Rifampicin + ethambutol + isoniazid or a macrolide (clarithromycin/azithromycin) Until 12 months of negative sputa M. xenopi Clarithromycin or azithromycin + rifampicin + ethambutol + either a quinolone or isoniazid Until 12 months of negative sputa M. abscessus A multidrug regime involving and induction and continuation phase with combinations of injectable, oral and nebulised antibiotics Variable

18.4.5 Pulmonary complications of HIV infection 40

18.4.5 Pulmonary complications of HIV infection 4031 Julia Choy and Anton Pozniak

18.4.5  Pulmonary complications of HIV infection 4031 Prevention The World Health Organization has prioritized the eradication of tu- berculosis and set the goal of reducing the incidence of TB to less than one per million population by 2050 in their STOP TB campaign. This requires commitment to finding and treating active cases of tubercu- losis, and also to identifying latent infection. Improving socioeconomic conditions is vital in reducing transmission. There are ongoing studies of new treatments and vaccinations, but the only available vaccine cur- rently is the BCG, which has limited evidence for effectiveness, pro- tecting mainly against miliary disease and meningitis in children. FURTHER READING Campbell I, et al. (2000). Management of opportunistic mycobacterial infections:  Joint Tuberculosis Committee guidelines. Thorax, 55, 210–​18. Griffith D, et al. on behalf of the ATS mycobacterial diseases subcom- mittee (2007). An official ATS/​IDSA statement: diagnosis, treatment and prevention of nontuberculous mycobacteria. Am J Resp Crit Care, 175, 367–​416. Haworth et al. (2017). British Thoracic Society guidelines for the management of nontuberculous mycobacterial pulmonary disease. Thorax, 72, 1–64. Lewinsohn et al. (2016). An official ATS/CDC and IDSA clinical prac- tice guidelines: diagnosis of tuberculosis in adults and children. CID, 64(2), 1–33. Nahid et al. (2016). An official ATS/CDC and IDSA clinical practice guidelines: Treatment of drug-susceptible Tuberculosis. CID, 63, 853–67. NICE Tuberculosis guideline NG33 (2016). Public Health England (2018). Tuberculosis in the UK 2018 report. Public Health England, London. World Health Organization (2006). The stop TB strategy: building on and enhancing DOTS to meet the TB-​related millennium development goals. World Health Organization, Geneva. World Health Organization (2018). Global tuberculosis report 2018. World Health Organization, Geneva. World Health Organization (2019). WHO consolidated guidelines on drug-resistant tuberculosis treatment. World Health Organization, Geneva. 18.4.5  Pulmonary complications of HIV infection Julia Choy and Anton Pozniak ESSENTIALS Most HIV-​positive individuals will experience at least one significant episode of pulmonary disease during their lifetime. The immune status of the HIV-​infected patient is the primary determinant of the risk of developing specific pulmonary diseases: those with advanced immunosuppression are predisposed to opportunistic infections and malignancies; those with mild or no immunosuppression are at greater risk of conditions including community-​acquired pneu- monia, chronic obstructive pulmonary disease, pulmonary hyper- tension, and interstitial lung disease. Pulmonary infections related to HIV infection with severe immuno- suppression include: (1) Pneumocystis jirovecii pneumonia—​typically presents with gradual onset of breathlessness and dry cough, and a chest X-​ray showing diffuse bilateral infiltrates. Diagnosis requires direct visualization of fungal spores in respiratory secretions. First-​ line treatment is with high-​dose trimethoprim/​sulfamethoxazole. (2) Tuberculosis—​is the leading cause of death among people with HIV. Presentation may be nonspecific and atypical, and tissue biopsy may be required for diagnosis. Treatment is as for HIV-​uninfected pa- tients, but great care is needed regarding drug interactions. (3) Fungal infections including aspergillosis and cryptococcosis. Lung malignancies related to HIV infection with severe immuno- suppression include: (1) Kaposi’s sarcoma—​caused by human her- pesvirus (HHV-​8), usually in patients with obvious mucocutaneous lesions and diagnosed by finding of purplish plaques at bronchos- copy; treatment is with systemic chemotherapy. (2)  Lymphoma—​ typically non-​Hodgkin’s B-​cell lymphoma or primary effusion lymphoma (also caused by HHV-​8). Introduction In 2017, 37 million adults were living with HIV, mostly in Low and Middle Income Countries (LMIC). In many countries it is becoming chronic disease with life expectancies approximating normal due to the use of highly active combination antiretroviral therapy (cART). This is testimony to the fact that the risk of developing an opportun- istic infection or malignancy is markedly reduced by being on cART and having an undetectable HIV-​1 viral load. Nevertheless, with un- equal access to diagnostics, treatment, and education worldwide, 1.8 million people are still infected every year and many develop oppor- tunistic infections and HIV-​associated neoplasms leading to almost one million AIDS-related deaths. The lungs are commonly affected in HIV-​positive individuals, 60% of whom will experience at least one significant episode of pulmonary disease during their lifetime. Subsequently, pulmonary disease re- mains a significant cause of morbidity and mortality. A wide range of conditions can occur, ranging from opportunistic infections and tumours to interstitial lung diseases. Available data suggest that both cellular and humoral lung immunity is impaired in HIV and that al- veolar macrophages are an important reservoir for HIV in the lung. This chapter will concentrate on common causes of HIV-​related lung disease and can be divided into: • HIV disease with mild or no immunosuppression (normal or near normal CD4 counts)—​in these patients typical community-​ acquired infections occur at greater frequency than in the general population, and chronic obstructive pulmonary disease (COPD), pulmonary hypertension, interstitial lung disease, and lung can- cers are common, partly related to immune defects and lifestyle factors. • HIV disease with advanced immunosuppression—​in these pa- tients abnormalities of the innate and adaptive lung immunity predispose them to opportunistic infections and opportunistic malignancies.

section 18  Respiratory disorders 4032 Clearly, the differential diagnosis for specific pulmonary diseases in HIV is influenced by the immune status of the HIV-​infected patient, which is the primary determinant for the risk of developing specific pulmonary disease. However, other elements such as demographic factors and the use of prophylactic antibiotics and cART also influ- ence the differential. Epidemiology Immune status In patients with HIV, the occurrence of specific infections/​opportun- istic infections is correlated with the degree of immunosuppression. The CD4 count of an uninfected adult/​adolescent who is gener- ally in good health ranges from 500 cells/​mm3 to 1200 cells/​mm3. There is an increased risk of developing a variety of illnesses when it falls below 350 cells/​mm3, and a very low CD4 count (less than 200 cells/​mm3) is associated with developing opportunistic infec- tions and tumours. The CD4 + lymphocyte count is therefore a useful surrogate marker for immune function in HIV. It provides information about the type of pulmonary disease to which the pa- tient is susceptible and also helps define the stage of HIV, although it should be noted that even at high CD4 counts opportunistic tu- mours and tuberculosis can occur. The Pulmonary Complication of HIV Infection Study Group examined the incidence of pulmonary complications over 5 years. Together with data from the Strategic Timing of Antiretroviral Treatment (START) study, which looked at early versus late initi- ation of HIV treatment, a list of respiratory pathologies based upon HIV disease severity (as indicated by the CD4 + count and whether someone is on antiretroviral therapy) is detailed in Table 18.4.5.1. TB and bacterial pneumonias often occur before subsequent opportunistic infections and neoplasms. With lower CD4 counts there is an increased incidence of all pulmonary pathologies, and different pulmonary infections occur with increasing frequency re- sulting in increased risk of bronchiectasis secondary to recurrent infections over time. The use of cART has dramatically diminished the incidence of all of these complications Demographic factors Injecting drug users are at increased risk of bacterial pneumonias compared to other persons with HIV. In this subgroup bacterial pneumonia is more common than Pneumocystis jirovecii pneumonia (PCP) and fungal pneumonias—​especially invasive aspergillosis—​ are more common. Ethnicity and geography may also influence the risk of developing certain pulmonary diseases in HIV; for example, the risk of tuberculosis (TB) is higher in those living in or coming from developing countries, and those that are black or Hispanic. Conversely, the risk of PCP, HIV malignancies, and cytomegalo- virus disease is higher in the white population. Consequently, there is a higher risk of PCP in Europe and the United States than there is in Africa, where TB is the most common pulmonary complication in HIV. There is a higher incidence of TB in enclosed populations, for example, in prisons and in hostels, and a higher incidence of fungal infections depending on the geographic distribution of en- demic fungi (e.g. histoplasmosis pulmonary infections in HIV-​posi- tive individuals living in the Mississippi Delta or from Africa, and Coccidioidomycosis in California). Prophylactic antibiotics and antiretroviral therapy As described earlier, untreated HIV infection is associated with progressive reduction in cell-​mediated immunity and an increased risk of opportunistic infection. This risk can be decreased by, firstly, starting cART to decrease HIV viral activity which leads to an in- crease in the CD4 count and improved immunity (the incidence of pulmonary opportunistic infection has declined dramatically following the widespread use of cART), and secondly, by putting patients on antimicrobial prophylaxis to decrease the risk of op- portunistic infection at low CD4 counts. The risk of PCP without prophylaxis is 40–​50% per year in those with a CD4 count less than 100: this risk is ninefold lower with the use of antibiotic prophylaxis. Diagnosis of pulmonary disease in HIV infection Patients with HIV-​associated pulmonary diseases often present with nonspecific symptoms such as cough, with or without sputum pro- duction, dyspnoea, and wheezing. The initial diagnostic approach is the same as for any other patient (i.e. history, examination, and appropriate diagnostic tests). However, some specific considerations have to be recognized in the context of HIV. For example, neutro- penia is a recognized complication of HIV, hence if neutropenia is present, empiric therapy covering Pseudomonas aeruginosa may be indicated. Elevated plasma levels of 1-3-beta-D-glucan, a compo- nent of the cell wall of P. jirovecii, have been found in HIV-infected patients with PCP. Lactate dehydrogenase levels may be useful to monitor response to treatment in PCP infection: they are often ele- vated in PCP but are nonspecific. Polymerase chain reaction (PCR) of respiratory fluid, in particular bronchoalveolar lavage (BAL), is increasingly used to make the diagnosis of PCP but cannot distin- guish between colonization and disease. Blood cultures are helpful in the diagnosis of disseminated mycobacteria, fungi, and bacterial Table 18.4.5.1  Respiratory pathologies in HIV infection CD4 + Count (cells/mm3) Pulmonary Disease Any CD4 + count Sinusitis Bronchitis Bacterial pneumonia Tuberculous Kaposi’s sarcoma 100–​≤200 Advanced HIV—​opportunistic infections (opportunistic infection) Pneumocystis (PCP) Fungal Cytomegalovirus (CMV) Primary pulmonary lymphoma ≤100 Late-​stage HIV Non-​TB mycobacteria

350 and viral load (VL) undetectable Well-​controlled HIV Systemic lymphoma (non-​Hodgkin’s lymphoma) Chronic obstructive pulmonary disease Interstitial lung disease Pulmonary hypertension Lung cancers

18.4.5  Pulmonary complications of HIV infection 4033 pneumonia, in particular that due to Streptococcus pneumoniae. Routine collection of expectorated sputum for Gram stain and cul- ture has low sensitivity and specificity in HIV infection, especially after antibiotics have been started. Induced sputum for PCP stain, AFB (acid fast) stain, and culture is the initial test of choice in most centres for diagnosis of Pneumocystis jirovecii, although sensitivity varies widely. This, along with exercise oximetry demonstration oxygen desaturation on exertion, is very useful in diagnosing PCP. If no causative organism is isolated using standard techniques and/​ or the patient has failed to improve on empirical therapy for PCP and bacterial pneumonia, fibreoptic bronchoscopy with bronchoalveolar lavage +/​-​ transbronchial biopsy may be performed. Bronchoalveolar lavage is highly sensitive for the diagnosis of PCP, and Kaposi’s sarcoma is often diagnosed by visualizing the characteristic purple plaques, often without biopsy due to the risk of bleeding. Lung biopsy is likely to be necessary to establish an alternative diagnosis such as cytomegalo- virus, Aspergillus, or lymphocytic interstitial pneumonitis, and video-​ assisted thoracoscopic biopsy can be useful in diagnosis of peripheral nodules or masses not reachable by bronchoscopic. Pulmonary infections The epidemiology of HIV-​related pulmonary infections (Table 18.4.5.2) has changed as a consequence of advances in cART and prophylaxis. However, the most common respiratory infections are: • Community-​acquired pneumonia (CAP) • Pneumocystis jirovecii pneumonia (PCP) • Mycobacterium tuberculosis (TB) In LMICs (e.g. sub-​Saharan Africa), TB remains the most common pulmonary infection in HIV-​infected patients, with CAP second. In resource-​rich countries rates of PCP have decreased considerably with the use of co-​trimoxazole prophylaxis and the introduction of cART. Rates of TB in HIV-​infected patients have also decreased with the introduction of cART and with public health measures, such that bacterial CAP is now the most common pulmonary in- fection in HIV-​infected individuals. Bacterial community-​acquired pneumonia Although HIV affects cell-​mediated immunity most profoundly, ab- normalities in antibody production and (in advanced AIDS) neu- trophil function all contribute to the increased risk of bacterial pneumonia. Bacterial pneumonia is a major cause of pulmonary in- fection in HIV-​infected individuals and can occur at any CD4 count. The annual incidence of CAP in HIV patients is 5.5–​29 per 100, com- pared to 0.7–​10 per 100 in HIV-​negative individuals. Use of cART has resulted in decreased incidence of bacterial pneumonia (from 22.7 to 9.1 episodes/​100 patient years), but this still remains approximately 40 times higher than the risk of age-​matched HIV-​negative adults. The epidemiology of bacterial pneumonia is influenced by both epi- demiologic and immunological factors. Risk factors, apart from HIV infection per se, include CD4 count (<200 cells/​mm3), detectable viral load, neutropenia, not being on cART, having had prior PCP, IV drug abuse, smoking, alcohol abuse and other comorbidities, and steroid use. Aetiology The spectrum of pathogens, in general, does not differ signifi- cantly from those patients who are HIV negative (Table 18.4.5.2). Similarly, the clinical presentation of CAP is very similar to that in HIV-​uninfected patients. Streptococcus pnemoniae, Haemophilus influenza, and Staphylococcus aureus are the most common bac- terial pathogens, often giving a characteristic lobar/​segmental focal consolidative picture on chest X-​ray (Fig. 18.4.5.1), but diffuse bilat- eral infiltrates and cavitation can also occur (Fig. 18.4.5.2). There is a higher rate of bacteraemia in HIV-​infected patients—​HIV-​positive adults are at approximately 40 times higher risk of invasive pneumo- coccal disease compared to age-​matched HIV-​negative adults. Other causative organisms include Gram-​negative pathogens, especially in the context of a low CD4 + count (e.g. Pseudomonas Table 18.4.5.2  Types of pulmonary infection patients with HIV Type of pulmonary infection Species Bacterial community-​acquired pneumonia Streptococcus pneumoniae Haemophilus Staph Aureus Pseudomonas Klebsiella Nocardia Legionella Atypicals Rhodococcus Tuberculosis (TB) Mycobacterium tuberculosis Non-​TB mycobacterium Mycobacterium kansasii, avium, xenopi Fungal PCP Cryptococcus Aspergillus Histoplasmosis (rare in United Kingdom) Viral Cytomegalovirus (CMV) Fig. 18.4.5.1  Chest X-​ray due to Strep pneumonia showing lobar pneumonia.

section 18  Respiratory disorders 4034 aeruginosa and Klebsiella pneumoniae). Atypical pathogens such as Chlamydia, Mycoplasma, and Legionella have been reported, but are relatively uncommon. Other uncommon pathogens causing CAP in HIV patients also include Nocardia asteroids and Rhodococcus equi. Management, prognosis, and prevention Treatment of CAP consists of a β-​lactam plus a macrolide—​ quinolones are avoided due to the risk of quinolone resistant TB. If PCP has been excluded by sputum analysis, commencement of PCP prophylaxis should be considered if the CD4 + count is less than 200 cells/​mm3 or the CD4 percentage is 14% or less. Compared with HIV-​negative adults, HIV-​positive persons show an increased risk of mortality after controlling for age and severity of presentation, and this risk is related to the CD4 cell count. With an increasing proportion of associated comorbidities in ageing HIV-​ positive populations (e.g. cirrhosis, chronic pulmonary disease) case fatality has tended to increase in recent years. Pneumococcal vaccine is recommended for all HIV-​infected people. Two types of pneumococcal vaccine are licensed in the United Kingdom; PPV-​23, the pneumococcal polysaccharide vaccine, and PCV-​13, the pneumococcal protein-​conjugated vaccine. The most ro- bust evidence for the use of pneumococcal vaccines in HIV-​positive adults relates to PCV-​13 use. The conjugated vaccines are immuno- genic and have proven to be clinically effective in randomized con- trolled trials, including one undertaken in HIV-​positive adults with low CD4 counts. Current British HIV Association (BHIVA) and European guidelines recommend that HIV-​positive adults receive a single dose of PCV-​13 irrespective of CD4 cell count, cART use, and viral load. Pneumocystis Pneumocystis jirovecii, formally called Pneumocystis carinii, is the cause of Pneumocystis pneumonia (PCP), a fungal pneumonia. The incidence of PCP has declined dramatically due to cART and PCP prophylaxis in those with low CD4 counts, but it still remains one of the leading opportunistic infections in HIV-​infected persons with low CD4 counts. Most cases occur in those who have undiagnosed HIV, or those who are not receiving or are not engaged in care. Risk factors for PCP include a CD4 + count 200 cells/​mm3 or less, or a CD4% of 14% or less, a previous episode of PCP, a high viral load (>100 000 copies/​ml), and/​or the presence of oral thrush. PCP is unlikely in a patient on cART with a persistently undetectable viral load even with a CD4 count 200 cells/​mm3 or less. Clinical features PCP typically presents with gradually increasing dyspnoea and dry cough with fever over days to weeks. Symptoms are usually gradual in onset (being present on average for 3 weeks), as opposed to CAP. Purulent sputum suggests CAP, although this can be present in one-​ sixth of patients with PCP as a copathogen. The chest X-​ray usually displays diffuse bilateral infiltrates (Fig. 18.4.5.3), which strongly suggests the diagnosis, but sometimes shows nodular opacities, lobar consolidation, or can be normal in up to 25% of patients. Spontaneous pneumothoraces in patients with HIV should prompt the diagnosis of PCP. High resolution computed tom- ography (HRCT) has a high sensitivity for PCP among HIV-positive patients when patchy or nodular ground-glass attenuation are found. A negative HRCT scan makes the diagnosis of PCP unlikely. There are no clinical features specific to PCP, but the diagnosis of PCP may be supported by adjunctive tests. Demonstration of a fall in oxygenation between rest and exercise has been validated as a reason- ably specific test for PCP, but is not reliable enough to make a diagnosis without confirmatory microbiology. Patients with a diagnosis of PCP have significantly higher median 1-3-beta-D-glucan levels than patients without the disease and the test is used in supporting the diagnosis, though it can be positive in other fungal diseases. Lactate dehydrogenase levels are high in 90% of HIV-​infected patients with PCP but have poor sensitivity and specificity diagnostically. A rising lactate dehydrogenase level despite appropriate treatment in PCP is a poor prognostic factor. Microbiological diagnosis PCP is a fungus that cannot be cultured. Diagnosis therefore re- quires direct visualization of the fungal spores in respiratory Fig. 18.4.5.2  Chest X-​ray showing bilateral diffuse infiltrate due to Strep pneumonia, but mimicking Pneumocystis jirovecii pneumonia. Fig. 18.4.5.3  Chest X-​ray showing typical bilateral infiltrates in Pneumocystis jirovecii pneumonia.

18.4.5  Pulmonary complications of HIV infection 4035 secretions by immunofluorescence tests, for which adequate sputum specimens are required. These are most often obtained with induced sputum (sensitivity 50–​90%), which is the least invasive technique. If induced sputum results are negative or inconclusive, then the patient should be assessed for bronchos- copy with bronchoalveolar lavage (diagnostic sensitivity >90%). Endotracheal aspirates and tissue biopsies may also be used in diagnosis. All specimens should be examined for the presence of acid-​fast bacilli, fungi, and viral cellular inclusions, since patients with suspected PCP may have another infection, or may be co-​ infected with other pathogens. Management Treatment is started empirically in a patient with typical clinical and radiographic features and a CD4 less than 200 or 14% and an elevated 1-3-beta-D-glucan level. Pending diagnosis by cytological analysis of induced sputum samples or bronchoalveolar lavage fluid. Indeed, treatment should be started promptly if PCP is suspected, and not delayed for confirmation of the organism. Immunofluorescence tests for Pneumocystis jirovecii will remain positive for several days after treatment is commenced. CART should be started as soon as is practicable and within 2 weeks of PCP diagnosis. Evaluation of the degree of hypoxia through arterial blood gas sampling helps assess the severity of the disease and the need to add glucocorticoids. A PaO2 less than 9.3 kPa on room air indicates se- vere PCP infection and the need for glucocorticoids in addition to antimicrobial agents (Table 18.4.5.3) to suppress the robust inflam- matory response to the Pneumocystis organism. The British HIV Association and American Centre for Disease Control Guidelines recommend high-​dose trimethoprim/​ sulfamethoxazole (TMP-​SMX or co-​trimoxazole) for 21 days as first-​ line treatment for PCP; patients with sulfa allergies require second-​ line regimens. If patients have concurrent gastrointestinal problems affecting swallowing or absorption (e.g. thrush/​diarrhoea), or have moderate or severe disease, then TMP-​SMX should be given intra­ venously rather than orally. Alternative therapies include atovoquone for mild disease and clindamycin-primaquine or IV pentamidine for severe disease. Up to 10% of patients will fail first-​line treatment with TMP-​ SMX (defined as deterioration after 5  days of first-​line therapy) and will have to be switched to second-​line treatments. The use of caspofungin as an adjunct therapy is still uncertain. Prognosis Despite highly active antiretroviral therapy, improvement in diagnos- tics, and the use of antipneumocystis prophylaxis, PCP pneumonia is still the most common cause of respiratory failure and admission to intensive care units in patients with HIV. When treatment is delayed or ineffective, severe PCP—​resembling acute respiratory distress syndrome—​may develop. Progressive respiratory deterioration while on therapy warrants early ICU/​HDU input because acute progression of hypoxia in PCP is associated with high mortality (up to 60%) and morbidity. Other complications of PCP include pneumothorax. Prevention PCP prophylaxis is given to patients with a CD4 count of less than 200 cells/​mm3 who are at greatest at risk of PCP (Table 18.4.5.4). First-​ line choice for prophylaxis is co-​trimoxazole; dapsone, atovaquone, and inhaled pentamidine are alternatives. Prophylaxis can be stopped in patients with an undetectable plasma viral load on cART who have maintained a CD4 count of more than 200 cells/​mm3 for 6 months. Pulmonary tuberculous HIV is a key driver in the global rise in TB cases through both ac- celerated progression of TB after exposure and greatly increased risk of reactivation. Most cases of TB in HIV-​positive individ- uals represent reactivation of latent bacilli. The lifetime risk of developing active TB in an HIV-​uninfected individual with latent TB infection is 10%, compared to 10% per year in an HIV-​infected person not on cART. Active TB can occur at even relatively high CD4 counts (>350 cells/​mm3). Many HIV-​positive patients living in LMICs are exposed to TB due to the nature of their environment, especially overcrowding and poverty. Where the background prevalence of TB is low, the disease is uncommon in HIV-​positive patients unless they can become ex- posed, for instance, through travel. Clinical features and diagnosis Typical clinical features of TB such as a subacute history of a pro- ductive cough, night sweats, and fevers accompanied with weight loss are common to both HIV-​positive and HIV-​negative patients. However, in advanced HIV disease/​CD4 <200, symptoms of TB are often nonspecific and atypical, and many investigations have less diagnostic sensitivity than in an HIV-​uninfected individual with TB (Table 18.4.5.5). Table 18.4.5.3  Treatment of Pneumocystis jirovecii pneumonia Disease severity Mild PaO2 >9.3 kPa Moderate–​severe PaO2 ≤9.3 kPa First choice Co-​trimoxazole Co-​trimoxazole Alternative therapy (second line) Clindamycin-​primaquine or Dapsone with trimethoprim or Atovaquone Intravenous pentamidine or Clindamycin-​primaquine or Dapsone with trimethoprim or Atovaquone Steroids No Yes Table 18.4.5.4  Indications for prophylaxis of Pneumocystis jirovecii pneumonia Primary prophylaxis CD4 ≤200 CD4 count ≤14% of total lymphocyte count Secondary prophylaxis All patients after an episode of PCP Table 18.4.5.5  Features of TB infection in presence and absence of HIV HIV uninfected HIV infected CD4 <200 Symptoms Focal symptoms predominate Nonspecific symptoms predominate Site Pulmonary predominantly Higher rates of extrapulmonary and disseminated disease Sputum smear (AFB) Good yield Low yield Mycobacterial burden (e.g. at biopsy/​autopsy) Low High

section 18  Respiratory disorders 4036 Patients with profound immunosuppression (e.g. CD4 <200 cells/​ mm3) are unable to control TB replication and hence have a greater mycobacterial burden. However, factors associated with reduced sputum smear positivity (e.g. lung cavitation), mean that sputum microscopy has a significantly lower diagnostic yield in HIV/​TB co-​infected patients. In HIV/​TB co-​infection mycobacterial blood cultures and tissue biopsy, for example, from a lymph node (for hist- ology, TB culture, TB-​PCR), may therefore be required to make a positive diagnosis of TB. Patients with advanced HIV infection are more likely to de- velop extrapulmonary TB involving lymph nodes, blood, pericar- dium, lived, bone marrow, or meninges. Extra adjunct tests include adenosine deaminase levels in pleural or ascitic fluid, which are elevated in TB. Immunological tests, such as the tuberculin skin test and ELISpot, performed to assess latent TB infection are often negative in HIV-​ infected individuals if CD4 counts show severe immunosuppres- sion and have poor utility in making a diagnosis of active TB. Radiographic features of TB in HIV-​positive patients with low CD4 counts are different from those in HIV-​negative patients (Table 18.4.5.6). Treatment Empirical TB treatment should start as soon as the diagnosis is confirmed and follows the same guidelines as for HIV-​uninfected patients (i.e. a rifampicin-​based regimen), but there are special considerations in TB/​HIV co-​infection. Firstly, adding cART to TB treatment improves treatment outcome and reduces mortality. Most patients benefit from stating cART within 2 weeks after anti-​TB treatment, especially if CD4 is less than 50 cells/​mm3. For those with higher CD4 counts treatment for HIV can be de- layed, but not beyond 8 weeks. Secondly, while initial TB therapy is empirical, therapy needs to be subsequently tailored to the drug resistance profile of the isolate, given the higher incidence of drug resistant TB in HIV. Thirdly, there should be close monitoring of treatment response and for immune reconstitution syndrome (IRIS), especially if the CD4 is less than 50 cells/​mm3. Lastly, ri- fampicin is a potent inducer of the cytochrome P450 enzyme, hence it interacts with drugs used in cART (especially protease inhibitors) leading to subtherapeutic levels, HIV treatment failure, and HIV drug resistance. A rifabutin-​based regimen, ra- ther than rifampicin, produces less drug-​to-​drug interactions with cART, but careful and expert dose management is required. Careful review for drug interactions is essential when initiating anti-​TB therapy in patients taking cART (see https://​www.hiv-​ druginteractions.org). Fungal pulmonary infections Fungal infections of the respiratory tract are less common than viral or bacterial infections in HIV. However, CD4 cells are critical for antifungal defence, and a decline in CD4 cell numbers and cell func- tion is a risk factor for invasive pulmonary infections in HIV-​infected individuals. Other risk factors include neutropenia, long-​term cor- ticosteroid therapy, intravenous drug use, iatrogenic immunosup- pression after organ transplantation, and abnormal lung architecture. In addition to PCP, the most prevalent pulmonary fungal infections in HIV are Aspergillosis and Cryptococcosis. With the introduction of cART, the prevalence of fungal infections has declined dramatic- ally, but they still substantially contribute to AIDS-​related mortality. Aspergillosis Aspergillosis refers to the illness caused by inhalation of spores of the fungal species Aspergillus from soil or air. Prior to cART, inva- sive aspergillosis was an important cause of death. Today, the infec- tion is rarely seen in patients with HIV, except those with very low CD4 counts (<50 cells/​mm3) +/​–​ other risk factors for fungal dis- ease. US databases have showed that a diagnosis of aspergillosis was found only in 0.43% of HIV-​infected patients. Aspergillus fumigatus is the most common species to cause disease: two clinical entities are recognized. Invasive pulmonary parenchymal aspergillosis—​this accounts for 80% of cases of disseminated aspergillosis in HIV-​infected pa- tients and is often fatal. Cavitating lesions form in the lung par- enchyma, leading to fever, shortness of breath, productive cough, and haemoptysis. Signs of disseminated infection (e.g. neurological signs from brain involvement), may also be present. Imaging may reveal nodular or cavitating lesions on chest radiography. CT images may be may be very helpful in the early diagnosis of aspergillosis if they show a characteristic ‘reverse halo sign’ caused by an area of ground-​glass infiltrate surrounding nodular densities. Tracheobronchial aspergillosis—​the disease site is predomin- ately tracheal and bronchial involvement leading to airway obstruc- tion, audible wheeze, and prominent shortness of breath. As with PCP diagnosis, the rational first step to establishing the diagnosis of invasive Aspergillus involves the use of noninvasive mo- dalities, such as serum biomarkers (galactomannan and β-​D-​glucan assays) and obtaining sputum for fungal staining and culture. If the diagnosis is not made by these methods, then a more invasive approach with bronchoscopy and bronchoalveolar lavage, transbronchial bi- opsy, CT-​guided biopsy, or video-​assisted thoracoscopic surgery is useful for histology, culture, and Aspergillus antigen assay. Treatment of aspergillosis is with voriconazole, although caspofungin is an alternative. Cryptococcosis Infections with the encapsulated yeast Cryptococcus neoformans in the most common fungal infection in HIV-​infected individuals worldwide, but unusual in resource rich countries. Diagnosis of pulmonary cryptococcosis is based on culture of the organism in respiratory secretions or from lung biopsy, and detection of crypto- coccal serum antigen. An HIV-​infected patient is at greatest risk of disseminated extrapulmonary Cryptococcus (e.g. Cryptococcus meningoencephalitis when their CD4 is <100 cells/​mm3). Non-​ specific symptoms such as fever, cough, and shortness of breath Table 18.4.5.6  Chest radiographic features of TB infection in presence and absence of HIV HIV uninfected (typical TB) TB in HIV/​low CD4 counts Upper zone cavitation Pulmonary infiltrates with no particular preference for upper zones or cavitation Bilateral hilar lymphadenopathy Mediastinal lymphadenopathy Pleural effusions

18.4.5  Pulmonary complications of HIV infection 4037 accompany chest radiographic changes including noncalcified pulmonary nodules, predominantly at the bases of the lungs, hilar lymphadenopathy, interstitial infiltrates, and lung masses. Treatment is with liposomal amphotericin (or oral fluconazole if not available) in combination with flucytosine. Lung malignancy Kaposi’s sarcoma and non-​Hodgkin’s lymphoma may involve the lung, and patients with HIV appear to have both increased rates of lung cancer and more aggressive disease compared with uninfected controls. Pulmonary Kaposi’s sarcoma Kaposi’s sarcoma, caused by human herpesvirus (HHV-​8), is the most common malignancy in persons with HIV infection. The skin is the major site of involvement, but visceral involvement with Kaposi’s sarcoma is common in advanced disease, and may involve the airways, lung tissue, mediastinal lymph nodes, and pleura. The lung is the only site of disease in up to 15% of cases. Patients with thoracic Kaposi’s sarcoma usually have obvious mucocutaneous lesions, and a lesion on the palate suggests pul- monary involvement. Lung lesions cause dyspnoea, cough, or haem- optysis, accompanied in severe cases by constitutional symptoms such as night sweats, fevers, and weight loss. The presence of char- acteristic purplish plaque lesions at bronchoscopy is usually con- sidered to be diagnostic. The yield from bronchoscopic lung biopsy, which carries a risk of bleeding, is low, and even open-​lung biopsy is nondiagnostic in about 10% of cases because of the focal distribution of the lesions. Pleural effusions are usually exudative and sanguineous, but cyto- logical examination is nondiagnostic. Closed pleural biopsy speci- mens are rarely positive for Kaposi’s sarcoma due to the focal nature of the pleural lesions and the predominant involvement of the vis- ceral (rather than the parietal) pleura. Radiographic findings are variable, but bronchial wall thickening, Kerley B lines, and nodular infiltrates with peribronchovascular distribution and pulmonary effusions are common (Fig. 18.4.5.4). Treatment is with systemic chemotherapy, namely liposomal anthracyclines plus cART. Lymphoma Non-​Hodgkin’s B-​cell lymphoma is associated with HIV infection and continues to occur despite the use of cART. Although pul- monary involvement is usually clinically asymptomatic the lung is a common site of extranodal disease. Primary effusion lymphoma is most commonly a high-​grade B-​cell tumour associated closely with HHV8 and occurring in the setting of advance HIV infection. Non-​Hodgkin’s B-​cell lymphoma The risk of developing non-​Hodgkin’s lymphoma is 200–​600 times greater in persons with HIV compared with those who are unin- fected. Non-​Hodgkin’s lymphoma associated with HIV infection is most commonly a high-​grade B-​cell tumour and tends to present more commonly with stage IV and extranodal disease. The lung is a site of extranodal disease, but in contrast to non-​AIDS patients, mediastinal and hilar lymphadenopathy is generally not prom- inent. Pulmonary symptoms tend to occur late in the disease and can simulate common opportunistic infections (e.g. lobar consoli- dations, nodules, reticular opacities, and pleural effusions or thick- ening). Airway involvement may cause atelectasis. B-​symptoms may also be present. The diagnosis is established by bronchoscopic or open-​lung/​pleural biopsy, or by cytological analysis of pleural fluid. Bronchoalveolar lavage has a very low diagnostic yield. Primary effusion lymphoma A few lymphomas are associated with HHV8. They present as body cavity lymphomas, causing pleural or peritoneal effusions (primary effusion lymphoma). In almost all cases tumour DNA shows HHV8, which is also the aetiological agent of Kaposi’s sarcoma (as previ- ously described). Non-​small cell carcinoma of the lung It appears that the incidence of non-​small cell lung cancer is in- creased in people living with HIV infection. Whether the increase simply reflects a higher smoking prevalence continues to be debated as there is no association with CD4 count, viral load, or the use of cART. Patients with lung cancer in the setting of HIV infection tend to be relatively young at presentation (mean age 45 years) and have mild or moderate immunosuppression. Most present with stage III or IV disease, and adenocarcinoma is the most common histological type, with its prognosis appearing to be worse in patients with HIV infection. The diagnostic and treatment approaches to HIV-​ associated lung cancer are the same as for those without HIV infec- tion although there is a potential for drug interactions with cART. Other pulmonary conditions In addition infections and malignancies, HIV is associated with an increased risk of other pulmonary diseases such as immune re- constitution inflammatory syndrome (IRIS), pulmonary hyperten- sion, COPD, interstitial lung disease, and lymphocytic interstitial pneumonitis. Immune reconstitution inflammatory syndrome IRIS refers to a disease-​ or pathogen-​specific inflammatory re- sponse in HIV-​infected patients that usually occurs after initiation Fig. 18.4.5.4  CT scan showing nodular infiltrates with peribronchovascular distribution due to Kaposi’s sarcoma.

section 18  Respiratory disorders 4038 or re-​initiation of cART. It has been reported as worsening of symp- toms and signs in those with mycobacterial, fungal, viral, or bacterial infections, and worsening of tumours such as Kaposi’s sarcoma. Most cases occur in patients who have low CD4 counts (usually less than 100 cells/mm3) at the time cART therapy is started and is usually coincident with a rapid increase in CD4 cell count. The time of presentation is usually within the first 8 weeks after starting cART therapy, but has been reported occurred many weeks after initiation. Treatment is with corticosteroids, but the course can be very pro- longed in some. Pre emptive steroids can reduce TB IRIS by 30%. Pulmonary hypertension Pulmonary hypertension is 6–​12 times more prevalent in HIV-​ infected patients compared to the general population. The patho- genesis still remains unclear and some cases are related to prior ARV use with Didanosine. Therapies for HIV-​related pulmonary hyper- tension are nearly identical to those used in non-​HIV patients, ex- cept the use of calcium channel blockers are not recommended. Chronic obstructive pulmonary disease There is high prevalence respiratory symptoms and COPD among HIV-​infected patients. Currently, cigarette smoking and previous bac- terial pneumonia seem to play a significant role in the development of respiratory symptoms and COPD. Smoking cessation is important, and COPD is managed as for the non-​HIV-​infected population. An important consideration is the drug interaction between the antivirals pharmaco boosting agents cobicistat and ritonavir with fluorinated steroids, which can cause Cushing’s syndrome. Asthma/​bronchial hyper-​responsiveness Asthma and airway hyper-​responsiveness may be more common among HIV-​seropositive individuals treated with cART. Again, as with COPD, caution with drug interactions of inhaled fluorinated steroids and antiretroviral therapy is required. Bronchiectasis May result from severe or repeated opportunistic infection, including tuberculosis. In children risk factors include recurrent pneumonia, severe immunosuppression, and lymphoid interstitial pneumonitis. Interstitial lung disease Interstitial pneumonitis and lymphocytic interstitial pneumonitis were frequently described in HIV-​infected adults prior to the use of cART. Post cART, these conditions are less frequent. However, sarcoidosis among HIV-​infected persons is increasingly recog- nized and may represent an immune reconstitution phenomenon. Table 18.4.5.7 compares clinical, radiological, and histo- logical features of the main causes of interstitial lung disease seen in HIV. Table 18.4.5.7  Clinical, radiological, and histological features of the main causes of interstitial lung disease seen in HIV NSIP LIP COP HP Sarcoid Dyspnoea and cough +/​–​ + + + +/​–​ fevers +/​–​ + + -​ +/​–​ Usual CD4 count (cells/​mm3/​μl) <200

350 Any Usually >350 200 Chest X-​ray Interstitial or alveolar infiltrates Normal in up to 50% Reticular or nodular shadowing Consolidation May be normal or diffuse nodules BHL +/​–​
reticulonodular opacities HRCT: Ground-​glass opacification Basal, may be prominent Present Present Diffuse or patchy Occasional diffuse HRCT: Consolidation May be present Not usually a feature Dominant feature Not usually a feature May be present HRCT: Honeycombing Rarely may be present Present in advanced disease Not usually a feature Present in advanced disease May be present if fibrotic disease Other HRCT features Reticular and nodular shadowing Cavitating nodules Mosaic attenuation Adenopathy and nodules on fissures Histopathological features Interstitial infiltrates of lymphocytes, plasma cells/​mm3 and macrophages Interstitial infiltrates of polyclonal lymphocytes, some histiocytes and plasma cells/​mm3 with extension into alveolar septae Organizing pneumonia, intraluminal polyps of granulation tissue Peri-​bronchiolar lymphocytic infiltrates and variable fibrosis in chronic disease Noncaseating granuloma Granulomata Not present Occasionally reported Not present Present Prominent Treatment and prognosis Usually self-​limiting Use of cART leads to improvement in lymphocytic alveolitis May be stable without treatment Some role for steroids and cART Rarely progresses to respiratory failure Responds rapidly to corticosteroids May be self-​limiting on removal of causative agent May require corticosteroids May spontaneously remit May require steroids HRCT, high-​resolution computed tomography; NSIP, nonspecific interstitial pneumonia; LIP, lymphocytic interstitial pneumonia; COP, cryptogenic organizing pneumonia; HP, hypersensitivity pneumonitis and sarcoidosis. Adapted from Clinics in Chest Medicine, 34(2), Doffman SR and Miller RF, Interstitial Lung Disease in HIV, pp. 296–​306, Copyright © 2013, with permission from Elsevier.

18.4.5  Pulmonary complications of HIV infection 4039 FURTHER READING Chu C, Pollock LC, Selwyn PA (2017). HIV-​associated complica- tions: a systems-​based approach. Am Fam Physician, 96, 161–​9. Crothers K, et al. (2011). HIV-​associated lung infections and compli- cations in the era of combination antiretroviral therapy. Proc Am Thorac Soc, 8, 275–​81. Datta S, Mahal S, Ravat V, et al. (2018). Hospitalization outcomes in pneumo- cystis pneumonia inpatient population: A comparison between HIV and Non-HIV patients. Cureus, 10(8), e3082. doi: 10.7759/cureus.3082 George MP, et al. (2009). Respiratory symptoms and obstruction in HIV-​infected subjects in the HAART era. PLoS One, 4, e6328. Gingo MR, et  al. (2010). Pulmonary function abnormalities in
HIV-​infected patients during the current antiretroviral therapy era. Am J Respir Crit Care Med, 182, 790–​6. Grubb JR, et al. (2006). The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy. AIDS, 20, 1095–​107. Kunisaki KM, et al. (2016). Pulmonary effects of immediate versus de- ferred antiretroviral therapy in HIV-​positive individuals: a nested substudy within the multicentre, international, randomised, con- trolled Strategic Timing of Antiretroviral Treatment (START) trial. Lancet Respir Med, 4, 980–​9. Presti RM, et  al. (2017). Mechanisms underlying HIV-​associated noninfectious lung disease. Chest, 152, 1053–​60. Thao C, Shorr AF, Woods C (2017). Non-​infectious pulmonary dis- orders in HIV. Expert Rev Respir Med, 11, 209–​20. Tornheim JA, Dooley KE (2017). Tuberculosis associated with HIV infection. Microbiol Spectr, 5, doi:  10.1128/​microbiolspec. TNMI7-​0028-​2016.

18.5 The upper respiratory tract 4040 18.5.1 Upper

18.5 The upper respiratory tract 4040 18.5.1 Upper airway obstruction 4040 James H. Hull and Matthew Hind

CONTENTS 18.5.1  Upper airway obstruction  4040 James H. Hull and Matthew Hind 18.5.2  Sleep-​related breathing disorders  4048 Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind 18.5.1  Upper airway obstruction James H. Hull and Matthew Hind ESSENTIALS The upper airway is anatomically defined by the carina inferiorly and pharynx superiorly, with pathology predominately arising from the trachea and larynx. Obstruction of the upper airway may arise because of a fixed structural pathology such as tracheal sten- osis or malignancy, but can arise following loss of normal function
(e.g. inappropriate vocal cord adduction). A high index of suspicion is required to make the diagnosis
because the clinical features of upper airway obstruction can mimic other respiratory conditions. Calculation of the ratio of forced expiratory volume in one second to peak expiratory flow (Empey index) may identify patients with unsuspected upper airway obstruction. Acute upper airway obstruction is a medical emergency and usu- ally caused by aspiration, oedema (allergic, hereditary, and acquired angio-​oedema, smoke inhalation) or infection (croup, epiglottitis, quinsy, retropharyngeal abscess). Nonacute causes of upper airway obstruction include malignancy, tracheal stenosis, tracheal compres- sion, dynamic large airway collapse, and laryngeal dysfunction. Introduction The upper airway can be defined as the section of the respiratory tract between the carina inferiorly and pharynx superiorly, with pathology predominantly arising from the larynx and trachea. This section of the airway should not be viewed as a simple conduit for ventilation, but serves important function including phonation and sphincteric protection of the lower airway. Obstruction of the upper airway may arise because of a fixed structural pathology, as seen in tracheal stenosis or malignancy, or because of a loss of normal function (e.g. vocal cord dysfunction). It is remarkable how the respiratory system is able to adapt to sig- nificant degrees of upper airway obstruction without obvious con- sequences for respiratory function. Indeed, the airway lumen may be reduced by 70% in a healthy individual at rest with little evidence of overt clinical or physiological compromise. Beyond this point further reductions in the luminal cross-​section of the airway may result in acute and catastrophic consequences for airflow and can precipitate asphyxia. This physiological reserve explains the clinical observation that patients with a developing stenosis often do not re- port a gradual deterioration in symptoms, but then present in acute respiratory distress. The principal clinical manifestations of upper airway obstruc- tion include exertional dyspnoea and ‘wheeze’, hence upper airway obstruction may mimic other respiratory conditions and is often treated as ‘resistant’ asthma or chronic obstructive pulmonary dis- ease before the correct diagnosis is established. It is therefore vital that any clinician managing new airway symptoms considers upper airway obstruction in the initial differential diagnosis. This chapter provides an overview of the clinical and investiga- tion findings in upper airway obstruction and details clinical and pathological features of the most relevant conditions. Clinical approach History The detection and diagnosis of upper airway obstruction often re- quires a high degree of clinical suspicion. This is especially true if pathology develops gradually or follows a variable time course. Indeed, while the cause may be obvious in acute disease, in a chronic and more insidious format, symptoms frequently overlap with other respiratory conditions. Establishing the chronicity and periodicity of symptoms forms an important part of the clinical assessment; a temporally variable history suggests transient upper airway closure, whereas persistent 18.5 The upper respiratory tract

18.5.1  Upper airway obstruction 4041 symptoms point to a structural aetiology. Likewise, the speed of symptom onset can be useful. A detailed history of previous head and neck surgery and of any prior intubation or upper airway intervention is important. This should include an evaluation of prior intubation and/​or tracheos- tomy. The development of subglottic stenoses may relate to intub- ation that occurred some years before. It is also important to consider multisystem conditions that can manifest with large airway pathology such as rheumatological and vasculitic conditions, or respiratory diseases with large airway manifestations. The presence of gastro-​oesophageal reflux and sino-​nasal disease should be sought, and a history of medications associated with periodic upper airway obstruction (e.g. angiotensin converting enzyme inhibitors (see later) is important). Details pertinent to laryngeal pathology include questions re- garding the location of symptoms, change in voice quality, and pres- ence of dysphagia. Importantly, several features typically taken to indicate an upper airway aetiology (e.g. a difficulty ‘breathing in’), have a poor discriminatory value in separating extrathoracic causes of dyspnoea from other respiratory conditions. Examination Clinical examination features indicating upper airway obstruction include the presence of stridor or a fixed monophonic wheeze, prolonged inspiratory time, and abnormal thoracic movement. The ‘wheeze’ or whistle sound present in upper airway obstruc- tion differs in nature from that arising from the lower airways. Specifically, wheeze or stridor arising from the upper airway is harsh and monophonic in nature, and it may be possible to iden- tify the origin of the sound as coming from the upper chest/​ throat. This noise may only become apparent when ventilation is increased or may be variably present, depending on the relation- ship to a trigger or precipitant (e.g. exercise). It is therefore im- portant to assess airway sounds through forced inspiratory and expiratory manoeuvres, not simply during passive respiration. Where symptoms are highly variable, it can be useful for patients to provide audio or video recording. When there is significant airway obstruction there may be evidence of abdominal paradox (i.e. abnormal inward movement of the lower thoracic cage and abdomen during inspiration). 0 –6 –4 –2 0 2 4 6 8 (a) (b) (c) (d) (e) (f) 1 2 3 Volume (L) Flow (L/s) 4 5 6 0 –4 –3 –2 –1 0 1 2 3 4 1 Volume (L) Flow (L/s) 2 3 0 –5 –4 –3 –2 –1 0 1 2 3 4 5 1 Volume (L) Flow (L/s) 2 3 0 –5 –4 –3 –2 –1 0 1 2 3 4 5 1 Volume (L) Flow (L/s) 2 3 0 –6 –5 –4 –2 –3 –1 0 1 2 3 4 5 6 1 Volume (L) Flow (L/s) 3 4 2 5 0 –10 –8 –6 –4 –2 0 2 4 6 8 10 1 Volume (L) Flow (L/s) 2 3 4 Fig. 18.5.1.1  Changes in the flow-​volume loop in the setting of upper airway obstruction. (a), Idiopathic subglottic stenosis (b); including a flow-​volume loop recorded at disease recurrence; granulomatosis with polyangiitis (c); relapsing polychondritis (d); and intubation-​related posterior commissure stenosis (e and f). Reproduced with permission from Nouraei, SM et al. (2014). Physiology-​based minimum clinically important difference thresholds in adult laryngotracheal stenosis. The Laryngoscope, 124(10), 2313–​20, copyright © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

section 18  Respiratory disorders 4042 Investigations Lung function Physiological measurements form a key part in the assessment of upper airway obstruction and indeed may often first highlight the presence of an abnormality. Spirometry forms the mainstay of physiological measurement. This manoeuvre requires an individual to perform a forced expiration, from total lung capacity to residual volume, and then to refill their lung immediately. This is displayed as a plot of expiratory and inspiratory flow against the volume ex- haled, creating a ‘flow-​volume’ loop. The normal appearance of the flow-​volume loop is typically depicted as a ‘triangle sitting on top of a semi-​circle’, but in many of the causes of upper airway obstruction this appearance is significantly altered—​hence the flow-​volume loop appearance may be considered a ‘window to the airways’. In vari- able obstruction that occurs above the thoracic inlet (extrathoracic obstruction) only inspiratory flow phase is attenuated, whereas in fixed obstruction both the inspiratory and expiratory phases flow is impaired (Fig. 18.5.1.1). Clinicians should note these abnormalities are not readily ap- parent from the standard clinic spirograph of volume versus time, or indeed in manoeuvres which do not include an inspiratory phase. It is also important to note that inspiratory manoeuvres are highly effort-​dependent and thus attenuation of the inspira- tory phase of the flow-​volume loop, while relatively sensitive for extrathoracic obstruction, may be nonspecific. The relationship between the peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) can be informative. It was recognized over 40 years ago that the PEF is ‘disproportion- ately’ reduced in relation to the FEV1 inpatients with upper airway obstruction. Such a reduction can be quantified by the ‘Empey index’, in which the FEV1 (ml/​sec) is divided by the PEF (litre/​min), Flow–volume curve at presentation Volume (litres) FEV1 1 10 (a) (c) (b) (d) 8 6 4 2 0 –2 –4 –6 2 3 PEFR FEV1/PEFR 2100 ml 167 litres/min 12.6 FEV1 PEFR FEV1/PEFR 2000 ml 338 litres/min 5.9 Flow (litres/sec) Flow (litres/sec) Flow–volume curve 6 mo after resection Nonirritant scar in the upper airway 6 mo after resection Subglottic stenosis at presentation Volume (litres) 1 10 8 6 4 2 0 –2 –4 –6 2 3 Fig. 18.5.1.2  Upper airway obstruction indicated by the change in appearance of flow-​volume loop and a raised Empey index (the forced expiratory volume in 1 second (FEV1) in millilitres divided by the peak expiratory flow rate (PEFR) in litres per minute). Reproduced with permission from Nussbaumer-​Ochsner Y and Thurnheer R (2015). Subglottic Stenosis. N Engl J Med, 373, 73, copyright © 2015, Massachusetts Medical Society.

18.5.1  Upper airway obstruction 4043 and upper airway obstruction is consistently associated with a ratio typically of 10 or more (Fig. 18.5.1.2). For further discussion of respiratory function tests, see Chapter 18.3.1. Radiology There are several techniques to enable rapid and focused assessment of large airway pathology. Modern, multiplanar techniques allow complex 3D airway re- construction and real-​time assessment of laryngeal and large airway movement in the dynamic expiratory phase (Fig. 18.5.1.3). These techniques are evolving and may not be available outside spe- cialist centres. Moreover, some CT protocols, if utilized incorrectly or if the obstruction is caused by a thin structure such as a tracheal web, may miss large airway pathology. Direct visualization techniques Clinic-​based nasendoscopy is increasingly available and essen- tial in visualization of the nasal cavity and larynx. The technique provides important information regarding laryngeal structure and movement and assessment of wheeze. It may reveal a cause for a patient’s respiratory symptoms immediately (Fig. 18.5.1.4). However, it is also important to recognize that nasendoscopy may be entirely normal if the assessment occurs in the absence of the typical precipitant, and it may need to be repeated following ex- posure to a trigger. In the context of acute upper airway obstruc- tion, direct visualization should only be carried out by clinicians with specific expertise in managing the upper airway. Subglottic causes of upper airway obstruction are not easily visualized with nasendoscopy and bronchoscopic evaluation is therefore required. Patients with nonacute suspected upper airway obstruction will initially often undergo flexible bronchoscopy, but may require a rigid procedure in order to allow safe diagnostic sampling. Bronchoscopy should include assessment of large airway move- ment and propensity for collapse during both tidal breathing and forced expiration (Fig. 18.5.1.5). (a) (b) Fig. 18.5.1.3  (a) Multiplaner and volumetric CT reconstruction of the computer-​generated image of the trachea. demonstrating a tight but thin tracheal web tracheal web (arrow) with a maximum diameter of just 2 mm at the site of a previous tracheostomy. (b) Rigid bronchoscopy allows clear visualization of a thin tracheal web which narrowed the diameter of the trachea to just 2 mm. Diathermy immediately improved ventilation. Images reproduced from Thorax, Nanzer AM et al., 70(1), 101, copyright © 2015, with permission from BMJ Publishing Group Ltd. Fig. 18.5.1.4  Clinic-​based nasendoscopy reveals posterior glottic stenosis, indicated by arrow, with chords maintained in fixed paramedian position. This patient was referred with treatment refractory asthma; symptoms resolved entirely following surgical intervention. Image courtesy of Dr J Hull, Royal Brompton Hospital.

section 18  Respiratory disorders 4044 Emergency causes of upper airway obstruction Acute airway obstruction is a life-​threatening medical emergency that requires prompt treatment to avoid irreversible end-​organ damage and death, which can occur within minutes following complete airway occlusion. Treatment and assessment are usu- ally carried out simultaneously, with the objective of securing the airway. The cause is often obvious (Table 18.5.1.1). Patients who report a problem in the neck should always be taken seriously. Pharmacological intervention with steroids, epinephrine, and heliox (21% oxygen in helium) may all be useful, but clinical deterioration can be unpredictable. The patient requires close observation in an appropriate environment with facility for urgent intubation or emergency tracheostomy. Aspiration In the United States, aspiration or choking on food has increased to be the fourth commonest cause of accidental death after road traffic accidents, falls, and fire. The ‘cafe coronary’ often involves a large, poorly chewed piece of meat which gets stuck and obstructs or partially obstructs the larynx or trachea. Incidence increases with age, comorbidities, and sedative and alcohol use. Patients usually present with immediate respiratory distress, aphonia, and cyan- osis, which can lead rapidly to death. Treatment requires imme- diate recognition and removal of obstructing matter. The Heimlich manoeuvre, which can be done on oneself, back slaps, and abdom- inal thrusts are all useful. These forms an essential part of basic life support training taught by international resuscitation councils. Endoscopy, preferably using a rigid bronchoscope which allows ventilation and access for larger, grasping tools to remove the for- eign body, is sometimes required. Emergency cricothryoidotomy where a small hole is made in the cricothyroid membrane can be lifesaving technique. Infection Infections of the upper airways rarely cause obstruction in adults but are significant causes in infants and children, particularly (a) (b) (c) (d) Fig. 18.5.1.5  Image stills taken during flexible bronchoscopy showing excessive dynamic airway collapse, with images taken during (a) passive respiration, and (b) forced expiration. Figures courtesy of Dr P. Shah, Royal Brompton Hospital. Table 18.5.1.1  Causes of upper airway obstruction Acute Subacute Oedema Tumour Allergy Subglottic stenosis (commonly following intubation/tracheostomy) infections: (tonsillitis, pharyngitis, epiglottitis, croup, retropharyngeal, tonsillar, and peritonsillar abscess) Tracheal compression (aneurism, tumour, thyroid enlargement) Foreign body Tracheal web Burn inhalation injury Tracheomalacia Tracheobronchomegaly Recurrent laryngeal nerve palsy Vocal cord dysfunction or inducible laryngeal obstruction (ILO)

18.5.1  Upper airway obstruction 4045 streptococcal pharyngitis, tonsillitis, croup, and retropharyngeal abscesses. Croup (viral laryngotracheobronchitis) This is very common in children and usually caused by Parainfluenza 1–​3 virus infection, but Adenovirus, Respiratory syncytial virus, and other viruses can also cause disease. The subglottic trachea is usually affected, causing tracheal narrowing which generates the steeple sign on a plain chest film. Patients usually present at night with hoarse- ness, a typical nocturnal barking cough, stridor, and drooling when severe. A croup score may be useful in stratification of disease. The condition usually resolves within 3–​7 days. Treatment is supportive and dependent on the degree of respiratory distress. Steroids, nebu- lized racemic epinephrine (equal volumes of d and l-​isomers of epi- nephrine which have prolonged action and reduced pressor effect compared with l-​epinephrine alone), and heliox may be useful. Epiglottitis Historically more than 90% of cases were due to Haemophilus influ- enzae, which is now rare in countries where there is a comprehen- sive vaccination programme. It characteristically presents abruptly with drooling, dysphagia, and distress. The affected patient often adopts the tripod position with extension of the neck. Examination should be conducted extremely carefully as this can provoke com- plete airway occlusion. The epiglottis has a typical beefy or cherry red appearance. Management is focused on immediate securing of the airway, which should be done by an experienced paediatric an- aesthetist. The prognosis is good once the airway secured. Treatment requires appropriate broad-​spectrum antibiotics. Tonsillar enlargement and peritonsillar abscess (quinsy) Treatment is both supportive and directed toward the infection, often caused by a group B streptococcus. Quinsy often requires surgical drainage. Lemierre’s disease, often secondary to a deep peritonsillar abscess caused by a Fusobacterium necrophorum, refers to thrombophlebitis of the internal jugular vein which can lead to sepsis and septic emboli to the lungs. Retropharyngeal abscess Though rare, the incidence in adults is rising and a high index of sus- picion is required. It usually presents with sore throat, stridor, fever, neck stiffness, neck pain, and odynophagia. There is a high mortality due to association with carotid artery rupture, mediastinitis, epidural abscess, aspiration pneumonia, necrotizing fasciitis, and jugular venous thrombosis. Urgent ear, nose, and throat (ENT) assessment is required, with drainage and appropriate antibiotic treatment. Oedema In the hospital environment, extubation is commonly associated with laryngospasm and laryngeal oedema, and it has been reported that variable upper airway obstruction caused by oedema compli- cates up to 30% of extubations in the intensive care unit setting and is responsible for 4% of reintubations. The risk of post-​extubation laryngeal oedema can be assessed by a cuff leak test where the endo- tracheal tube cuff is deflated and the leak determined. There are data suggesting the systemic steroids may be useful in preventing post-​ extubation laryngeal oedema. Early tracheostomy has also been sug- gested as a useful prevention strategy. Once identified, the airway must be protected with reintubation, emergency tracheostomy, or treated with medical therapy. Systemic steroids, nebulized epineph- rine, and heliox are all thought to be useful. Respiratory support with noninvasive ventilation should be avoided as this may delay definitive airway stabilization. Outside of hospital, acute oedema of the larynx or pharynx is usually due to allergy, a hereditary abnormality of the complement pathway, or occurs following inhalation of noxious gases. Allergic oedema Oedema affecting the face and upper airway can appear without warning. Usually, however, there is a history of atopy with a known allergy, prior history of hay fever, or the oral-​allergy syndrome with pruritis of the lips, tongue, and palate after certain fruits and nuts. Whereas oral ingestion of allergens rarely progresses to IgE-​mediated anaphylaxis with life-​threatening upper airway obstruction (the pro- teins are broken down before absorption, exceptions being certain nuts, fish, and egg), insect stings can do so as they are directly injected. Some apparent allergic reactions are not based on atopy and IgE but occur via IgG, direct activation of other inflammatory pathways, or ingestion of vasodilator substances. Treatment of allergic upper airways obstruction consists of intramuscular epinephrine (0.5 mg IM) with antihistamines and steroids (Chapter 17.3). Aerosolized epinephrine may also be useful. Hereditary and acquired angio-​oedema Nonallergic hereditary and acquired angio-​oedema are due to defi- ciency of plasma C1 inhibitor, a serene protease inhibitor, produced by the liver and monocytes, which regulates the first component of the complement pathway. This deficiency allows abnormal activation of the whole complement pathway, leading to activation of C1, C2, and C4 and production of vasoactive products such as bradykinin responsible for the resulting oedema. See Chapter  4.5 for further discussion. Smoke inhalation Smoke inhalation can cause thermal injury to the upper airways and contributes significantly to deaths due to fire. Upper airway ob- struction due to heat injury and mucosal swelling usually develops within 24 h of exposure, but stenosis due to scarring can present later. A hoarse voice, stridor, severe conjunctivitis, burnt nasal hairs, and falling peak flow all suggest significant upper airway damage. Direct visualization with bronchoscopy is the best tool to determine whether there is oedema or mucosal ulceration obstructing the airways. Management usually consists of simple measures such as elevating the head of the bed and inhaling cool moist air with added oxygen. If peak flow falls, then transfer to an intensive care unit and bronchoscopy with the capability to perform an intubation, guided by direct vision, is required. Subacute causes of upper airway obstruction Malignancy Cancers arising from the larynx and airway can cause airway obstruc- tion. They are usually squamous carcinomas and are more common in smokers. Spread of a bronchial carcinoma into the trachea is probably the most common cause of upper airway obstruction seen

section 18  Respiratory disorders 4046 by chest physicians. Laryngeal tumours commonly present with a change in voice and cough. Large airway tumours often present late as the chest radiograph is often normal. Assessment requires direct visualization and biopsy (Fig. 18.5.1.6). Aside from intubation or tracheostomy (when appropriate), emergency treatment of tumours compromising the upper airway consists of dexamethasone (12  mg daily), nebulized adrenaline (10 ml of 1:10 000 up to six times daily), humidification of inspired air, and the use of heliox (21% oxygen in helium). Improvement in the airway may then be achieved by treatment of the tumour with chemotherapy or radiotherapy, but sometimes these may provoke tumour swelling, such that steroids are often prescribed first, with emergency treatments kept close to hand (heliox, adrenaline). If these therapies do not help, palliation can be achieved with the use of bronchoscopically guided laser therapy or cryotherapy, which ei- ther burn or freeze away tumour tissue with a low incidence of ser- ious haemorrhage. However, these techniques are only of use with intraluminal tumours and cannot be applied when narrowing is due to external compression. Another approach is the use of silicone or metal endobronchial stents, some of which can be inserted either via a flexible or rigid bronchoscope. These are particularly useful when external compression is present, and can produce dramatic resolution of symptoms. It is rarely appropriate to ‘debulk’ a malig- nant tumour at thoracotomy in an attempt to improve large airway patency. Upper airway obstruction from tumour often becomes a terminal event. Adequate palliation and sedation must be given. Some rare, nonmalignant tumours can obstruct the trachea (Fig. 18.5.1.7), and rarely granulomatous conditions such as sarcoid, Wegener’s granulomatosis, and amyloid infiltration may mimic tumour. Tracheal compression A variety of abnormalities of adjacent structures can cause external compression of the trachea and lead to symptoms of upper airway (a) (b) Fig. 18.5.1.7  (a) Tracheal mass virtually occluding the airway at the level of the aortic outlet on axial CT thorax. (b) Highly vascular endotracheal mass visualized at bronchoscopy. Reproduced from Thorax, Orton C, et al., 70(3), 302, copyright © 2015, with permission from BMJ Publishing Group Ltd. Fig. 18.5.1.6  Endotracheal malignancy viewed through rigid bronchoscope. Figures courtesy of Mr S. Jordan, Royal Brompton Hospital.

18.5.1  Upper airway obstruction 4047 obstruction. When present a thyroid goitre usually grows outwards, but occasionally it can wrap around the trachea and oesophagus and extend inferiorly into the superior mediastinum, causing narrowing and airway obstruction. Haemorrhage into a pre-​existing cyst can cause acute worsening of symptoms. Surgery usually provides im- mediate relief of symptoms with the caveat that occasionally the goitre contributes to structural support of the trachea and removal can precipitate tracheomalacia. A variety of congenital and acquired vascular abnormalities often involving the innominate artery or aorta can result in airway com- promise. Mediastinal lymphadenopathy, thymoma, and fibrosis can all present with airway symptoms. Treatment for tracheal compres- sion is dependent on the underlying aetiology, but a multidiscip- linary approach is recommended with access to optimal diagnostic physiology and imaging, thoracic surgery, and/​or stenting, and re- spiratory support with continuous positive airway pressure or non-​ invasive ventilation. Tracheal stenosis Tracheal stenosis is an important cause of iatrogenic upper airway obstruction and usually occurs at the level of the subglottis, typ- ically caused by the cuff of an endotracheal tube or the first tra- cheal ring following tracheostomy. The incidence after intubation has been reported to be up to 20%, but may be less following the widespread use of low pressure cuffed tubes. CT reconstruction of the trachea may be useful, but examination with bronchoscopy and assessment by a specialist thoracic surgeon or ENT surgeon is re- quired (Fig. 18.5.1.3). Dynamic large airway collapse Several conditions can be associated with an apparent collapse or excessive inward movement of the tracheal wall. Diagnostic criteria remain under discussion, but in some individuals the posterior tra- cheal wall may collapse to such a degree (i.e. >90%) that it almost completely occludes the large airway tract during expiration, and even during passive tidal respiration. This can have flow conse- quences and result in impaired exercise tolerance and cough, with difficulty clearing secretions. It is important to highlight, however, that a degree of large airway collapse occurs in healthy individuals and there can be a poor relationship between the degree of collapse visualized (e.g. on bronchoscopy or CT imaging) and impact on symptoms or lung function. The terminology in this field is confusing and several terms have been used to describe large airway collapse (e.g. excessive dynamic airway collapse and/​or expiratory central airway col- lapse). These conditions are probably best considered under an umbrella term of large airway collapse with symptoms, encompassing the conditions tracheobronchomalacia and exces- sive dynamic airway collapse. Tracheobronchomalacia is a term that should be specifically reserved to describe a pathological condition with structural weakness in the cartilaginous rings of the trachea and large airways, whereas excessive dynamic airway collapse describes invagination of the posterior membrane of the trachea leading to a 70% or more reduction in airway lumen (Fig. 18.5.1.8). Relapsing polychondritis is a severe progressive form of tracheobronchomalacia. This is an inflammatory condition typic- ally involving cartilage of the nose, ears, and large airways. There is often significant delay in diagnosis, with no specific diagnostic test available, although positron emission tomography scans and car- tilage biopsies can be helpful. Treatment usually involves immuno- suppression, with anecdotal success using novel biologic agents in addition to supportive treatment of the tracheal collapse with re- spiratory support, stents, and surgery. See Chapter 19.11.9 for fur- ther discussion. Tracheomalacia and excessive dynamic airway collapse are thought to occur in a significant number of patients suffering from chronic obstructive pulmonary disease and asthma. Treatment is largely supportive and directed at coexistent conditions; optimal airway support with continuous positive airway pressure and non-​ invasive ventilation is often very useful. Mounier-​Kuhn syndrome or tracheobronchomegaly is a rare, ab- normal dilatation of the trachea caused by atrophy of the muscular and elastic tissues of the trachea. Secondary tracheobronchomegaly can be caused by connective tissue disease. Recurrent respiratory tract infection is common. Treatment is supportive. (a) (b) Fig. 18.5.1.8  CT images demonstrating (a) excessive dynamic airway collapse and (b) tracheobronchomalacia. See text for discussion. Figures courtesy of Dr A Devaraj, Royal Brompton Hospital.

18.5.2 Sleep- related breathing disorders 4048 Mar

18.5.2 Sleep- related breathing disorders 4048 Mary J. Morrell, Julia Kelly, Alison McMillan, and Matthew Hind

section 18  Respiratory disorders 4048 Laryngeal dysfunction The anatomical position of the larynx dictates its role as the true ‘gateway’ to the airways, and complex reflex mechanisms have evolved to prime the larynx in a state of ‘readiness for closure’ (i.e. in order to protect the lower airways). Despite this, on a day-​to-​day basis, and in most individuals, the larynx functions autonomously many thousands of times daily, and without higher cortical re- sponse. However, in some situations the larynx may adopt a physio- logical state that could be considered maladaptive or ‘dysfunctional’ and close acutely (e.g. in the state of laryngospasm). There is a spectrum of ‘laryngeal dysfunction’ disorders, which may be viewed as overlapping conditions with shared manifest- ations. Many patients with chronic nonproductive cough can de- scribe features of a general ‘laryngeal hypersensitivity’, and at times this may extend to a clinical situation characterized by laryngeal nar- rowing with symptoms arising from the voice box (e.g. dysphonia or globus). However, it is important that clinicians consider and ex- clude structural or neurological causes of laryngeal disease before they consider the diagnosis of dysfunction or hypersensitivity. The term vocal cord dysfunction has been used for over 40 years to describe the phenomenon of inappropriate vocal cord adduction, which results in distressing symptoms such as dyspnoea, wheeze, and laryngeal discomfort. Several terms have subsequently been used to describe a variety of laryngeal closure syndromes, and most re- cently the term periodic occurrence of laryngeal obstruction (POLO) has been advocated. This term is preferred because it aptly describes the temporal nature of the condition, but also acknowledges the fact that, in many cases, the obstruction may involve structures within the larynx that are distinct from the vocal cords (i.e. supraglottic adduc- tion classically seen in exercise-​induced laryngeal obstruction). The term laryngospasm is best reserved for the condition of acute, cata- strophic laryngeal closure, which can result in a loss of consciousness. This typically occurs following laryngeal instrumentation. A diagnosis of POLO may be suggested by features in the his- tory (Table 18.5.1.2) and intermittent abnormalities on lung func- tion testing, but ultimately a secure diagnosis is often dependent on nasendoscopy being performed when symptoms are present. Treatment is targeted at minimizing any aggravating factors (e.g. reflux or sino-​nasal disease) and use of speech and language therapy. Low doses of amitriptyline have been used to treat vocal cord dys- function, and local botulinum toxin injection has been used success- fully to treat laryngospasm. FURTHER READING Gibson GJ (2008). Clinical tests of respiratory function, 3rd edition. CRC Press, Boca Raton, FL. Halvorsen, T, et al. (2017). Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. European Respiratory Journal, 50, 1602221; doi: 10.1183/13993003.02221-2016. Pavitt MJ, et al. (2017). Choking on a foreign body: a physiological study of the effectiveness of abdominal thrust manoeuvres to increase thoracic pressure. Thorax, 72(6), 576–78. doi: 10.1136/thoraxjnl-
2016-209540. Resuscitation Council (UK). Emergency treatment of anaphylactic
reactions:  Guidelines for healthcare providers. https://​www.resus. org.uk/​anaphylaxis/​emergency-​treatment-​of-​anaphylactic-​reactions/​ Sandhu GS, Nouraei SAR (2015). Laryngeal and tracheobronchial stenosis. Plural Publishing, San Diego, CA. World Allergy Organization. Upper airway edema. http://​www. worldallergy.org/​education-​and-​programs/​education/​allergic-​ disease-​resource-​center/​professionals/​upper-​airway-​edema 18.5.2  Sleep-​related breathing disorders Mary J. Morrell, Julia Kelly, Alison McMillan,
and Matthew Hind ESSENTIALS Obstructive sleep apnoea and other sleep-​related breathing prob- lems significantly impair the functioning of about 0.5–​1% of the population. Obstructive sleep apnoea Obstructive sleep apnoea in adults is usually caused by obesity and fat deposits in the neck area (typically collar size of 17 inches (43 cm) or more), when the withdrawal of postural muscle tone during sleep allows the pharyngeal dilators to be overwhelmed, leading to Table 18.5.1.2  Features distinguishing periodic occurrence of laryngeal obstruction from asthma Inducible laryngeal obstruction Asthma Onset Rapid (within seconds) Variable (within minutes) Pattern Can resolve rapidly Variable but typically symptoms but persistent during exacerbation Inhaled drug therapy Largely ineffective B2 agonist usually effective Breathing characteristics Monophonic inspiratory wheeze, prolonged inspiratory phase Polyphonic expiratory wheeze, prolonged expiratory phase Regional limitation Upper airways, neck Lower airways, chest Symptoms Dyspnoea, wheeze, stridor, cough, throat/chest tightness, dysphonia Dyspnoea, wheeze, cough, chest tightness Precipitating factors Exercise, emotional stress, cold air, strong odours/scents Exercise, infections, cold air, allergies, stress

18.5.2  Sleep-related breathing disorders 4049 excessive narrowing or collapse of the airway, with consequent ap- noea and sleep fragmentation. Clinical features—​there is a continuum from light intermittent snoring through to severe obstructive sleep apnoea, the main symptom of which is daytime hypersomnolence. Other common symptoms are loud snoring, restless or unrefreshing sleep, observed apnoeas, nocturia, and changes in mood. Diagnosis—​the Epworth Sleepiness Scale, in which the patient is asked to state how likely they are to doze off or fall asleep in several or- dinary situations (e.g. sitting and reading), is well validated. Patients with high scores generally merit a sleep study to (1) assess sleep fragmenta- tion, (2) establish if a respiratory problem is responsible, and (3) decide if upper airway obstruction is the primary cause. Classical obstructive sleep apnoea causes a snoring–​silence–​snoring pattern of sleep, to- gether with body movements and oscillations in the pulse and Sao2. Management—​mild symptoms may resolve with lifestyle changes such as:  (1) losing weight, the most important recommendation; (2) learning to sleep on the side and avoiding sleeping on the back; (3) no alcohol after 18.00 h; (4) no sedatives; (5) stopping smoking; (6) keeping the nose as clear as possible. There is only one fully ef- fective therapy for moderate to severe obstructive sleep apnoea—​ continuous positive airway pressure. Prognosis—​vascular mortality is higher than average, although some studies have questioned this link. Sleep-​induced hypoventilation and central sleep apnoea Aetiology—​breathing during sleep may decrease because of a reduc- tion in Central neural output to the respiratory muscles, which can be caused by (1) absent ventilatory drive—​Ondine’s curse; (2) unstable ventilatory drive; (3) REM-​related oscillations. Clinical features—​some central apnoeas present with daytime sleepiness (similar to obstructive sleep apnoea), whereas others pre- sent with symptoms of respiratory failure such as morning headaches with confusion, cyanosis, and ankle oedema. Management—​without treatment, the chronic ventilatory failure associated with some neurological disorders usually progresses rap- idly to death, or more slowly in lung disease or chest wall disease. Supporting breathing overnight can reverse both nocturnal and day- time ventilatory failure in the short term, and can also prolong life. Introduction Establishing and maintaining sleep involves complex neural pro- cesses. The deregulation of these processes can result in sleep dis- orders, including those caused by breathing-​related complaints. Sleep is a fundamental requirement for life and as such the symp- toms associated with breathing disorders that occur during sleep are common (e.g. hypersomnolence) and changes in mood. All physicians from all specialties are likely to encounter them and need to understand their aetiology and treatment. This chapter fo- cuses on the diagnosis and clinical management of sleep-​related breathing disorders, the most common of which is obstructive sleep apnoea (OSA). It will also include brief descriptions of the differential diagnosis for respiratory and nonrespiratory sleep disorders. Breathing during sleep Healthy sleep Sleep onset occurs through a process of reciprocal inhibition be- tween wake and sleep promoting neurons located in the ventrolateral preoptic nucleus, and other areas of the hypothalamus and reticular activating system; an ‘all-​or-​nothing’ neural switching mechanism prevents occurrence of intermediate conscious states. Sleep is most often initiated (in adults) as nonrapid eye movement (NREM) sleep, defined by the synchronization of electro-​encephalogram (EEG) producing characteristic waveforms. NREM predominates early in sleep and is split into light sleep (stages 1 and 2) and deep or slow wave sleep (stage 3; see Fig. 18.5.2.1a). Episodes of rapid eye movement (REM) sleep occur approxi- mately every 90 minutes, and the duration of REM sleep increases as the night progresses. REM sleep is also called desynchronized sleep, because it is defined by EEG desynchronization, postural muscle atonia, and rapid eye movements; in patients with sleep-​related breathing disorders, muscle atonia during REM can exacerbate dis- ease severity. Each night, the 90 minute NREM–​REM cycles are repeated approximately 3–​6 times. The occurrence of NREM sleep early 21:11 (a) w R 1 2 3 Stage 3 3 Rem Rem 2 22:00 23:00 00:00 01:00 02:00 03:00 04:00 05:00 06:00 07:00 23:00 (b) 00:00 01:00 02:00 03:00 04:00 05:00 06:00 07:00 W Wake Stage 3 1 2 3 R Fig. 18.5.2.1  (a) Overnight sleep patterns (hypnogram), obtained from electroencephalography, illustrating sleep cycles in a young healthy person. Note that NREM is the first sleep, and the first REM sleep occurs after approximately 90 minutes; throughout the night there are occasional brief arousals from sleep. (b) Sleep cycles in a patient with OSA. Note, throughout the night there are frequent, brief arousal from sleep with a reduction in both NREM stage 3 and REM sleep. W: wake; R: REM sleep (marked in blue); 1, 2, 3: NREM stage 1, 2, and 3 sleep.

section 18  Respiratory disorders 4050 in the night is regulated by the need to sleep (sleep homeostasis). The predominance of REM sleep later in the night is controlled by circadian rhythm. Sleep cycles can be disturbed by sleep-​related breathing disorders that typically cause a reduction in the amount of NREM stage 3 sleep, delayed or reduced REM sleep, and fre- quent arousal from sleep (Fig. 18.5.2.1b). Nonrespiratory sleep disorders, such as narcolepsy and parasomnias, can also disrupt overnight sleep and their recognition is essential when making a differential diagnosis. Regulation of breathing during sleep Minute ventilation is reduced by approximately 10% at sleep onset, mainly due to a reduction in tidal volume. The sleep-​related changes in breathing result from a loss of the ‘wakefulness drive to breathe’, a reduction in chemosensitivity and metabolism (with an associated de- crease in both CO2 production and oxygen consumption) plus changes in respiratory mechanics. The ability to establish stable breathing during sleep depends on the respiratory control system responding ap- propriately to these changes. If it does not, breathing disorders occur, such as OSA, central sleep apnoea, and Cheyne–​Stokes respiration (Fig. 18.5.2.2). The term ‘wakefulness drive to breathe’ describes the influence of wake-​related cerebral activity on the regulation of breathing. The specific neural origin of the drive to breathe remains uncertain, though it includes suprabrainstem structures. The wakefulness drive is by definition absent during sleep, which means that breathing is primarily controlled by the central and peripheral chemoreceptors. In the case of the central chemoreceptors (located in the brainstem), changes in the pH of the cerebral spinal fluid elicit a central chemo- receptor response resulting in an appropriate change in ventilation. Cerebral blood flow is exquisitely sensitive to CO2, which effectively modulates the stimulation of the central chemoreceptors. The cere- bral blood flow response to CO2 is reduced in NREM sleep, as are the ventilatory responses, contributing to a relative hypercapnia. In healthy people at sea level, the sleep-​related increase in PaCO2 is ap- proximately 0.2–​1 KPa, with a decrease in arterial oxygen saturation of approximately 1–​2%. Waking from sleep triggers hyperventilation (due to sleep-​related hypercapnia), with a resulting fall in PaCO2 to presleep (wake) levels. Upon resumption of sleep, the wake-​related PaCO2 is detected as a relative hypocapnia that causes a subsequent hypoventilation (hypopnoea), or apnoea if the PaCO2 is below the level required to maintain stable breathing (the apnoeic threshold). This feedback and feed-​forward mechanism explains how one respiratory event begets another to perpetuate (central) respiratory instability (Fig. 18.5.2.2). Failure of the regulation of breathing during sleep
in heart failure Close proximity of the sleeping PaCO2 to the apnoeic threshold in- creases the propensity to develop central sleep apnoea. In chronic heart failure, stimulation of juxtacapillary receptors, due to pulmonary oe- dema exacerbated by a supine posture (increased venous return), pro- duces hyperventilation and a lowering of the PaCO2 towards the apnoeic threshold. There is a high prevalence of central sleep apnoea in patients with chronic heart failure, independent of the severity of heart failure, as measured by left ventricular ejection fraction. Additional mechan- isms which may contribute to central sleep apnoea in heart failure include: (1) poor sleep with increased spontaneous arousal, due to increased sympathetic activity or related to medication (e.g. diur- etics, β-​blockers, ACE inhibitors, and ARBs); (2) increased central and peripheral chemosensitivity; (3)  prolonged circulation time; (4) development of OSA due to upper airway oedema. Respiratory muscle activity during sleep Sleep is associated with a reduction in efferent activity to the thor- acic and pharyngeal muscles. In young, nonobese people who do not snore, the sleep-​related reduction in neural drive results in a rela- tively small reduction in pharyngeal airway lumen calibre, whereas in people who snore the reduction in the size of the airway lumen is greater, with a subsequent increase in resistance and turbulent air- flow passing over the vocal cords causing snoring. Further reduction in airway calibre and flow can lead to mild sleep apnoea and upper airway resistance syndrome (Fig. 18.5.2.2). The mechanical load on the respiratory system during sleep must be overcome if stable breathing is to be maintained. The ability to elicit a compensation to the added load is protective, and occurs as a result of stimulation of the chemo and mechanoreceptors, plus upper airway reflex mech- anisms. When compensation is incomplete, obstructive apnoeas and hypopnoeas develop (Fig. 18.5.2.2). Breathing during REM sleep The respiratory control system is particularly vulnerable in REM sleep due to both inhibition of respiratory muscles and reduced chemosensitivity. REM sleep is associated with a 5–​15% reduction in ventilation, and respiratory rate is more variable, notably during phasic REM, which is associated with bursts of rapid eye movements; tonic REM sleep is REM sleep with the absence of the eye movements. The REM-​related muscle atonia, reduces upper airway reflexes and in- creases airway compliance, contributing to the REM-​related increased prevalence of snoring, airway obstruction, and OSA. In patients with pre-​existing respiratory conditions (such as obstructive (COPD) and restrictive (neuromuscular disease, obesity, or chest wall disease) pathophysiologies), REM-​related hypoventilation is often the first sign of nocturnal hypoventilation (discussed further in Chapter  18.15). Untreated, this can lead to daytime hypercapnia and chronic respiratory failure. Conversely, central sleep apnoea is uncommon in REM sleep the ventilatory responses to both hypercapnia and hypoxia are reduced. Obstructive sleep apnoea Classification Obstructive sleep apnoea is caused by occlusion of the upper airway during sleep. The closure can be complete with no airflow (apnoea), or partial narrowing with reduced airflow (hypopnoea), as shown in Fig. 18.5.2.2. Both events are associated with hypoxia and hypercapnia. Respiratory effort continues during the occlu- sion, producing increasing inspiratory effort that leads to a brief cortical arousal from sleep, which in turn restores airway patency. The resumption of breathing is accompanied with an acute surge in blood pressure and heart rate. Many hundreds of apnoeas and hypopnoeas can occur throughout the night, leading to sleep frag- mentation (Fig. 18.5.2.1b), symptoms of daytime sleepiness and arterial hypertension, plus other consequences.

18.5.2  Sleep-related breathing disorders 4051 OSA falls into the broad category of a dyssomnia when classified using the International Classification of Sleep Disorders (American Academy of Sleep Medicine). Dyssomnias are disorders character- ized by either difficulty initiating or maintaining sleep, or exces- sive sleepiness. They are divided into three groups: intrinsic sleep disorders, extrinsic sleep disorders, and circadian rhythm sleep disorders. OSA is an intrinsic sleep disorder which is commonly associated with the term ‘sleep-​disordered breathing’. This is an umbrella term used to describe a group of disorders characterized by abnormalities of respiratory pattern, or quantity of ventilation, Fig. 18.5.2.2  Types of sleep-​disordered breathing measured using a microphone (snore) and cardiorespiratory signals (nasal flow, respiratory effort, oxygen saturations, and pulse) recorded during 5-​minute epochs of breathing asleep. Hypopneas are highlighted in yellow, obstructive apnoea in pink, and central apnoea in red.

section 18  Respiratory disorders 4052 that occur periodically during sleep (e.g. primary or secondary central sleep apnoea), Cheyne–​Stokes respiration, high-​altitude periodic breathing, nonobstructive hypoventilation, or hypox- emia disorders secondary to pulmonary parenchymal, vascular, neuromuscular, or chest wall disorders, as well as upper airway resistance syndrome. Some of these disorders are illustrated in Fig. 18.5.2.2. Aetiology During wakefulness, patency of the pharyngeal airway is maintained by upper airway dilator muscles. The tone of the dilator muscles de- creases at sleep onset, which results in airway narrowing. In patients with neuromuscular weakness (e.g. Bulbar weakness), neurological degenerative disorders (e.g. motor neurone disease), and myop- athies (e.g. Duchenne muscular dystrophy), the sleep-​related reduc- tion in pharyngeal dilator muscle activity is exacerbated, increasing the risk of OSA. Drugs that reduce muscle tone (e.g. alcohol, seda- tives, and antidepressants) also increase the risk of upper airway oc- clusion and OSA. The transmural pressure across the airway lumen, which in turn is influenced by the extraluminal pressure, is also a key factor regu- lating pharyngeal airway patency. Therefore, increased soft tissue surrounding the upper airway, such as neck obesity, macroglossia, and oedema due to heart failure or endocrine disorders (e.g. hypothyroidism) plus normal physiological changes that occur in pregnancy or menopause are also risk factors for OSA. Other factors that predispose to OSA are those that reduce the size of the airway lumen including an enlarged uvula, tonsillar hyper- trophy, and acromegaly. Anatomical risk factors include retrognathia and mandibular hypoplasia. If narrowing occurs at multiple sites along the pharynx, this can accelerate precipitating pharyngeal col- lapse. The role of nasal blockage as a risk factor for OSA is debated, and that increased inspiratory effort could in theory increase pha- ryngeal collapse. Overall, obesity is by far the most common, and potentially modifiable, established risk factor for the development of OSA (Table 18.5.2.1). Community-​based observational cohort studies have shown that excess body weight is uniformly associated with a graded increase in OSA prevalence. Additionally, longitudinal studies have shown that weight gain, and loss, influenced the severity of OSA. Increased weight gain is a contributory factor for progression of disease se- verity from snoring, though upper airway resistance syndrome, to OSA, which occurs in some people. Other interrelated markers of obesity such as neck or waist circumference are independently asso- ciated with OSA severity. In the early 1990s, the seminal Wisconsin Sleep Cohort reported 4% of men and 2% of women met the diagnostic criteria for OSA with symptoms of sleepiness. Around the same time in the United Kingdom, a similar study of middle-​aged men suggested a more con- servative figure of 0.3%. More recent estimates from the Wisconsin Cohort have predicted that up to 14% of males and 5% of females have OSA with symptoms of sleepiness. This represents a substantial increase in the last two decades, in part due to the increasing preva- lence of obesity. There is also a high prevalence of OSA with increasing age. The mechanisms proposed for the age-​related increase in prevalence in- clude: (1) a reduction in pharyngeal muscle function; (2) age-​related differences in pharyngeal morphology; (3) changes in the central control of breathing; (4) the increased prevalence of comorbidities associated with sleep apnoea such as heart failure. Symptoms The most common symptom of OSA is excessive sleepiness that occurs in most, but not all patients. When OSA is associated with symptoms, it is referred to as obstructive sleep apnoea syndrome (OSAS) or obstructive sleep apnoea/​hypopnoea syndrome. OSA also causes loud snoring, reported by bed partners in over 60% of patients, witnessed episodes of gasping or choking, dyspnoea during sleep, and frequent movements that disrupt sleep are also seen. Patients awaken in the morning feeling tired and unrefreshed regardless of the duration of their time in bed. Quality of life is ad- versely affected by the unrefreshing sleep, and by the disruption of the bed partner’s sleep and resultant irritability. Less common symptoms (10–​60%) include morning headaches, enuresis, reduced libido, nocturnal sweating, and a partner worried by apnoeic epi- sodes. Less common symptoms such as insomnia, nocturnal cough, and oesophageal reflux are also reported. A useful observation for identifying patients with OSA is noc- turnal choking or gasping. Snoring, although common in OSA pa- tients, is not useful for establishing a diagnosis as it lacks specificity. The presence of loud intermittent snoring can be of value when combined with daytime symptoms. Several clinical prediction formulae have been used in the diag- nosis of OSAS, most are based on body mass index (BMI) and male gender. None have been shown to be sufficiently accurate to discrim- inate between patients with or without OSAS, hence a diagnostic test is required to confirm the diagnosis and inform treatment choices. Diagnosis OSA is diagnosed using a combination of history, clinical examin- ation, and a diagnostic study that measures physiological variables before and during sleep. The history should include the presence of the symptoms discussed earlier. Excessive sleepiness is commonly assessed using the Epworth Sleepiness Scale (ESS). This subjective questionnaire is used to determine how likely the patient is to doze in eight frequently encountered situations (Fig. 18.5.2.3). An Epworth score of 10 is usually considered abnormal. The ESS, while not a perfect measure of sleepiness, is very useful in monitoring efficacy of treatment. The clinical examination is frequently normal in patients with OSA but silent features may include obesity, BMI more than 30 kg/​ m2, and neck circumference (>43 cm in men and 37 cm in women). Examination of the pharynx with a tongue depressor and light Table 18.5.2.1  Mechanisms linked to obesity that contribute to the pathogenesis of Obstructive Sleep Apnoea Increased pharyngeal fat deposits and subsequent narrowing of the pharyngeal airway Reduced lung volumes by a combination of increased abdominal fat and recumbent posture Impairment of the Leptin signalling pathway and other endocrine signals The possibility of pro-​inflammatory cytokines derived from visceral adipose impacting on sleep or inflammatory response in upper airway tissues

18.5.2  Sleep-related breathing disorders 4053 source is essential; an increased Mallampati score, narrowing of lateral upper airway walls, enlarged tonsils, a high arched palate, retrognathia, or micrognathia should be noted. Systemic arterial hypertension is found in 50% of patients with OSA, and coexistent congestive cardiac failure, pulmonary hyper- tension, stroke, and type II diabetes may be evident. Measurement of blood pressure, fasting blood sugar, lipid status, and thyroid func- tion should be considered. Arterial, blood gas sampling, either from the radial artery or preferably an arterialized blood gas from the ear lobe, can be requested together with lung function if nocturnal hypo- ventilation suspected. A raised Paco2 should suggest the possibility of lower airways obstruction (so-​called ‘overlap syndrome’) because patients with ‘simple’ OSA rarely have hypercapnia when awake: an additional factor(s) such as plus chronic obstructive pulmonary dis- ease (COPD) or morbid obesity usually needs to be present. The most comprehensive test for the diagnosis of OSA is a noc- turnal polysomnogram (NPSG) which simultaneously records the electroencephalogram, electrooculogram, electromyogram, oronasal airflow, and oxygen saturations. This test is used in some UK tertiary referral centres, however, it is not required for diagnosis in the majority of cases. The most common test used in UK sleep centres is a cardiorespiratory study (e.g. respiratory polygraphy) or Epworth Sleepiness Scale Name: Your age (Yrs): How likely are you to doze off or fall asleep in the following situation, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you haven’t done some of these things recently try to work out how they would have affected you Use the following scale to choose the most appropriate number for each situation: 0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing It is important that you answer each question as best you can. Situation Sitting and reading Watching TV Sitting, inactive in a public place (e.g a theatre or a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in the traffic THANK YOU FOR YOUR COOPERATION Chance of Dozing (0–3) Your sex (Male = M, Female = F): Today’s date: Fig. 18.5.2.3  The Epworth Sleepiness Scale (ESS) is commonly used to assess excessive sleepiness. The likelihood of dozing in eight frequently encountered situations is measured on a four point scale (0 to 3) with a maximum score of 24. A score of 0–​7 is considered normal, 8–​9 is considered as average sleepiness, 10–​15 is considered excessively sleepy, while 16–​24 is considered excessive, with a need for medical treatment. From Johns MW (1991). A new method for measuring daytime sleepiness: The Epworth Sleepiness Scale. Sleep, 14(6), 540–​5, by permission of Oxford University Press.

section 18  Respiratory disorders 4054 continuous single or dual bioparameter recording (e.g. overnight pulse oximetry). A comprehensive overview of the tests used to diag- nose OSA, including, nocturnal polysomnogram, cardiorespiratory studies (respiratory polygraphy) and overnight pulse oximetry is shown in Video 18.5.2.1. The diagnostic tests for sleep-​related breathing disorders allow the measurement of apnoeas and hypopnoeas. An apnoea is defined as a complete cessation of airflow lasting for at least 10 seconds. Apnoeas are further classified as obstructive, central, or mixed based on whether there is respiratory effort during the event. A hypopnoea is defined as a reduction in airflow. Different cut-​off criteria are used for the required reduction in airflow; usually a 30% reduction for more than 10 seconds with a 4% reduction in oxygen saturation, or a 3% reduction in oxygen saturation with an arousal from sleep. The average number of apnoeas and hypopnoea per hour of sleep is de- fined as the apnoea-​hypopnoea index (AHI). The amount of noc- turnal hypoxia can be expressed as the oxygen desaturation index (ODI), mean oxygen saturation, the time spent with an oxygen desaturation of less than 90%, or the nadir saturation overnight. Overnight oximetry traces in a healthy person, and a patient with severe OSA are shown in Fig. 18.5.2.4. Complications and their mitigation Cardiovascular disease Physiological studies in animals and humans have identified bio- logically plausible mechanisms whereby OSA can cause cardio- vascular injury, including increased sympathetic nervous system activity, hypoxic and oxidative stress, systemic inflammation, and mechanical factors secondary to intrathoracic pressure oscillations such as reduced left ventricular stroke volume, systemic arterial pressure, cardiac output, and heart rate. Early studies in people with severe OSA showed a threefold in- creased likelihood of developing hypertension over 4 years, inde- pendent of other risk factors. Additionally, randomized treatment trials in patients with severe OSAS produced a 2–​3 mm Hg reduction in blood pressure sufficient to reduce vascular risk by about 20%. Subsequently the cardiovascular impact of OSAS has been estab- lished using community based epidemiological studies to show that people with untreated severe OSAS have an increased incidence of coronary heart disease, myocardial infarction, heart failure, stroke, and mortality after adjusting for established cardiovascular disease risk factors. Observational studies comparing OSAS patients treated with continuous positive airway pressure (CPAP) versus those not treated with CPAP have also found elevated cardiovascular risk in those with untreated OSAS. Whether or not to recommend OSA treatment in patients who do not report excessive daytime sleepiness is controversial, with some arguing that OSA should be treated even in subjects without daytime symptoms due to elevated cardiovascular risks. In a long-​ term observational cohort study, OSA with and without sleepiness was equally predictive of cardiovascular mortality. A multicentre randomized controlled trial of CPAP found no reduction in car- diovascular risk in minimally symptomatic OSA despite improve- ments in sleepiness. Furthermore, a meta-​analysis of randomized controlled treatment trials of CPAP on blood pressure in mildly symptomatic patients suggested CPAP treatment elevated blood pressure. Cerebrovascular disease Observational cohort studies within the general population have shown an increased risk of stroke in patients with moderate to severe OSA. However, it has been difficult to determine whether OSA preceded the stroke or was independent of the confounding risk factors of age, sex, smoking, BMI, diabetes mellitus, and car- diovascular disease. Longitudinal analysis of OSA and stroke risk found moderate to severe OSA (AHI ≥20) was associated with increased risk of stroke, whereas no increased risk was observed in patients with mild OSA. Others have also reported an in- creased incidence of stroke, including transient ischaemic attacks, or death from any cause in patients with pre-​existing OSA, and demonstrated a relationship between OSA severity and risk, inde- pendent of confounding factors. Taken together, these data sug- gest that a trial of CPAP treatment may be advised where the risk of stroke is high. Metabolic disease OSA is associated with obesity (Table 18.5.2.1). Observational co- hort studies have found that OSA is also associated with insulin resistance, which is correlated with the severity of OSA but inde- pendent of general obesity. It is postulated insulin resistance in OSA is due to visceral obesity and increased sympathetic drive from fre- quent arousals, intermittent hypoxia, and sleep fragmentation. The metabolic response to CPAP treatment has been variable and at this time randomized controlled trials do not support the use of CPAP Fig. 18.5.2.4  An example of overnight oxygen saturation, recorded by oximetry in a healthy person (left) and a patient with OSA (right). Note the hundreds of dips in oxygen saturation overnight in the patient with OSA.

18.5.2  Sleep-related breathing disorders 4055 treatment solely for treatment of metabolic syndrome in OSA in the absence of sleepiness symptoms. Social/​lifestyle impact OSAS patients experience mood changes, depression, and reduced quality of life that is attributed to reduced social functioning and vitality. Cognitive function OSAS is characterized by chronically fragmented sleep and day- time sleepiness both of which are thought to contribute to cog- nitive dysfunction, although the relative contributions of each remains poorly understood. More recently, chronic intermittent hypoxia has been proposed as a third factor contributing to neural inflammation. Research is now concentrated on the role of OSA on accelerated cognitive decline. It should be noted that in a subset of OSA patients who do not report daytime sleepiness, CPAP treat- ment has been proven to successfully improve memory and cog- nitive function. OSA and driving Daytime sleepiness impairs function and importantly increases ac- cident risk. OSAS patients are 2–​4 times more likely than healthy people to have road traffic accidents as a result of reduced alertness while driving. United Kingdom law (2015) stated that drivers are must tell the Driver and Vehicle Licensing Agency (DVLA) if they have OSAS, or OSA with symptoms that affects their ability to drive safely, who then send a questionnaire to the patient. In January 2016 new guide- lines were adopted to comply with the conclusions of a European Union OSA Working Group published in 2013 (see Ghosh et al., 2016). In an attempt to guide decision making here is now a require- ment to submit information about sleep test measurements, notably the AHI. Patients are advised to stop driving until their condition has been successfully treated. Licences are only revoked if sleepiness continues following treatment. Guidance for UK patients is given by the Sleep Apnoea Trust (see ‘Further reading’ and for healthcare professionals up-​to-​ date information can be found in the British Thoracic Society Driving and Obstructive Sleep Apnoea (OSA)/​Obstructive Sleep Apnoea Syndrome (OSAS) Position Statement (see ‘Further reading’). Management Treatments for OSA depend on the disease severity, patient symp- toms and the presence of cardiovascular or metabolic disease (Fig. 18.5.2.5). Treatments include advice on modifying lifestyle, including weight loss, stopping smoking, and increasing cardiovas- cular exercise, improving sleep opportunity and environment, op- timizing medical management of comorbidities, and reducing the use of stimulants such as caffeine, and substances such as alcohol, sedatives, and recreational drugs. Positional measures and oral mandibular advancement splints are recommended in mild to moderate OSAS, with upper airway and bariatric surgery also being considered by some patients. However, positive airway therapy is the mainstay treatment for pa- tients with moderate to severe OSA and as such will be the focus of this chapter. Positive airway therapy There are several variants of positive airway therapy including CPAP (see Video 18.5.2.2), auto-​titrating CPAP (autoCPAP), com- pensated pressure waveform, bilevel and adaptive servoventilation. Each of these modes may be used in the treatment of OSAS, al- though the last two are considered forms of ventilation and there is little evidence in the nonhypercapnic patients for their use however in selected cases these modes of respiratory support may be very useful. The use of overnight ventilation in overlap syndromes is covered in Chapter 18.15. Most evidence for the treatment of OSAS is based on CPAP and autoCPAP treatment. Multiple systematic reviews and meta-​ analyses of randomized controlled trials have assessed the efficacy of CPAP in OSAS. These data are summarized in National Institute of Clinical Excellence (NICE) systematic review and economic ana- lysis which supports the use of CPAP as the evidence-​based treat- ment of choice for moderate to severe OSAS in middle-​aged patients and more recent evidence has extended the evidence base for older people with OSAS. The therapeutic benefit of CPAP is typically defined as an im- provement in sleepiness, using the ESS (Fig. 18.5.2.3) as a measure of subjective sleepiness. The mean difference between patients treated with CPAP versus conservative (or placebo) treatment is a reduction of 2.7 points (95% CI interval –​3.45 to –​1.96) and the magnitude of change is greater in patients with severe symptoms (mean differ- ence in ESS –​5.0, 95% CI –​3.0 to –​1.6). Not only is CPAP efficacious, Mild OSA/UAR (AHI 5–15 events/hr) without symptoms Absence of CVD, Metabolic syndrome Lifestyle measures no specific treatment required Lifestyle measures consider MAS or CPAP Lifestyle measures CPAP Lifestyle measures CPAP Lifestyle measures CPAP Lifestyle measures consider MAS or CPAP Presence of CVD, Metabolic syndrome Absence of CVD, Metabolic syndrome Presence of CVD, Metabolic syndrome Mild OSA (AHI 5–15 events/hr) with symptoms Mod/severe OSA (15–30 events/hr) without symptoms Mod/severe OSA with symptoms Fig. 18.5.2.5  An algorithm for the treatment of mild, moderate, and severe obstructive sleep apnoea (OSA). CPAP, continuous positive airway pressure; CVD, cardiovascular disease; MAS, mandibular advancement splints; UAR, upper airway resistance.

section 18  Respiratory disorders 4056 it was also deemed to be cost-​effective treatment for moderate to severe OSA in well-​defined middle-​aged populations. The cost of CPAP therapy is approximately £4000 per quality-​adjusted life year gained; allowing for changes in sleepiness, quality of life, vascular risk, driving performance, and CPAP equipment costs. Adherence to CPAP The adherence to CPAP is estimated to range from 46% to 83%, with an average nightly usage of 2.39 hours per night in minimally symp- tomatic middle-​aged OSA patients and 2 hours 22 mins in older OSA patients at 12 months. This is somewhat lower than the 4 hours per night on 70% of nights which is commonly used as the benchmark for CPAP adherence, and less than the optimal outcomes archived with at a usage of least 5 hours per night. Factors that impact CPAP compliance are shown in Table 18.5.2.2. The percentage of patients who continue using their CPAP de- vice falls over time, (e.g. 84% at the end of the first year to 68% after 4 years), remaining at this level for a further 3 years. This equates to a discontinuation rate of 5% per annum over 4 years. The weighted average for studies that report discontinuation rates over more than 3 years was estimated to be 3.8% per annum. Telemedicine is increasingly being used in the management of chronic diseases and in the management of OSA patients it has been used to enable remote CPAP titration and follow-​up. It has also been used to provide additional feedback aimed at promoting and reinforcing CPAP adherence, with improved CPAP adherence and reduced associated symptoms observed in some, but not all, studies. The mechanisms for the improved CPAP adherence include early detection of issues such as air leak around the mask and nasal drying, with prompt intervention to improve mask fit and initiate humidification. Since adherence to CPAP in the first week of treat- ment has been shown to be a good marker of long-​term compliance, and intensive support has been shown to increase CPAP usage it is proposed that the use of telemonitoring in the early management of OSAS could improve CPAP compliance. Other treatment approaches Upper airway surgery Procedures vary depending on the amount of soft tissue and palate that is removed. Uvulopalatopharyngoplasty typically removes the tonsils and adenoids, plus tissue from the uvula, soft palate, and pha- ryngeal walls, to enlarge the airway lumen. Before upper airway sur- gery is recommended, it is important to establish the site of airway collapse. Unsuccessful surgery can cause complications (typically air leaks and nasal problems) if subsequent CPAP treatment is required. The use of laser or radiofrequency to scar and stiffen the uvula is a less radical surgical technique that is carried out to reduce snoring and mild sleep hypopneas. More radical maxillofacial surgical techniques are performed in a small number of patients to advance the maxilla and increase the size of the oropharyngeal airway lumen. Typically, these patients have specific craniofacial abnormalities, are young and nonobese. In these patients, high success rates are reported. Bariatric surgery Bariatric surgery has been shown to successfully treat OSAS as well as associated metabolic abnormalities. It is important to note these patients are particularly vulnerable during the perioperative period because of a predisposition towards airway collapse. Full multidis- ciplinary assessment prior to bariatric intervention is recommended. Oral mandibular advancement splints Evidence shows they are clinically effective in mild to moderate OSAS, reducing subjective sleepiness. Mandibular advancement splints are worn intraorally during sleep to bring the mandible and tongue forward, which reduces airway narrowing. There are many splints commercially available, ranging from simple self-​moulded, fixed devices, to bespoke splints that allow adjustment to gradually advance the jaw. A UK-​based study has shown that nonadjustable devices can produce clinically important improvements in mild to moderate OSAS and are cost-​effective. A microchip has been devel- oped that allows adherence or splint used to be monitored. However, tolerance can be an issue, with mouth problems, discomfort, and excess salivation being the most common side effects. Patients with significant periodontal disease or tooth decay, partial or complete edentulism, fixed orthodontic devices, or temporomandibular joint pain may find it difficult to use these devices. Positional therapy When patients with OSA are supine, the pharyngeal lumen is re- duced in size as the tongue and soft palate are pushed back due to gravitational force. Positional therapy should be considered in mild to moderate OSAS, when the disease severity is increased twofold during supine sleep. Moving to the lateral position can increase the size of the airway lumen and prevent collapse. Newer targeted vibro- tactile feedback to deter patients from the supine position is also now available. Central sleep apnoea Central sleep apnoea is much less common that OSA and caused by factors that disrupt the neural regulation of breathing, as in the example of heart failure described previously. Central sleep apnoea may also occur following stroke, or be induced by centrally acting drugs, with opioids being the most common respiratory depressant. Complex sleep apnoea is a term recently used in cases where patients with OSA develop central sleep apnoea following CPAP treatment. The term ‘complex’ therefore refers to combination of obstructive and central sleep apnoea. The symptoms of central sleep apnoea are similar to those of OSA. Apnoeas lead to awakenings and are sometimes associated with shortness of breath, especially in heart failure. However, daytime sleepiness appears to be less common in central sleep apnoea, com- pared to OSA; perhaps due to arousals from sleep being less intense. Symptoms of insomnia, mood changes, poor cognitive function, and difficulty in concentrating are all reported by patients with cen- tral sleep apnoea. Table 18.5.2.2  Predictors of poor CPAP adherence include Patient characteristics—​increased nasal resistance, depression Disease characteristics—​either severe or mild minimally symptomatic disease Psychological or social—​less self-​efficacy, poor social support, limited disease and/or treatment knowledge Technical—​lack of heated humidification and flexible pressure

18.5.2  Sleep-related breathing disorders 4057 The diagnosis of central sleep apnoea depends on documenting an absence of respiratory efforts during the apnoea; or reduced ef- forts during the hypopnoea. This can be very difficult to distinguish, especially as some patients have one or two obstructed breaths at the end of the apnoea due to passive collapse of the upper airway lumen, which is secondary to the central apnoea. The presence of snoring indicates obstruction to airflow, and can be used as a marker of OSA in most cases; however, snoring often occurs in complex sleep apnoea. Treatment of central sleep apnoea should be based on optimizing care of the underlying cause (e.g. heart failure). Specialized positive pressure support (e.g. adaptive servoventilation) may be considered in patients with both obstructive and central hypopnoea, and an ejection fraction of more than 45%. For patients who cannot tol- erate CPAP, nocturnal oxygen may be considered. For patients with ejection faction less than 45% and with mainly central sleep ap- noea, adaptive servoventilation is not recommended. In these cases noninvasive ventilation may be helpful as the first-​line therapy with a backup respiratory rate. Future pharmacological approaches may be useful in this patient group. Acetazolamide, a carbonic anhydrase inhibitor and diuretic, increases urinary bicarbonate ex- cretion lowering blood pH resulting in compensatory hyperventi- lation which modulates the apnoeic threshold, has been used in a research setting. Congenital central hypoventilation syndrome CCHS is a rare autosomal dominant inherited disease; approxi- mately 1000 individuals worldwide have been identified to date. Patients with CCHS hypoventilate or stop breathing during sleep. In these patients, chemosensitivity is reduced or absent and breathing during wakefulness is controlled via the motor cortex. The disease is usually diagnosed after birth in children and associated with mu- tations in the PHOX2B gene. These mutations inhibit the PHOX2B protein’s role in neuronal development of the autonomic nervous system, causing other co-morbidities such as Hirschsprung’s dis- ease. The patients have an increased risk of tumours, and learning may also be impaired, either due to sleep deprivation, or hypoxia- related neural damage. Eye abnormalities are also common. Patients also report a decreased pain threshold and difficulty in regulating body temperature (low body temperature). It is treated with long term nocturnal ventilation. Overlap syndromes Obstructive sleep apnoea plus chronic obstructive pulmonary disease Where OSA and COPD coexist there is a combined effect to worsen lung function with a greater risk of morbidity and mortality and re- duced quality of life. Nocturnal oxygenation is adversely affected, with nocturnal desaturation being more profound in overlap pa- tients due to the lover waking saturations exacerbating the sleep-​ related hypoventilation. Treatment may require oxygen therapy in addition to CPAP. The systemic consequence of OSA combined with COPD is cardiovas- cular disease, via shared pathways of inflammation and oxidative stress. Investigation of spirometry and lung volume measurements, as well as arterial blood gas analysis should be undertaken in pa- tients with OSA and a history of smoking. Obstructive sleep apnoea plus obesity
hypoventilation syndrome Obesity hypoventilation syndrome is defined as the combination of obesity (BMI >30 kg/​m2), sleep-​disordered breathing, and day- time hypercapnia. OSA is present in approximately 90% of patients with obesity hypoventilation syndrome. Nocturnal hypoventilation in these patients is due to an interaction of obesity-​related respira- tory impairment and OSA, and has several proposed mechanisms. A high AHI is an independent risk factor for the development of hypercapnia. The duration of the disordered breathing events and the interim period of relative hyperventilation are also thought to influence the loading/​unloading balance of CO2. Long-​term buf- fering and reductions in chemosensitivity, plus reduced respiratory drive lead to the presence of daytime hypercapnia. This is associated with significant morbidity and a greater risk of pulmonary hyper- tension and mortality. Bilevel positive pressure (NIV) may be necessary in symptomatic patients with daytime hypercapnia (Pco2 >7.3 kPa (>50 mm Hg)) primarily induced by nocturnal hypoventilation. However in pa- tients where OSA predominates, CPAP is the first-​line treatment. CPAP has also been shown to be effective in 50–​80% of patients with mild nocturnal hypoventilation and is assessed by the control of overnight AHI, SaO2, and PtcCO2 on CPAP therapy. Differential diagnosis for nonrespiratory sleep disorders There are several nonrespiratory sleep disorders that can produce excessive daytime sleepiness that should be considered in the dif- ferential diagnosis of sleep-​related breathing disorders. Periodic limb movements during sleep Periodic limb movements occur during NREM sleep, and frequently present in association with restless leg syndrome, which manifests during wakefulness usually in evening when tired. The periodic limb movements are simple, repetitive movements that cannot be controlled; often tightening of the lower leg muscles (e.g. flexing the foot). The movements tend to be of short duration (0.5 to 5 seconds) and occur every 20–​40 seconds for up to an hour (movements occurring after 90 seconds are not counted as peri- odic), usually just one leg is affected at a time. The movements do not delay sleep onset, but they can produce brief arousals from sleep that disrupt nocturnal sleep and can lead to daytime sleepiness. However, the limb movements do not always cause cortical arousals from sleep, and not all patients in whom arousals occur complain of daytime sleepiness. The bed partner can be disturbed by restlessness. Periodic limb movements are common in older people, and pa- tients with renal impairment (especially if on dialysis), those with low ferritin level, peripheral neuropathy, and previous sciatica. The limb movements are diagnosed on a nocturnal recording of limb electromyography, and/​or video. If symptomatic they may be treated with iron replacement, aiming for stores at the high end of the normal

section 18  Respiratory disorders 4058 range, or with dopaminergic agonists (e.g. ropinirole, pramipexole, L-​dopa, and rotigotine), benzodiazepines (e.g. clonazepam), opioids (e.g. codeine), or anticonvulsants (e.g. pregabalin and gabapentin). Restless legs syndrome This is typically described as an unpleasant sensation (burning and/​ or itching) in the legs, causing an overwhelming urge to move the legs. The syndrome is often worse when tired, making falling asleep, or laying still difficult. Women are more likely than men to develop the condition, sometimes triggered by the hormonal changes of pregnancy, and there may be a family history. It can cause patients to have reduced nocturnal sleep with an associated irritability and difficulty in concentration. Treatment is similar to that for periodic limb movement disorder. Narcolepsy Narcolepsy is produced by a reduction in the orexin (also known as hypocretin) neurons in the hypothalamus, which play a key role in maintaining the conscious state. The loss of neurones is thought to be immunological, and there is a very strong association with human leukocyte antigen (HLA) DQB1 0602 subtype (>95% compared to 30% in the general population). There is also thought to be a genetic predisposition that can produce a family history of narcolepsy. Narcolepsy is associated with a tetrad of symptoms: (1) excessive uncontrollable sleepiness ‘sleep attacks’; (2) cataplexy, loss of muscle tone/​falling in response to strong emotion or laughter); (3) hypna- gogic hallucinations, vivid disturbing dreams—​particularly at sleep onset; (4) plus sleep paralysis, persistence of REM atonia into wakefulness. Diagnosis is based on history, rather than a sleep study. Early-​ onset REM sleep, disrupted night time sleep patterns, and multiple daytime (refreshing) naps are helpful disease markers. A multiple sleep latency test (consisting of five opportunities of nap during the day spaced by 2 hour intervals) that results in a mean sleep latency of less than 8 minutes and two or more naps (20 minutes) that contain REM sleep strongly suggests narcolepsy. When available, measure- ment of orexin in cerebrospinal fluid can be used to aid diagnosis, and the patient can be HLA typed, with absence of the relevant HLA type strongly refuting the diagnosis Narcolepsy is a lifelong condition with multiple implications for lifestyle, employment, and driving. Specialist referral is required for diagnosis and management. See Chapter  24.5.2 for further discussion. Parasomnia Parasomnias are nonrespiratory disorders that manifest as un- wanted behaviour and events that occur during sleep. The behav- iours may be complex, but the patient remains asleep during the event, and importantly has no memory that it has occurred on waking, although patients often find their sleep is not refreshing. Parasomnias include behaviours that occur during NREM sleep, typically during the first half of the night, such as sleep walking, sleep talking, sleep eating, and bedwetting. Additionally arousal disorders such as confusion arousals, sleep terrors, and exploding head syndrome, and finally REM behaviour disorder, which occurs during REM sleep typically towards the end of the night. REM behaviour disorder is produced by damage to neurons in the pons (around the locus coeruleus) that cause a loss of the atonia normally present during REM sleep. It is often described as acting out vivid (and sometimes violent, action-​packed) dreams. The epi- sodes can result in injury to the patient or the bed partner and are likely to get worse with ageing. The diagnosis of parasomnia is based on history, and patients do not typically complain of excessive daytime sleepiness, although they may have fatigue. REM behaviour disorder typically occurs in older men, sometimes with neurologic comorbidity. More recent data suggests that approximately one-​third of patients with the con- dition go on to develop Parkinson’s disease, and up to 90% will de- velop multiple system atrophy. It can be treated with clonazepam, which generally reduces muscular tone. Patients should also be ad- vised on keeping the environment safe (e.g. removing furniture close to the bedside, and moving the bed away from any windows) and avoiding alcohol. See Chapter 24.5.3 for further discussion. Multisystem atrophy Patients with multisystem atrophy can present to respiratory sleep clinics with apparent snoring and sleep fragmentation. However, the ‘snoring’ can be caused by laryngeal abductor weakness and laryngeal closure during sleep, with inspiratory stridulous ob- struction. These patients can suddenly die from nocturnal re- spiratory arrest, but may be successfully treated with standard CPAP therapy. FURTHER READING Bratton DJ, Stradling JR, Barbe F, Kohler M (2014). Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea:  a meta-​analysis using individual patient data from four randomised controlled trials. Thorax, 69, 1128–​35. British Thoracic Society (2018). Position Statement:  Driving and Obstructive Sleep Apnoea (OSA) 2018. https://​www.brit-​ thoracic.org.uk/​document-​library/​about-​bts/​documents/​ position-​statement-​on-​driving-​and-​obstructive-​sleep-​apnoea/​ Craig SE, et al. (2012). Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minim- ally symptomatic obstructive sleep apnoea: the MOSAIC random- ised controlled trial. Thorax, 67, 1090–​6. Crook S, et al. (2019). Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials. Thorax, 74(4), 390–6. Ghosh, D., Mackay, T. W., & Riha, R. L. (2016). European Union directive 2014/​85/​EU on driver licensing in obstructive sleep ap- noea:  early experiences with its application in the UK. Breathe (Sheff), 12(3), e59–​e63. McDaid C, et  al. (2009). Continuous positive airway pressure de- vices for the treatment of obstructive sleep apnoea-​hypopnoea syn- drome: a systematic review and economic analysis. Health Technol Assess, 13, iii–​iv, xi–​xiv, 1–​119, 143–​274. McMillan A, et  al. (2014). Continuous positive airway pressure in older people with OSAS (PREDICT): a 12-​month, multicentre, ran- domised trial. Lancet Respir Med, 2, 804–​12. Rosenzweig I, Glasser M, Polsek D, Leschziner GD, Williams SC, Morrell MJ (2015). Sleep apnoea and the brain: a complex relation- ship. Lancet Respir Med, 3, 404–​14. Sleep Apnoea Trust (2018). Detailed DVLA guidance for UK drivers with sleep apnoea (updated September 2018). http://​www.sleep-​ap- noea-​trust.org/​detailed-​guidance-​to-​drivers.htm

18.6 Allergic rhinitis 4059 Stephen R. Durham and

18.6 Allergic rhinitis 4059 Stephen R. Durham and Hesham A. Saleh

ESSENTIALS Allergic rhinitis affects more than 20% of the population of Westernized countries and has a significant impact on quality of life and school/​work performance. Aetiology and clinical features—​important environmental factors
include tree and grass pollens (seasonal allergic rhinitis); house dust mite and domestic pets, most often cats (perennial allergic rhinitis); and a variety of occupational exposures (occupational rhinitis). Pathogenesis involves activation of type 2 (Th2) lympho- cytes resulting in IgE antibody production and tissue eosinophilia. Immediate symptoms (itching, sneezing, and watery nasal dis- charge) result from allergen cross-​linking adjacent IgE molecules on the surface of mast cells in the nasal mucosa, resulting in the release of histamine and tryptase, and generation of bradykinin. Diagnosis and classification—​diagnosis is usually straightforward and based on the history, examination, and (when indicated) the results of skin prick tests and/​or serum allergen-​specific IgE levels. Classification is according to the severity and duration of symptoms as defined by ARIA (allergic rhinitis and its impact on asthma) guide- lines, which describe four categories of disease: (1) mild intermittent; (2) moderate/​severe intermittent; (3) mild persistent; and (4) mod- erate/​severe persistent. Management—​allergen avoidance, topical intranasal cortico- steroids, and nonsedating oral antihistamines are the mainstays of treatment. Combination intranasal sprays containing a cor- ticosteroid and an antihistamine are recently available. Treat­ ment failure often results from poor compliance or inadequate
technique in use of nasal sprays. Allergen injection immunotherapy or sublingual immunotherapy is indicated in patients with severe seasonal allergic rhinitis who fail to respond to usual measures: both have been shown to induce long-​term disease remission. The reper- toire for immunotherapy has recently been extended to include pa- tients with perennial rhinitis and mild asthma due to house dust mite allergy. Rhinitis is often accompanied by significant comorbidities that include conjunctivitis, sinusitis, otitis media, and bronchial asthma: these require separate recognition and treatment. Introduction Rhinitis refers to inflammation of the nasal mucosa: in clinical terms it may be defined as symptoms of nasal itching, sneezing, watery discharge, or blockage, that occur for more than 1 h on most days. The lining of the nose and paranasal sinuses is in continuity with the lower respiratory tract such that diseases of the upper and lower airways frequently coexist. The World Health Organization position paper ‘Allergic Rhinitis and its Impact on Asthma’ (ARIA) recog- nized this association and provided a classification of the disease based on the severity and duration of symptoms, and a recent update provides the basis for the modern management. In this section a his- torical perspective and the aetiology, epidemiology, and pathogen- esis of allergic rhinitis are described, followed by practical guidelines for diagnosis and management. Finally, immunotherapy (desensi- tization), including novel approaches are discussed. Historical perspective The term ‘hay fever’ was originally coined by John Bostock in 1819. It is a misnomer, since the disease is not caused by hay and there is no fever. Nonetheless, the term highlighted the seasonality of the disease ‘being associated with the effluvium of hay’ and the associ- ation of severe hay fever with constitutional upset. William Gordon in 1829 referred to ‘the aroma emitted by the flowers of grass  . . . ’, whereas Elliotson in 1831 considered ‘. . . it [hay fever] to depend upon the flower of grass and probably the pollen’. Charles Blackley, a physician in Manchester, referred in 1873 to hay fever (Catarrhus Aestivus) as ‘an aristocratic disease . . . rarely, if ever, met with but among the educated’, and measured pollen counts in the air and re- lated them to the intensity of hay fever symptoms. He also repro- duced the disease in himself by experimental challenge with grass pollen, a technique still widely used today to investigate patho- genesis and to test novel treatment approaches. In 1911 Noon and Freeman published their classic paper on desensitization for hay fever. William Frankland, who was a student of Freeman at St Mary’s 18.6 Allergic rhinitis Stephen R. Durham and Hesham A. Saleh

section 18  Respiratory disorders 4060 Hospital, London, published the first randomized controlled trial of desensitization for hay fever in the same journal in 1958. Aetiology Both environmental and genetic factors are important in the aeti- ology of allergic rhinitis. Major causes include seasonal pollens, mould spores, and perennial allergens such as house dust mite and domestic pets. Potential occupational causes should not be missed. Climate change has altered the geographic distribution and timing of pollen exposures. Exposures to a farm lifestyle in early childhood has been shown to be protective against development of allergic rhinitis, asthma, and eczema. Environmental irritants such as tobacco smoke, exhaust fumes, and cold air may exacerbate allergic symptoms. Environmental allergens Seasonal allergic rhinitis The pollens of temperate grasses (including perennial rye, timothy, and cocksfoot) are major causes of seasonal rhinitis during sum- mertime. Grass pollen counts above 50/​m3 are considered high and are the threshold level at which most hay fever sufferers experience symptoms. Tree pollens (including from birch, alder, ash, and plane trees) cause symptoms during springtime. Weed pollens (Artemisia, Parietaria) and mould spores (Alternaria, Cladosporium, and Aspergillus species) predominate in the latter part of the summer and autumn (Fig. 18.6.1). Pollen allergy (particularly birch) is commonly associated with pollen-​food syndrome where sufferers experience imme- diate itching and swelling in the lips and mouth on eating apples, hazelnuts, and stone-​containing fruits such as plums, nectarines, peaches, and (occasionally) root vegetables (carrots, potatoes). Symptoms are generally mild, throat oedema may rarely occur, but anaphylaxis is not a feature. The syndrome results from cross-​ reactivity between the major birch pollen allergen (Bet v 1) and pro- teins (PR-​10 proteins) contained within the peel of offending fruits and vegetables. The allergens are heat labile such that the cooked foods are well-​tolerated. Perennial allergic rhinitis By far the commonest cause of perennial allergic symptoms are house dust mites (Dermatophagoides pteronyssinus, D. farinae, and Euroglyphus maynei). These are found in almost every home, where they live in the dust that accumulates in carpets, bedding, fabrics, and furniture. They live on shed human skin scales and thrive in temperatures of between 15 and 20°C and a relative humidity of 45–​ 65%, conditions which are typical of many modern centrally heated homes. The major allergen of the house dust mite (Der p 1) is a di- gestive enzyme (a cysteine protease) present in the gut and excreted in high concentrations in the mite faeces. Domestic pets are the second important cause of perennial al- lergy, relevant in up to 40% of children with asthma and/​or rhinitis. The major allergen (Fel d 1) is a salivary protein that is preened on to the fur and released on very small particles (<2.5 µm diameter) which remain airborne for many hours, explaining why a sensi- tized person can experience symptoms almost immediately upon entering a home containing a cat, without being directly exposed to the animal. Dog allergens are less well characterized (Can f 1). Cockroaches have been described as a cause of perennial allergic rhinitis and asthma, particularly in inner-​city areas. Food allergy is unusual as a primary cause of rhinitis in the ab- sence of other organ involvement. However, rhinitis may be one component of IgE-​mediated food-​induced symptoms commonly due to egg, milk, and nuts in children, and to nuts, fish, shellfish, and fruit in adults. Preservatives such as tartrazine, benzoates, and sulphites may provoke symptoms of rhinitis. Important drugs that can trigger rhinitis include β-​blockers, aspirin, and (occasionally) angiotensin converting enzyme (ACE) inhibitors. Occupational rhinitis Occupational rhinitis refers to rhinitis caused by an agent inhaled in the workplace. Like other causes of seasonal and perennial rhinitis, occupational rhinitis may also be associated with bronchial asthma. Occupations at risk include laboratory animal workers (rats, guinea pigs, mice), bakers (flour, grain mites), agricultural workers (cows, pollens, fungal spores), electronic solderers (colophony), paint sprayers (toluene di-​isocyanate, acid anhydrides), and health workers and other users of rubber gloves (latex). Genetic influences Atopy (the predisposition to develop allergic disorders as defined by a positive skin prick test or raised IgE antibody level to one or more common allergens) and allergic diseases such as hay fever and asthma occur as a complex interaction between genetic and envir- onmental factors. Twin studies in which a higher concordance rate Grass pollens Tree pollens Weed pollens Fungal spores Ash Pine Nettle dock Apr May Jun Jul Aug Sep Oct Timothy Rye Cocksfoot Meadow Dogstail Fescue etc. Birch plane Cladosporium Alternaria Fig. 18.6.1  Calendar of common seasonal aeroallergens. By courtesy of Professor A B Kay, Imperial College London.

18.6  Allergic rhinitis 4061 of atopy and allergic diseases is found in monozygotic twins com- pared to dizygotic twins provides unequivocal evidence of genetic influences. Candidate gene approaches (which study a narrow region of the genome around a suspected gene with highly polymorphic markers) have been difficult to interpret because of variability in the defin- ition of clinical phenotypes within atopy and allergy. Nonetheless, multiple genetic loci have been identified, including the high-​ affinity IgE receptor β-​chain (localized on chromosome 11q), and the interleukins IL-​4, IL-​3, IL-​5, IL-​9, IL-​13, the β-​glucocorticoid receptor, and leukotriene C4 (LTC4) synthase (all co-localized to chromosome 5q). All of these genes have biological functions con- sistent with a role in pathogenesis of allergic disorders. A genome-​wide association study identified strong linkage be- tween asthma and bronchial hyper-responsiveness with the gene for ADAM33, a cell surface protease that is part of the matrix metalloproteinase family, considered important in remodelling re- sponses in the basement membrane to damaged epithelium and airway smooth muscle. Another study identified novel suscepti- bility loci for allergic rhinitis that included genes associated with T lymphocytes, B lymphocytes, and epithelial cells. Epigenetic changes such as altered DNA-​methylation status of CD4 + T lymphocytes may also result in altered genetic susceptibility to developing allergic rhinitis. Epidemiology Recent estimates based on community surveys in Western Europe have suggested that approximately 20% of the population have per- ennial and/​or seasonal allergic rhinitis. Peak prevalence occurs between the second and the fourth decade, with some evidence of re- mission during adult life. The prevalence has increased over the past 4–​5 decades, placing an increased burden on medical services: for example, in the United Kingdom in 1955–​56 there were 5.1 consult- ations with general practitioners for hay fever per 1000 population per year; in 1981–​82 this had increased to 19.8. Some studies suggest that a plateau has now been reached. The increased prevalence of hay fever in countries with a ‘Westernized’ lifestyle, together with the known increased preva- lence associated with small sibships, has given rise to the ‘hygiene hypothesis’ which suggests that reduced exposure to bacterial pathogens may be the basis of the modern epidemic of allergic disorders. Further support comes from studies that have shown a strong protective effect of a farm lifestyle in early childhood against developing allergic disorders, likely due to an associated altered gut microbiome. These observations tie in with Blackley’s recognition of hay fever as a disease more common in the privileged classes over 140 years ago. Pathogenesis The cardinal features of allergic rhinitis are IgE production and tissue eosinophilia that are driven by an underlying Th2-​type T lymphocyte response. Immediate symptoms of allergic rhinitis occur as a consequence of allergen cross-​linking adjacent IgE molecules on the surface of mast cells in the nasal mucosa (in Coombs’ classification, type I, immediate hypersensitivity). This results in the release of granule-​ derived mediators, including histamine and tryptase, and the gen- eration of bradykinin. IgE-​dependent activation of mast cells also results in the release of newly formed membrane-​associated medi- ators derived from arachidonic acid associated with the membrane lipid, including LTC4, LTD4, LTE4, and prostaglandin D2. Other characteristic features of allergic rhinitis include tissue eosinophilia and the epithelial migration of inflammatory cells, including mast cells and basophils, during natural allergen exposure. These events occur under the regulation of a distinct population of T lymphocytes, Th2 CD4 + T cells. Th 2 cytokines released include interleukin 4 (IL-​4) and IL-​13 that induce B-​cell switching in favour of IgE production, and IL-​5 and granulocyte macrophage-​colony stimulating factor (GM-​CSF) that result in production and release of eosinophils from the bone marrow and their prolonged survival in tissues due to inhibition of apoptosis. The localization of a popu- lation of innate lymphoid cells (innate lymphoid type 2 cells (ILC2s) that do not express the T-​cell receptor (CD3-​negative) and therefore are unable to respond directly to allergen, whilst remaining capable of producing large amounts of type 2 cytokines, particularly IL-​5 and IL-​13, is likely to augment and sustain type 2 inflammation in allergic rhinitis. These features are similar to events occurring in the bronchial mucosa in allergic asthma. In contrast, there are no asso- ciated features of airway remodelling such as basement membrane zone thickening, mucus gland hypertrophy, nor of the epithelial dis- ruption that characterizes asthma. The mechanism of selective localization of Th2 lymphocytes, eo- sinophils, and basophils to the nasal mucosa is likely due to their sur- face expression of the chemokine receptors (CCR3 and CCR4) and the selective release of their ligands—​eotaxin, monocyte-​derived chemokine, and thymocyte-​associated and released chemokine during allergic reactions. Experimental nasal allergen provocation in humans with grass pollen extract in allergic subjects results in release of tryptase within minutes and increases in Th2 cytokines and eosinophil-​derived protein eosinophil cationic protein during the late-​phase at 4–​12 hours following challenge. Influence of treatment on T-​cell and antibody responses in allergic rhinitis Whereas intranasal corticosteroids act by inhibiting the pro- duction of Th2 cytokines within the nasal mucosa, allergen im- munotherapy has been shown to induce long-​lived changes in the mucosal Th2/​Th1 balance in favour of interferon-γ-producing Th1 cells. In addition, immunotherapy induces antigen-​ specific T regulatory cells that express the transcription factor FOXP 3. Distinct T regulatory cell subsets have been shown to downregulate Th2 responses directly by mechanisms involving cell–​cell contact and by the production of the inhibitory cyto- kines IL-​10 and TGFβ (Fig. 18.6.2). In addition to their effects on Th2 cells, these cytokines induce B-​cell switching, respectively, in favour of allergen-​specific IgG4 and IgA. These ‘protective’ anti- bodies are noninflammatory and compete with IgE for allergen and inhibit the formation of allergen-​IgE complexes, thereby preventing mast cell IgE-​cross-​linking and IgE-​facilitated activa- tion of T cells. These long-​lived changes in memory T cells and B cells underpin the induction of long-​term antigen-​specific toler- ance following immunotherapy.

section 18  Respiratory disorders 4062 Clinical diagnosis The diagnosis of allergic rhinitis is usually straightforward (Fig. 18.6.3), but the differential diagnosis should be considered in every case: frequently more than one cause coexists. History A careful history is essential both to establish the diagnosis of rhinitis and to assess the severity of symptoms. An allergic aetiology is sug- gested by dominant itching, sneezing, and watery nasal discharge. Associated eye or chest symptoms (asthma) also point to an allergic cause, and a history of potential allergic triggers should always be sought. However, in addition to provoking immediate nasal symp- toms, allergen may also cause late symptoms several hours after ex- posure, and these may not be recognized as being related. A history of potential allergic triggers includes enquiry into the seasonality of symptoms and whether symptoms are work related (i.e. do they occur at work or in the evening following work, with improvement at weekends and during holiday periods). The home environment, including the presence of domestic pets, birds, fitted carpets, central heating, and the use of blankets on beds should be established. A personal or family history of atopy is extremely common in patients with allergic rhinitis. There are many alternative causes of rhinitis symptoms. It is common for there to be more than one cause, and important to consider the differential diagnosis (Box 18.6.1). The presence of facial pain, fever, systemic upset, and mucopurulent discharge suggests infection. Nasal obstruction, which alternates with the nasal cycle, is common to both allergic and infective causes. Nasal crusting and/​or bleeding may occur in granulomatous disorders, atrophic rhinitis, or (rarely) tumours (particularly if associated with persistent unilateral symptoms). Impaired taste and/​or smell may occur with many forms of rhinitis, but is particularly common with nasal polyposis and may occasionally follow trauma (olfactory nerve damage). Box 18.6.1  Causes of rhinitis • Allergic -​ Seasonal (tree or grass pollens) -​ Perennial (house dust mite, domestic pets) -​ Occupational (latex, laboratory animals, antibiotics, and so on) • Nonallergic -​ Infective (acute, chronic) -​ Autonomic -​ Hormonal (premenstrual, pregnancy, hypothyroidism) -​ Drugs (aspirin, β-​blockers) -​ Mucociliary abnormalities (Kartagener’s, Young’s syndromes) -​ Immunodeficiency syndromes (congenital and acquired, includ­ ing HIV) -​ Atrophic -​ Idiopathic • Differential diagnosis -​ Structural (polyps, deflected nasal septum, etc) -​ Connective tissue disorders -​ Granulomatous disorders (sarcoid, granulomatosis with polyangiitis) -​ Tumours (benign, malignant) -​ Cerebrospinal fluid rhinorrhoea (secondary to trauma or surgery) Fig. 18.6.2  Pathogenesis of allergic rhinitis and influence of treatment. Th2 cells are predominantly T lymphocytes, although mast cells, basophils, and eosinophils represent alternative sources of Th2-​type cytokines. Topical corticosteroids down-​regulate the production of Th2-​type cytokines from T lymphocytes and other cells. Allergen immunotherapy acts by immune-​deviation of Th2 responses in favour of Th1 responses and/​or by inducing a population of antigen-​specific T regulatory cells. Both mechanisms may act directly to downregulate Th2 responses and indirectly by inducing ‘protective’ antibody responses. APC, antigen presenting cell; IFN, interferon; Ig, immunoglobulin; IL, interleukin; TGF, transforming growth factor; Tr, regulatory T cell. Rhinitis definition 2 or more symptoms for > 1 hour on most days Allergy (seasonal, perennial, or occupational) Infection (acute or chronic) Structural (polyps, septum, turbinates, etc) Other (idiopathic, NARES, hormonal, etc) Nasal discharge Blockage Sneeze/itch History Examination Skin-prick tests/RAST Fig. 18.6.3  Diagnostic approach to patients presenting with nasal symptoms. A careful history, clinical examination, and skin prick tests and/​or measurement of serum allergen-​specific IgE (RAST or ELISA) should be performed in every case. More than one cause may be present. ‘Other’ causes include hormonal (pregnancy, premenstrual), drugs (aspirin, β-​blockers, ACE inhibitors, cocaine abuse, and atrophic, postsurgical, and ageing). Idiopathic rhinitis refers to nasal hyperreactivity of unknown cause, manifest as an exaggerated response to nonspecific stimuli such as changes in temperature, tobacco smoke, domestic sprays, and other possible factors. The differential diagnosis includes vasculitis (Churg–​Strauss syndrome), granulomatous conditions (Wegener’s, sarcoidosis), atrophy (old age, surgical), and—​rarely—​tumours of the nose and paranasal sinuses.

18.6  Allergic rhinitis 4063 The presence of infertility and recurrent respiratory infections (including bronchiectasis) should raise the possibility of mucus ab- normalities (Young’s syndrome or cystic fibrosis) or ciliary dysfunc- tion (primary ciliary dyskinesia, Kartagener’s syndrome). Recurrent respiratory infections or a history of chronic rhinosinusitis should also raise the possibility of immune deficiency disorders including hypogammaglobulinaemia and AIDS. Hormonal imbalance (premenstrual symptoms, pregnancy, hypothyroidism, or acromegaly) may be associated with rhinitis. A history of trauma or previous nasal surgery should be sought. Enquiry regarding associated chest disease is important. Rhinitis and asthma frequently coexist and recognition and appropriate treatment of rhinitis may potentially also improve the control of asthma. Similarly, allergic conjunctivitis may be particularly bothersome in patients with seasonal disease and requires recog- nition and treatment. A very common cause of treatment failure is poor adherence with treatment. The efficacy, frequency, and regularity of previous treat- ments should be carefully documented. The patient’s perception of possible side effects of treatment, particularly corticosteroids including steroid nasal sprays, is a frequently missed cause of poor compliance. Nasal spray technique should be checked as poor tech- nique is another potential cause of treatment failure. Examination Local examination may be performed with a head mirror/​headlamp and speculum or an auriscope. Allergic rhinitis is accompanied by a pale ‘boggy’ appearance of the nasal mucosa only if the patient has current symptoms. A red inflamed appearance with pus suggests an infective cause. A granular appearance with fine pale nodules is diagnostic of sarcoidosis. Enlarged turbinates may be confused with polyps by the unwary. If doubt exists, further examination with a rigid and/​or flexible endoscope should be performed (Fig 18.6.4). The identification of structural abnormalities such as polyps, de- flected nasal septum, or enlarged turbinates is important: surgical treatment may be indicated (a major advance being the development of minimally invasive endoscopic sinus surgery). Examination of the nose should also include tests of smell and examination of the ears, eyes, mouth, and throat. Examination of the chest, skin and general examination should be performed, and peak expiratory flow and/​or spirometry measured when indicated in view of the common association of nasal disease with lower respiratory tract and systemic conditions. Investigations Skin prick tests In the presence of a clear history, particularly of seasonal hay fever symptoms, skin prick testing is not essential. However, skin prick tests are useful for several reasons (Box 18.6.2). They should only be interpreted in conjunction with the clinical history, and not per- formed when the patient is taking antihistamines. In these circum- stances, measurement of serum IgE antibodies by enzyme-​linked immunosorbent assay (ELISA) is indicated. Skin prick tests should employ standardized commercially avail- able allergen extracts in aqueous solution that are in-​date and have been stored at –​4oC. Prick tests are performed with a sterile 23-​gauge needle or lancet, which is lightly inserted through the epidermis without inducing bleeding. Responses are recorded as the mean weal diameter at 15 minutes, a positive test being defined as a weal diameter 3 mm greater than that of the negative control (allergen diluent). In pollen-​food syndrome, where the offending allergens are heat labile and unstable with storage, then prick–​prick testing may be performed by pricking through the surface of the fruit before pricking the skin with the same needle. Allergen-​specific IgE To obtain objective confirmation of IgE sensitivity in the context of a relevant clinical history, measurement of serum allergen-​specific IgE is an alternative to skin prick testing, particularly in patients with severe eczema, dermographism, or if antihistamines have been taken in the preceding 1–​3 days. In general, IgE-​testing is less Fig. 18.6.4  (a) An endoscopic view of the left nasal cavity in a patient with allergic rhinitis. Note the pale colour of the nasal septum and turbinate in addition to the clear secretions. (b) An endoscopic view of nasal polyps in the left nasal cavity. Polyps have glistening greyish colour in contrast to the red colour of the turbinate and rest of the nasal mucosa. (c) A coronal CT section of the nasal cavity and sinuses showing extensive opacification in a patient with severe chronic rhinosinusitis.

section 18  Respiratory disorders 4064 sensitive than skin prick testing although there is access to testing with a wider panel of potential allergens. Advances in molecular cloning have led to the characterization of many major allergen components of common inhalant and food allergens (a ‘major’ allergen component is one that is recognized by more than 50% of allergic individuals). By use of allergen micro- chip technology it is now possible to obtain component-​resolved diagnosis, which may allow more accurate allergy diagnosis and re- solve irrelevant allergen cross-​reactivities. For example, there are 13 known grass pollen allergens, whereas Phleum p 1 (Phl p 1) and Phl p 5 are the dominant major allergens responsible for summer hay fever. In the context of symptoms during the summer months, the detection of IgE to Phl p 1 and Ph p 5 therefore confirms clinically relevant IgE sensitivity to grass pollen. In contrast, the detection of IgE to Phl p 12 is likely due to cross-​reactivity with the birch-​derived profilin Bet v 2. In the absence of a history of springtime symptoms associated with a positive IgE to the major birch allergen Bet v 1, the patient may exhibit a false-​positive skin test to birch pollen extract due to presence of IgE to the irrelevant cross-​reacting profilin Ph p12. Such considerations are helpful in selecting suitable patients and the relevant allergen extract for allergen immunotherapy. Component-​resolved diagnosis may also be valuable for risk as- sessment in patients with pollen-​food syndrome. For example, cross-​reactivity between Bet v 1 and the hazel nut allergen Cor a 1 results in pollen-​food syndrome with symptoms confined to local itching and swelling in the mouth, whereas Cor a 14 reactivity is as- sociated with true food allergy with an increased risk of anaphylaxis on eating hazelnut. Treatment Treatment for allergic rhinitis involves the avoidance of provoking allergens where possible and the use of topical corticosteroids and H1 selective antihistamines. Allergen immunotherapy has a place in patients who do not respond to these measures. The approach is summarized in Box 18.6.3 and in relation to the ARIA classifi- cation (Fig. 18.6.5), which emphasizes that rhinitis and asthma are commonly associated and that patients with one condition often also have the other. Allergen avoidance It is impossible to avoid pollens, although sensible advice includes wearing sunglasses and keeping car windows tightly shut. All win- dows should be kept closed, particularly in high buildings. Walking in parks and wide open spaces should be avoided, particularly during the late afternoon or evening when pollen counts are highest. A holiday by the sea or abroad during the peak pollen season may be helpful. House dust mite control and avoidance measures should be con- sidered in sensitive individuals with disease. Although some success has been achieved in children, the value of mite avoidance meas- ures in adults, such as a single intervention with mite-​proof bedding, has been questioned. Further studies involving more effective and multiple interventions are needed, including—​in addition to covers for the pillow, duvet, and mattress—​restriction of soft toys, which should be washable, changing to hardwood, vinyl, or cork flooring, and thorough vacuum cleaning and damp-​dusting at least once weekly. There is no firm evidence to recommend the additional use of air conditioners, air ionizers, or acaracides. Saline irrigation Isotonic saline irrigation in adults and children with allergic rhin- itis is well tolerated, inexpensive, and may be used regularly with no Box 18.6.3  Treatment of allergic rhinitis • Allergen avoidance (house dust mite, animal dander, occupational causes) • Oral nonsedating antihistamines, or intranasal antihistamines • Topical corticosteroids; check technique and place emphasis on regular use • Intranasal spray containing combined corticosteroid and antihistamine • Topical sodium cromoglycate, nedocromil, or antihistamine for eye symptoms • Immunotherapy in pollen-​sensitive patients unresponsive to the aforementioned measures • If the patient fails to respond, review the diagnosis and treat any asso- ciated conditions (e.g. antibiotics for infection, surgery for structural problems) Box 18.6.2  Advantages of skin prick tests • They diagnose atopy—​the underlying predisposition to develop al- lergic disorders • They provide helpful supportive evidence (positive or negative) for the clinical history • They are essential when potentially expensive and time-​consuming environmental control measures, the removal of a family pet, or a change of occupation are involved • They have educational value, providing a clear illustration to the pa- tient and reinforcing verbal advice A useful basic skin prick testing kit should include the following: • a positive control (histamine 10 mg/​ml) • a negative control (allergen diluent solution) • house dust mite (D. pteronyssinus) • grass pollen • cat fur • Aspergillus fumigatus mild intermittent mild persistent moderate severe intermittent moderate severe persistent allergen and irritant avoidance immunotherapy intranasal decongestant (<10 days) or oral decongestant intranasal steroid oral or local nonsedative H1-blocker Fig. 18.6.5  A stepwise approach to management of allergic rhinitis. Classification of rhinitis according to ARIA guidelines.

18.6  Allergic rhinitis 4065 evidence of adverse effects on health. Isotonic saline is available on prescription as a pressurized aerosol nasal spray and commercially as a high-​volume, low-​pressure irrigation device. Where animal exposure is relevant, there is frequent resistance to advice to remove a family pet. However, patients can be advised to not replace animals, to confine them to the kitchen or outdoors where possible, and to avoid contact with animals or with individ- uals with clothing contaminated with animal dander. Pharmacotherapy The availability of potent specific histamine H1 receptor antagonists with a low potential for anticholinergic side effects and a low seda- tive profile has been a major advance. Antihistamines are particu- larly effective for sneezing, itching, and watery nasal discharge, but unlike topical corticosteroids they have less effect on nasal blockage. They are also effective for eye and throat symptoms. A rare but important complication of older antihistamines, including terfenadine and astemizole, is prolongation of the QT interval on the ECG. This only occurs when doses in excess of those recommended are employed, or in the presence of hepatic impair- ment or concomitant use of ketoconazole or erythromycin, both of which modify the hepatic metabolism of terfenadine. Modern antihistamines including acrivastine, loratadine, desloratadine, cetirizine, l-​cetirizine, fexofenadine, and mizolastine are effective H1 antihistamines with an extremely low (or absent) potential for cardiac side effects. H1-​selective antihistamines can also be given as a topical nasal spray (azelastine) which is more effective than an oral antihistamine in reducing rhinitis but without impact on histamine-​mediated ef- fects elsewhere such as the skin. Antihistamines should be avoided when possible during pregnancy, particularly during the first tri- mester. If antihistamines are considered essential then recent guide- lines from the United States Food and Drug Administration include (category B) the use of loratadine and cetirizine. Topical corticosteroids are highly effective in allergic rhinitis, superior to oral antihistamine and leukotriene antagonists, and are first-​line treatment in patients with moderate–​severe disease. Preparations include beclomethasone dipropionate, budesonide, fluticasone propionate, triamcinolone acetonide, fluticasone furoate, and mometasone furoate. Aqueous formulations are better tolerated and have a better local distribution in the nose. Recent data suggests that intranasal steroids may also improve allergic eye symptoms by suppressing the nasolacrimal reflex. Treatment should begin be- fore the hay fever season for maximal effect, and the importance of regular treatment, even when symptoms are absent, should be em- phasized. Ease of use of different devices may influence adherence with treatment. Side effects are minor, although around 5% develop nose bleeds which is a class effect and may require their discontinu- ation. Systemic effects are virtually absent at conventional doses, but caution should be exercised in children, particularly those receiving additional corticosteroids by other routes (e.g. for associated asthma and/​or eczema). The topical anticholinergic agent ipratropium bromide is a potent inhibitor of glandular secretion and may be effective where watery nasal discharge is the dominant symptom, uncontrolled by the measures described here earlier. Sodium cromoglycate is available as a topical nasal spray for use four times daily. It is less effective than topical corticosteroids. Topical cromoglycate eye drops are effective for allergic eye symp- toms. Olopatadine (an antihistamine) eye drops have the advantage of a longer duration of action, allowing twice daily administration. A combination nasal spray containing fluticasone propionate and azelastine has recently been shown to have an earlier onset of ac- tion and be more effective for allergic rhinoconjunctivitis than ei- ther drug administered separately. At present it should be reserved for patients who do not respond to intranasal corticosteroids alone. In patients whose symptoms are not otherwise controlled, there is a place for a short course of prednisolone (e.g. 20 mg daily for 5 days). This approach may unblock the nose, thereby improving access for topical corticosteroids, which may then be more effective. Topical decongestants (oxymetazoline) are effective in treating nasal blockage, although they should only be used for short periods (no more than 2 weeks) in view of the risk of tachyphylaxis and rebound persistent nasal blockage (so-​called rhinitis medicamentosa). Allergen immunotherapy Immunotherapy (desensitization) is a treatment option in patients with severe summer hay fever unresponsive to topical steroids and antihistamines, and in those reluctant to take long-​term medica- tion. This involves the subcutaneous injection of increasing con- centrations of allergen (standardized pollen extract) at weekly intervals for 6–​12 weeks, followed by monthly injections of a main- tenance dose for 3 years. It should only be given by those who are properly trained, with adrenaline (epinephrine) and facilities for cardiopulmonary resuscitation immediately available. In view of known occasional systemic side effects following injections, pa- tients should be kept under medical observation for at least 60 min following injections. Randomized controlled trials have confirmed the efficacy of immunotherapy, particularly for patients with summer hay fever. Recent studies have also shown efficacy in those with perennial rhinitis due to house dust mite allergy, although careful selection of patients in whom mite is the dominant cause of symptoms is required. Perennial rhinitis is frequently heterogeneous with mul- tiple allergic sensitivities and/​or other causes of ongoing symp- toms. The risk/​benefit ratio is less favourable in patients with chronic bronchial asthma, in whom the risks of systemic adverse reactions are greater. Recent data suggests that pollen immunotherapy may confer long-​term benefits including prolonged disease remission, preven- tion of onset of new sensitizations and—​in one controlled trial—​a threefold reduction in the risk of progression of rhinitis to asthma in children with pollen-​induced rhinitis that persisted for 10 years after initiating treatment. The data suggest that allergen immunotherapy, unlike pharmacotherapy, has the potential to modify the course of the disease (see proposed mechanisms in Fig. 18.6.2). The sublingual route has emerged as an effective and safe alterna- tive form of immunotherapy suitable for home use, although the ini- tial prescription and first dose should be administered by physicians trained in the diagnosis and treatment of allergic disorders. Recent data confirms efficacy of sublingual treatment in perennial mite al- lergy and that 3 years’ grass pollen sublingual immunotherapy con- fers long-​term benefits for at least 2 years after discontinuation of the treatment. At present there is equipoise regarding choice of either the injection or sublingual route for immunotherapy. Both treat- ments are effective, but the sublingual route appears safer and can

section 18  Respiratory disorders 4066 be self-​administered. An adequately powered head-​to-​head trial of allergen vaccines of proven value is needed. Future prospects for immunotherapy include the use of adju- vants (lipopolysaccharide derivatives, bacterial CpG-​containing DNA oligonucleotides) combined with conventional allergen ex- tracts for subcutaneous immunotherapy, and the use of recom- binant natural allergens and their mutated hypoallergenic variants. In addition to proven sublingual immunotherapy, alternative routes currently being tested include intradermal administration and the intralymphatic route involving direct injection of allergen into the inguinal lymph nodes under ultrasound guidance. Low-​molecular-​ weight allergen peptides have the potential to modify human T-​cell responses with clinical benefit without the potential for IgE cross-​ linking and attendant risk of serious IgE-​mediated side effects. T-​ cell peptides derived from the major cat allergen Fel d 1 have been shown to be effective in an environmental chamber model and a phase 3 trial is ongoing. All these approaches aim to improve safety and tolerability while preserving the efficacy and long-​term benefits that are associated with the subcutaneous and sublingual routes. Role of surgery For the small group of patients with allergic rhinitis and predom- inant nasal obstruction and no appreciable response to medical therapy, surgery may be indicated. Clinically, significant inferior turbinate hypertrophy must be present for surgery to be effective. Inferior turbinate reduction is mostly preformed endoscopically and can be done under local or general anaesthetic. Submucous resection together without fracture of the turbinate bone is the most effective method. In some patients with allergic rhinitis, symptoms of chronic rhinosinusitis may prevail. These may include postnasal drip/​puru- lence, sinus pain/​pressure and hyposmia in addition to endoscopic signs of infection/​inflammation. In these patients CT scanning and the need for surgery is assessed if medical treatment fails. FURTHER READING Berings M, et al. (2017). Advances and highlights in allergen immuno- therapy: on the way to sustained clinical and immunologic toler- ance. J Allergy Clin Immunol, 140, 1250–67. Brozek JL, et al. (2017). Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines - 2016 revision. J Allergy Clin Immunol, 140, 950–8. Eifan AO, Durham SR (2016). Pathogenesis of rhinitis. Clin Exp Allergy, 46, 1139–​51. Matsuoka T, Shamji MH, Durham SR (2013). Allergen immuno- therapy and tolerance. Allergol Int, 62, 403–​13. Scadding GK, et al. (2017). BSACI guideline for the diagnosis and management of allergic and non-allergic rhinitis (Revised Edition 2017; First edition 2007). Clin Exp Allergy, 47, 856–​89. Seidman M, et al. (2015). Clinical practice guideline: allergic rhinitis. Otolaryngol Head Neck Surg, 152(1 Suppl), S1–​43. Slovick A, Durham SR, Till SJ (2014). Grass pollen immunotherapy for treatment of allergic rhinitis. BMJ, 349, g6586.

18.7 Asthma 4067 Alexandra Nanzer- Kelly, Paul Cul

18.7 Asthma 4067 Alexandra Nanzer- Kelly, Paul Cullinan, and Andrew Menzies- Gow

ESSENTIALS Asthma is a chronic inflammatory disease of the bronchial airways that is characterized pathologically by a desquamative eosino- philic bronchitis and clinically by reversible airway narrowing and increased airway responsiveness to nonspecific provocative stimuli. The condition is common, frequently disabling, and can cause death. In the Western world it now affects more than 10% of children and more than 5% of adults, and in England and Wales it is the cause of more than 100 000 hospital admissions and is the certified cause of death of 1000–​1500 people each year. Asthma triggers The risk of developing asthma is increased in atopic individuals, and in asthmatics natural allergen exposure induces asthma and airway hyper-​responsiveness. Viral infections, most commonly with rhino- viruses, cause 80–​85% of exacerbations of asthma in children and 50–​75% in adults. Occupational asthma—​agents inhaled at work can be the primary cause (induce) or can exacerbate (provoke) asthma. Such occupa- tional asthma may be due to inhalation of irritant chemicals (‘irritant-​ induced asthma’) or substances that induce an allergic reaction (‘hypersensitivity-​induced asthma’). Drugs—​some can exacerbate asthma, with β-​blockers and non-​ steroidal anti-​inflammatory drugs being the most important. Clinical features History—​symptoms are nonspecific, typically shortness of breath, wheezing, chest tightness, and cough. They are usually variable in severity over short periods of time, but can be persistent, and are typically worse at night. Because occupational causes are poten- tially avoidable, all cases of asthma that have occurred or recurred in adult life should be questioned about symptomatic improvement when away from work, and, if present, enquiry made about potential causes of asthma in the workplace. Clinical examination—​outside the context of an acute exacerba- tion, the physical signs of mild or moderate asthma may be limited to expiratory polyphonic wheezes audible over the lungs. Because of the variable nature of airway narrowing some patients have normal lung sounds, but this would not be expected in those with persistent symptomatic asthma. Diagnosis Asthma needs to be differentiated from localized airways obstruc- tion, other causes of generalized airways obstruction, and other causes of intermittent breathlessness. Demonstration of airflow limitation—​asthma is most typically diag- nosed by the demonstration that this varies spontaneously over short periods of time, or improves after inhalation of a short-​acting β-​agonist or, over a more prolonged period of time, use of a cortico- steroid either by inhalation or by mouth. The most clinically useful measurements of airflow limitation are (1) forced expiratory volume in 1 s (FEV1), which may be expressed as a proportion of the forced vital capacity (FVC) as FEV1/​FVC%, and (2) peak expiratory flow rate. Occupational asthma—​(1) in irritant-​induced asthma, the associ- ation of the onset of asthma with inhalation of a toxic chemical is usually clear; (2) in hypersensitivity-​induced asthma the diagnosis depends on (a) exposure to a sensitizing agent at work; (b) a char- acteristic history of onset of asthma after an initial symptom-​free period of exposure, with deterioration in symptoms during periods at work and improvements during absence from work; and (c) the re- sults of objective investigations—​lung function tests, immunological tests, and inhalation tests. Classification—​patients with asthma can be categorized, at any one time, by whether their symptoms are intermittent or persistent, and by the severity of their symptoms and underlying airway narrowing (measured by lung function tests). Management aims The aims of treating patients with intermittent or persistent asthma are to: (1) educate the patient about their disease and the object- ives of its management; (2) minimize or eliminate asthma symptoms; (3)  achieve best possible lung function and prevent an acceler- ated decline in lung function; (4) prevent exacerbations of asthma; (5) achieve these objectives with fewest drugs, keeping short-​term and long-​term adverse effects to a minimum. The objectives for effective asthma control in individual patients are to: (1) allow normal daytime activities as well as the ability to enjoy physically demanding activities; (2) permit sleeping through night, without being awoken by respiratory symptoms; (3) achieve a situation where use of ‘rescue’ medication with inhaled β2-​agonists is needed less than once per day; (4) achieve normal or near normal 18.7 Asthma Alexandra Nanzer-​Kelly, Paul Cullinan, and Andrew Menzies-​Gow

section 18  Respiratory disorders 4068 peak expiratory flow rate and FEV1 with less than 20% variability be- tween best and worst values; (5) to avoid drug side effects. Education—​there is clear evidence that patient education to en- able adults to manage their asthma can reduce the frequency of unscheduled visits to general practitioners, hospital admissions, and time off work. The four important components of effective patient education are (1) information, (2) self-​monitoring, (3) regular med- ical review, and (4) having a written action plan. Avoidance of precipitants—​the identification and, where feasible, the avoidance of relevant allergens at home or at work is an essential part of the management of asthma. A ‘stepped’ approach to treatment is the basis of current guidelines for asthma management: Step 1—​mild intermittent asthma is controlled by the use of an in- haled shorter-​acting β2-​agonist (e.g. salbutamol or terbutaline) less than once a day. Requirement for more regular treatment implies the need for regular anti-​inflammatory treatment (i.e. a higher step). Step 2—​mild persistent or intermittent asthma that is of suffi- cient frequency to require regular anti-​inflammatory treatment. Treatment with an inhaled corticosteroid should be started at a dose of beclometasone 400 µg twice daily (or equivalent) in adults and continued for at least 3 months, before reducing the dose to the min- imum required to maintain good control. Short-​acting β2-​agonists are used as required for symptomatic relief. Step 3—​moderate persistent asthma that is not controlled by Step 1 and Step 2. The treatment of choice is the addition of a long-​acting β2-​agonist. If it provides benefit but asthma remains inadequately controlled, the dose of inhaled corticosteroid should be doubled. If it provides no benefit it should be discontinued and the inhaled steroid dose doubled, and if this does not provide adequate control a trial of other treatments such as a slow-​release theophylline or leukotriene antagonist should be instituted. Step 4—​asthma control remains poor despite the measures re- commended in Step 3.  Consideration should be given to further increasing the dose of the inhaled corticosteroid to the equivalent of beclometasone 2000 μg/​day or to the addition of a fourth drug (e.g. slow-​release theophylline, a leukotriene antagonist, or a long-​acting antimuscarinic agonist). Step 5—​failure to respond to combinations of Step 4 treatments requires the addition of an oral corticosteroid while continuing high-​ dose inhaled corticosteroid treatment. Patients should be considered for anti-​IgE therapy, bronchial thermoplasty, or alternative immuno- suppressant therapies. Targeted therapies such as the biologics anti-​ IL-​5 or anti-​IL-​13 are going to be available for selected patients in the near future Acute exacerbations of asthma Asthma exacerbations are episodes of progressively worsening airway narrowing that can vary in severity from those that patients are able to manage themselves by following an agreed treatment plan, to severe attacks which at their most dramatic develop rapidly and become life-​threatening within minutes or hours. Fatal or near-​fatal attacks—​these are associated with (1) patients who have previously required hospital admission for severe asthma and who require regular oral steroid treatment; (2) failure to recog- nize severity of asthma by the patient; (3) failure to recognize the se- verity of asthma by the doctor; (4) undertreatment or inappropriate treatment, with failure to use oral corticosteroids in adequate doses early in an exacerbation probably being the single commonest re- mediable factor. Clinical features—​in acute severe asthma, the patient is usually ex- tremely short of breath, sitting up or leaning forward to use their accessory muscles of respiration, with impaired speech and increas- ingly prolonged expiration alternating with short inspiratory gasps. Tachycardia and pulsus paradoxus are often found. Airway narrowing may become sufficiently severe for no wheeze to be audible and gas exchange sufficiently impaired to cause detectable cyanosis, when the patient will be distressed, anxious, apprehensive, and confused. Exhaustion ultimately leads to inadequate ventilation and a rising, PCO2 the two cardinal features that indicate the need for transfer to an intensive care unit in the event that assisted ventilation is required. A value of peak expiratory flow rate of less than 50% of predicted or of the recent best value in an adult aged less than 50 years usually in- dicates severe asthma; a value of less than 33% indicates a potentially life-​threatening attack. Management—​initial treatment of a severe attack of asthma should be with (1) oxygen to maintain an SpO2 level of 94%-​98% (2) β2-​agonist—​nebulized salbutamol 2.5 to 5 mg or terbutaline 5–​ 10 mg driven by oxygen; (3) steroid—​oral prednisolone 30–​60 mg or intravenous hydrocortisone 200 mg. If there is a poor response to initial treatment after 15–​30 min, then (1) continue oxygen; (2) repeat nebulized salbutamol 5 mg after 15 min; (3) add ipatropium 0.5 mg to nebulized β2-​agonist; (4) give intravenous hydrocortisone 200 mg four hourly; (5) consider intravenous magnesium sulphate 1.2–​2 g over 20 min. Investigations—​chest radiograph to exclude pneumothorax, pneumomediastinum or lobar collapse; arterial blood gases to as- sess oxygenation and ventilation; monitor serum K+ (risk of hypokal- aemia with high-​dose β2-​agonist). The patient in extremis—​indications for transfer to intensive care and for consideration of intermittent positive-​pressure ventilation are (1) hypoxia (PaO2 <8 kPa) despite high flow oxygen; (2) hypercapnoea (PaCO2 greater than 6 kPa); (3)  exhaustion with feeble respiration; (4) confusion or drowsiness; (5) unconsciousness; (6) respiratory arrest. Introduction Asthma is a chronic inflammatory disease of the bronchial airways (Fig. 18.7.1). The defining clinical characteristics of asthma—​ reversible airway narrowing and increased airway responsive- ness to nonspecific provocative stimuli—​are associated with an underlying chronic inflammatory process. Definitions of asthma which have focused on these clinical characteristics to distinguish it from diseases associated with predominantly irreversible airway narrowing have emphasized the intermittent nature of asthma rather than the persistence of the underlying inflammation, with potentially inappropriate implications for treatment. Epidemiology Asthma is a common disease. It is frequently disabling, and—​ uncommonly—​can cause death. In the Western world it now has an

18.7  Asthma 4069 estimated prevalence of more than 10% in children and more than 5% in adults. It is the cause of more than 100 000 hospital admissions and is the certified cause of death of some 1000 people in England and Wales each year. The prevalence of asthma has markedly increased in the Western world, most obviously but not exclusively in children. Studies of disease frequency in the last half of the twentieth century suggest a doubling in asthma prevalence in developed nations every 15 years. More recent evidence suggests that in some countries the increase in both children and adults may have slowed or plateaued. There have been similar trends in the prevalence of specific IgE sensitization to common aeroallergens. Although in part changes in prevalence may reflect a greater awareness of and tendency to diagnose asthma, repeat cross-​sectional studies of children in the United Kingdom, using identical methods of ascertainment at different time points, have shown a definite increase. A study of Aberdeen schoolchildren found the prevalence of wheeze and of diagnosed asthma had in- creased 2.5-​fold in the 25 years between 1964 and 1989. A similar study in South Wales at two time points 15 years apart found a his- tory of reported asthma to have doubled from 6 to 12%, and also reported similar increases of reported hay fever and eczema and of the proportion of children in whom exercise-​provoked asthma. A third study of the same population in 1998 found a further in- crease in asthma symptoms but a decrease in exercise-​provoked bronchoconstriction, possibly reflecting more frequent use of ef- fective treatments by asthmatic children. Comparison of the prevalence of asthma in different parts of the world suggests that the high prevalence in the Western world is asso- ciated with urbanization and material prosperity, and comparisons between countries are reflected in comparisons within countries. A study of school children in Zimbabwe found asthma to be un- common in those living in a rural area, more common in poor urban dwellers, and most common in the affluent urban dwellers, equally in all racial groups, in Harare. In Europe, the reunification of Germany allowed comparison of the prevalence of asthma and associated con- ditions in cities in former East and West Germany. The prevalence of asthma, hay fever, eczema, and atopy (identified as immediate skin test responses to common inhalant allergens) was greater in school-​ age children living in the West German city of Munich than in the East German cities of Leipzig and Halle. Interestingly, the preva- lence of atopy (particularly skin test responses to pollens) and hay fever, but not asthma, subsequently increased in children living in reunified Germany who had lived the first 5 years of their lives in Leipzig. Other intranational studies of European populations sug- gest stark differences in disease prevalence between urban and rural communities, even where these are geographically close. Many explanations have been advanced to explain these obser- vations. These include increased indoor allergen exposure (particu- larly house dust mite and cat), increased exposure to vehicle exhaust pollution, increased tobacco smoking by women of childbearing age, changing diet, and reduced infection rates in childhood. Several dietary explanations have also been advanced, including reduced circulating levels of vitamin D and E, increased salt, and reduced antioxidant intake. The most plausible explanation for increased prevalence of atopy and asthma advanced to date is that it is a consequence of reduced levels of microbial exposure during childhood. The evidence is both indirect and direct, although not yet conclusive. The ‘hygiene hy- pothesis’ suggests that the rapid global increase in asthma prevalence seen over the last decades is a direct result of an inverse relationship between family size and/​or birth order and the risk of atopy and hay fever, a pattern that is evident in populations born almost a century ago. This has been interpreted as being consistent with the age at which a child encounters microbial agents: children in large families and those with older siblings are more likely to encounter infections earlier in life, reducing their risk of becoming atopic. More directly, several studies, most of them in European populations, have shown a relationship between growing up on a farm and a reduced risk of developing atopy, hay fever, and asthma, and the effects may persist into adult life. If a farm childhood confers protection then it remains Fig. 18.7.1  The defining pathology of asthma: desquamative eosinophilic bronchitis (a) in comparison with normal histological appearances (b).

section 18  Respiratory disorders 4070 unclear which exposure(s) may be responsible; unpasteurized milk, pig farming, haymaking, and endotoxin in domestic dust have all been proposed, but none as yet confirmed. Pathophysiology Most asthma originates in childhood following sensitization of the airways to common aero allergens such as pollen, house dust mite, animal dander and fungi, and is typically associated with other atopic diseases such as allergic rhinitis or eczema. In atopic children dermatitis can precede asthma in the ‘atopic march’, sug- gesting a role for epicutaneous allergen transfer in the development of asthma. Asthma has long been termed a T-​helper cell type 2 (Th2) driven disease characterized by thickened airway smooth muscle cells, subepithelial fibrosis, and an aberrant immune regulation with a predominance of Th2 cells secreting cytokines IL-​4, IL-​5, and IL-​ 13. These cytokines drive eosinophilic inflammation and bron- chial hyperreactivity. They also lead to increased mucus production and promote B cell class switching to IgE production. Other cells known to be central to allergic inflammation are mast cells, eo- sinophils, neutrophils, macrophages and dendritic cells, and innate lymphoid cells. However, up to a third of asthma patients are nonatopic, increasing to up to half of patients with severe disease, and several nonallergenic exposures such as bacterial endotoxins, air pollution, or viral infections during early life are believed to contribute to the development of their disease. Despite normal IgE levels, these pa- tients are frequently found to have eosinophilic airway inflamma- tion. A distinct class of cells, discovered in 2010 as nuocytes and eventually named innate lymphoid cells (ILC’s), are believed to be responsible for eosinophilic inflammation in nonatopic indi- viduals. Airway epithelial damage, for example by viruses, results in the production of IL-​25, IL-​33, and thymic stromal-​derived lymphopoietin (TSLP), which in turn activate ILCs to release IL-​5 and IL-​13 but not IL-​4. TSLP is an epithelial-​cell-​derived cytokine that is produced in response to inflammation and drives allergic responses. Asthma phenotypes Asthma is a heterogenous disease encompassing multiple pheno- types or subgroups. With many of the pathophysiological mechan- isms involved in asthma incompletely understood, much effort has been directed at characterizing asthma better, involving biased and unbiased approaches. The term asthma endotypes developed as a conceptual framework that included pathophysiological mechan- isms of the disease. This allows the design of targeted treatments dir- ected at specific, causative molecular mechanisms. Molecular phenotyping of asthma patients identified a group with distinctly higher levels of the Th2 cytokines IL-​5 and IL-​13. A high expression of the genes chloride channel, calcium activated family member-​1 (CLCA1), periostin (POSTN), and SERPINB2 were iden- tified in patients with a strong Th2 inflammatory signature, termed Th2-​high asthma. This was in contrast to patients with cytokine ex- pression similar to healthy controls, including Th1 cytokines such as IL-​12 and IFNγ, which were significantly lower in the Th2-​high group. The Th2-​high and Th2-​low groups also differ clinically with the Th2-​high group showing significant higher atopy and higher eosinophil levels in peripheral blood and bronchoalveolar lavage, and a better response to treatment with corticosteroids compared to Th2-​low asthmatics, who show a much diminished treatment re- sponse to corticosteroids. The early-​onset  allergic type and the late-​onset eosinophilic phenotype are both orchestrated by Th2 cells. They are clinically distinct yet overlap immunologically. A Th2-​cell signature is also predominantly seen in exercise-​induced asthma, with mast cells and their mediators understood to be driving inflammation and in aspirin-​exacerbated respiratory disease. A lack of Th2 biomarkers is seen in a phenotype termed obesity-​ related asthma, which has a predominantly late onset and is more commonly seen in women. Severe asthma with largely neutrophils found in inflamed airways is described as neutrophilic asthma. The mechanisms of Th2-​low asthma is currently less well understood. Proinflammatory cytokines such as IL-​17 have been proposed to play a role, and indeed higher levels of IL-​17 are found in sputum and bronchoalveolar lavage samples of patients with severe asthma that is less responsive to corticosteroids. Phenotyping of patients with asthma is likely going to develop further and become more readily available in clinical practice as part of the endeavour to improve asthma treatments. Asthma biomarkers Because asthma is an inflammatory disease of the airways, markers of airway inflammation have been sought both for diagnostic pur- poses and as a guide to the effectiveness of treatment. Currently, sputum eosinophil counts and measurements of fractional exhaled nitric oxide (FeNO) can be considered useful tools in identifying specific asthma phenotypes and in improving asthma diagnosis and management in a selected population. An increase in sputum eosinophil count (>2% or >3% total cell count in sputum) is an indicator of reversible airway narrowing and is associated with corticosteroid responsiveness. Management of asthma with the additional intention of decreasing sputum eosino- phil counts to normal has been shown to reduce the frequency of asthma exacerbations. FeNO is increased in patients with asthma:  it correlates with sputum eosinophilia, particularly in steroid-​naive patients, and is reduced by treatment with inhaled corticosteroids. However, the range of FeNO in the normal population overlaps with the range in patients with asthma, and FeNO is a less good discriminator be- tween nonasthmatics and asthmatics than sputum eosinophilia. Current data suggests FeNO is a more practical biomarker than sputum eosinophilia to monitor the severity of asthma and its re- sponse to treatment. Inducers and provokers of asthma The distinguishing abnormalities of lung function in bronchial asthma are (1) reversible airway narrowing, and (2) airway hyper-​ responsiveness to nonspecific provocative stimuli. Airway responsiveness describes the ease with which acute airway narrowing can be provoked by a variety of stimuli. Non-​ specific provocative stimuli include exercise, inhalation of cold dry air, inhaled respiratory irritants such as sulphur dioxide, and

18.7  Asthma 4071 pharmacological agents such as histamine and methacholine (Table 18.7.1). Provocation of asthma by specific allergens can induce airway hyper-​responsiveness to nonspecific stimuli. Patients with hyper-​responsive airways require smaller doses of such stimuli to provoke acute airway narrowing. Inhaled nonspecific provocative stimuli such as histamine or methacholine incite airway narrowing that usually resolves within minutes; exercise provokes asthma within minutes that resolves within 1 hour. The degree of airway responsiveness can be expressed as the dose or concentration of the stimulus which provokes a specified fall in forced expiratory volume in 1 second (FEV1)—​commonly the dose or concentration of histamine or methacholine which provokes a 20% fall in FEV1—​PD20 or PC20, histamine, or methacholine. Whereas provokers of asthma incite acute airway narrowing in individuals with hyper-​responsive airways, inducers (or triggers) of asthma increase the magnitude of airway hyper-​responsiveness and the clinical manifestations of asthma by increasing the severity of the underlying airway inflammation, which can persist for days or weeks. The principal inducers of asthma are inhaled allergens, viral respiratory tract infections, and low-​molecular-​weight chemicals encountered at work (Table 18.7.1). Allergen inhalation tests are a good model of the airway response to an inducer and demonstrate the interrelationship between airway inflammation, airway narrowing, and airway hyper-​responsiveness. Inhalation of an allergen by an individual allergic to it with asthma will provoke: • an immediate fall in FEV1 that develops within minutes and usu- ally resolves spontaneously within 1–​1.5 h; • a subsequent late fall in FEV1 that develops in about 50% of cases 2–​4 h or more after the inhalation test and persists for several hours, on occasions for days; • an increase in airway responsiveness, usually associated with the late fall in FEV1, which is frequently of longer duration than the late FEV1 fall. The immediate fall in FEV1 is IgE dependent and due to airway smooth muscle contraction and airway wall oedema provoked by mediators, such as histamine, released from mast cells resident in the airways. It is not associated with an increase in airway respon- siveness. The late fall in FEV1 is the outcome of recruitment to the airways of inflammatory cells, particularly Th2 lymphocytes and eosinophils, reducing airway calibre. It is associated with an in- crease in airway responsiveness (manifest as a reduction in PC20) which can persist, with associated increased diurnal variation in airway calibre, for several days after resolution of airway narrowing (Fig. 18.7.2). Atopy and allergy Atopy is defined as the production of specific IgE antibody to common inhalant allergens, such as grass pollen, house dust mite, animal dander, or fungi. It may be identified by the presence of im- mediate skin prick test responses (or of specific IgE in serum) to extracts of common inhalant allergens and has a prevalence of some 40% in the adult population of the United Kingdom. The risk of developing asthma as well as eczema and hay fever is increased in atopic individuals. In a random population sample in the south-​western United States of America, a close relationship was found at all ages between skin test responses to local inhalant aller- gens and the prevalence of asthma and allergic rhinitis. Similarly, in Canadian university students the prevalence of airway hyper-​ responsiveness to inhaled histamine correlated significantly with the degree of atopy. In asthmatics, natural allergen exposure induces asthma and airway hyper-​responsiveness. In a study of hospital admissions during seven years in Canadian cities, admission rates correlated with increases in levels of aeroallergens, including grasses, trees, weeds, and moulds, with an interaction with ozone levels. Both the severity of asthma and airway responsiveness are increased in asthmatic patients allergic to ragweed pollen during the season. Similarly, avoidance of relevant allergen exposure is associated with an improvement or resolution of asthmatic symptoms, improved lung function, and decreased airway responsiveness. Patients with asthma allergic to house dust mite have shown considerable symp- tomatic and objective improvement when avoiding house dust mite for several months at altitude in Davos in the Swiss Alps. In the south-​ eastern United States of America, asthma deaths in patients allergic to the mould Alternaria alternata increased during the months of the year when Alternaria spore counts were highest. Indoor and out- door exposure to fungal components is a well-​recognized trigger factor, with allergenic fungi of the genera Alternaria, Aspergillus, and Cladosporium being the most important allergenic sources. Observational studies have described increases in asthma attacks following thunderstorms believed to be due to a sudden release of aeroallergens, such as pollen grains or fungal spores. Respiratory virus infections Respiratory virus infections have long been suspected to be the major cause of exacerbations of asthma, but it is only with the development and use of the polymerase chain reaction (PCR) in controlled studies that the true proportion of virus-​induced asthma exacerbations, in both children and adults, has become clear. There is now consistent evidence that 80–​85% of exacerbations of asthma in children and 50 to 75% of exacerbations in adults are caused by viral infections, of which the great majority are attributable to respiratory syncytial virus (RSV) and human rhinoviruses. RSV infections are the most common cause for acute bronchiolitis in infancy, but human rhino- virus infections are associated with more severe disease and are the most frequent viral cause for asthma exacerbations in adults. Other viruses associated with asthma exacerbations include influenza, Table 18.7.1  Inducers and provokers of asthma Inducers of asthma Allergens Increased airway inflammation Viral respiratory tract infections → Increased airway responsiveness Low-​molecular-​weight chemicals Increased severity of asthma Provokers of asthma Exercise Cold dry air Respiratory irritants (e.g. sulphur dioxide) → Acute transient airway narrowing in individuals with hyperresponsive airways Histamine Methacholine

section 18  Respiratory disorders 4072 parainfluenza, coronaviruses, human metapneumoviruses, adeno- viruses, and bocaviruses. Exacerbations of asthma provoked by respiratory infections are often severe, can be prolonged, and are as- sociated with increased airway responsiveness. Peak flow measure- ments in schoolchildren have been shown to remain abnormal for several weeks after a respiratory tract infection. Several studies have suggested that asthma exacerbations occur particularly in atopic children infected with rhinovirus concur- rently exposed to relevant allergens. In one study in the United Kingdom of children aged between 3 and 17 years the risk of ad- mission to hospital with asthma was markedly increased in chil- dren with detectable virus infection with allergen-​specific IgE and heavily exposed to the sensitizing allergen, as compared to age-​ and sex-​matched children with stable asthma or admitted to hospital with nonrespiratory disease. Virus infection, allergen, or sensitization alone, were not associated with increased risk in this study. In another study in the United States of America of chil- dren aged between 2 and 16 years, the strongest risk factors for wheezing requiring emergency care were RT-​PCR evidence of rhinovirus together with atopy or eosinophilic inflammation in nasal secretions. These observations demonstrate the importance of viral infection, particularly human rhinovirus infection, in ex- acerbations of asthma in children and adults. Recent studies have found evidence of impaired innate immunity in airway epithelial cells in patients with asthma: interferon produc- tion is deficient, and the magnitude of deficiency is related to the severity of asthma exacerbations. There is some evidence that infection with Chlamydia or Mycoplasma pneumoniae may also play a role in asthma exacerba- tions. Studies have identified altered host defence immune mechan- isms in individuals with viral and bacterial coinfection. Pollution Air pollutants such as ozone, particulate matter of less than 2.5 μm and less than 10 μm in diameter (PM2.5 and PM10), and oxides of nitrogen are linked to adverse health outcomes, particularly respira- tory health. Traffic-​related air pollution is associated with asthma exacerbations and there is a clear relation between pollutants and increased susceptibility to common allergens. It has been suggested that major allergens in pollen can bind to the diesel exhaust par- ticles, leading to aggregation of pollen allergens and resulting in IgE-​mediated reactions. The relationship between air pollution and the development of asthma is less clear and studies looking at changing levels of PM25 have failed to see an effect on asthma incidence. The incidence of asthma in urban parts of the United Kingdom is no greater (and pos- sibly less) than in rural parts, including Skye, where measured levels of air pollutants are the lowest in United Kingdom. However, several reports have demonstrated a role for indoor environmental pollu- tion in the development of asthma. Exclusive use of biomass burning for cooking is associated with higher prevalence of wheeze when compared to those using biomass as only one of the cooking fuels. Smoking Smoking asthmatics have a more rapid decline in lung function, and more unscheduled healthcare visits and exacerbation rates, than nonsmokers. Smokers also have an impaired response to the most widely prescribed medications for asthma, inhaled corticosteroids, and hence are more likely to have poor symptom control. Although there is only limited evidence for an association between smoking and asthma incidence in adults, there is a clear relationship between second-​hand smoking and an increased risk for asthma and aller- gies in children. A  study in Scotland demonstrated a significant Allergen inhalation 2.5 2.0 1.5 10.0 5.0 1.0 0.5 PC20 Histamine (mg/ml) FEV1 (1) Control Period 4 5 6 7 8 13 15 19 0 1 2 3 FEV1 VC 3.0 VC (1) 2.5 Days after allergen inhalation Fig. 18.7.2  Increased airway responsiveness associated with late asthmatic reaction provoked by inhalation of ragweed pollen.

18.7  Asthma 4073 reduction of asthma-​related hospital admissions in children after the public smoking ban was introduced in 2006. Psychological factors Patients suffering from chronic disease are at higher risk of developing anxiety disorders and depression. Stress and emotional factors can lead to poor adherence to treatment, resulting in decrease in asthma control and higher exacerbation factors. Children exposed to acute or chronic stress have been found to have decreased expression of β-​2-​ adrenergic and glucocorticoid receptor genes, putting them at increased risk of acute asthma attacks. Obesity Obesity is an independent risk factor for asthma. Insulin resist- ance, altered adaptive and innate immunity, changes in mechan- ical loading of the chest wall and abdomen, and increased airway hyper responsiveness secondary to low lung volume breathing are all thought to contribute to the development or symptom control of asthma. While treatment of obesity-​related asthma with inhaled or oral corticosteroids often proves disappointing, there is clear evi- dence that weight loss improves asthma control. Drugs Few drugs exacerbate asthma, with β-​blockers, and nonsteroidal anti-​inflammatory drugs (NSAIDs) being the most notable. Although angiotensin-​converting enzyme (ACE) inhibitors may cause cough, and occasionally rhinitis and angio-​oedema, they have not been associated with the provocation of asthma and are there- fore not contraindicated in asthma. β-​Blockers Precipitation or worsening of asthma was first reported with pro- pranolol, but subsequently found to occur with all nonselective β-​adrenoceptor antagonists. This reaction to β-​blockers implies ad- renergic bronchodilator tone in asthmatic airways. The severity of the airway narrowing provoked by β-​blockers is not predictable, nor is it closely related to the severity of airway hyper-​responsiveness. The dose provoking asthma can be low: severe asthma can be pre- cipitated by timolol eye drops, a nonselective β-​blocker used to treat glaucoma. Selective β1-​antagonists such as atenolol, acebutolol and metoprolol provoke less severe reactions than nonselective β-​ blockers such as propranolol. Although the fall in lung function provoked by a β-​blocker can be reversed by an inhaled β2-​agonist, patients with asthma should avoid β-​blockers—​including β1-​selective antagonists—​because of the unpredictable and potentially serious consequences of a severe asthmatic reaction, and alternative drugs should be used for treat- ment of hypertension and angina. Aspirin and NSAIDs Aspirin and other NSAIDs which inhibit cyclooxygenase 1 (COX1) can provoke severe attacks of asthma in some 10% of adults with asthma, more frequently in women than men. Aspirin-​induced asthma (AIA) may be part of a well-​recognized association of as- pirin intolerance, asthma, and rhinitis with nasal polyps (Samter’s triad) that is characterized by severe mucosal eosinophilic inflam- mation of the nose and airways. The onset is usually in the third or fourth decade, with chronic nasal congestion, discharge, and nasal polypi. Subsequently asthma and AIA develop, when ingestion of aspirin or an NSAID typically provokes acute severe asthma within 1 h, accompanied by profuse nasal discharge, periorbital oedema, conjunctival injection, in some cases with flushing of the head and neck and, on occasions, vomiting and diarrhoea. AIA can provoke life-​threatening asthma resistant to bronchodilators: in one survey, 25% of 145 patients requiring mechanical ventilation for acute se- vere asthma had AIA. Despite avoidance of aspirin and NSAIDs, severe asthma and rhinitis with nasal polyps usually persist, associated with raised blood eosinophil count and intense eosinophil infiltration of the nasal and airway mucosa. The most plausible explanation of AIA is that it occurs as a consequence of specific inhibition in respiratory cells of intracellular COX enzymes. NSAIDs with anti-​COX activity provoke asthma in patients with AIA; NSAIDs which do not inhibit COX activity do not provoke asthma; the potency of NSAIDs to in- hibit COX correlates with their ability to provoke asthma in AIA individuals; and cross-​tolerance to NSAIDs that inhibit COX oc- curs after desensitization to aspirin. Cross-​tolerance involving such chemically distinct moieties argues strongly against AIA being an immunological reaction. The intense tissue eosinophilia associated with AIA is accom- panied by overproduction of cysteinyl leukotrienes, which are im- portant mediators of nasal inflammation and asthma. These are continuously synthesized in AIA patients, even in the absence of aspirin ingestion, are released into nasal and bronchial secretions, and can be collected in urine, and COX inhibition is associated with their release. Aspirin provoked nasal and asthmatic reactions are attenuated by leukotriene antagonists, both cysteinyl-​leukotriene receptor antagonists (zafirlukast, montelukast, and pranlukast) and 5-​lipoxygenase inhibitors (zileuton). Patients with AIA should avoid all aspirin-​containing prod- ucts and other analgesics or anti-​inflammatories that inhibit COX (Table 18.7.2). Patients with AIA can usually, although not always, take paracetamol. Selective inhibitors of COX-​2, celecoxib and rofecoxib, while potentially safe in AIA are associated with an in- creased frequency of cardiovascular events, and rofecoxib has been withdrawn. Tolerance to aspirin and NSAIDs can be induced in patients with AIA by the ingestion of increasing doses of aspirin over 2–​3 days, until 400–​650 mg aspirin can be tolerated. Daily doses of between 80 and 325 mg aspirin can maintain tolerance, allowing aspirin and other COX inhibitors to be taken safely. A dose of aspirin of 650 mg twice daily can provide improvement in asthma and particularly in nasal inflammation. One report has suggested that regular aspirin treatment after sinus surgery for polypectomy may delay recurrence of nasal polyps, on average by 6 years. However, aspirin desensitiza- tion requires daily maintenance of high-​dose aspirin that may not be well tolerated. Furthermore, omission of aspirin for 2–​3 days can result in complete loss of tolerance, in which case the initial desen- sitization protocol needs to be repeated. It is also not clear whether aspirin desensitization has the potential to modify the long-​term course of asthma. For these reasons, aspirin desensitization has not been widely adopted. Occupation Agents inhaled at work can be the primary cause (induce) or can exacerbate (provoke) asthma. Asthma whose primary cause is an

section 18  Respiratory disorders 4074 agent inhaled at work is called ‘occupational asthma’ to distin- guish it from ‘work-​exacerbated’ asthma. Occupational asthma can be (1) ‘irritant-​induced asthma’, caused by the inhalation of an irritant chemical in toxic concentrations, also known as re- active airways dysfunction syndrome, or (2)  ‘hypersensitivity-​ induced asthma’, the outcome of an acquired hypersensitivity (allergic) reaction to an inhaled protein or chemical. Irritant-​ induced occupational asthma can follow the inhalation, in suf- ficient concentration, of a toxic soluble chemical such as sulphur dioxide, chlorine, or ammonia. The number of described causes of hypersensitivity-​induced occupational asthma is now legion, but a relatively small number cause most cases. These include chemical sensitizers such as isocyanates, complex platinum salts, and colophony fume, and proteins such as flour, enzymes used in baking and detergent manufacture, latex, and laboratory animal urine proteins (Table 18.7.3). It is estimated from a national reporting scheme that in the United Kingdom some 2500 new cases of occupational asthma occur each year. An American Thoracic Society systematic review found that 15% of new or relapsed cases of asthma in adult life are attributable to an occupational exposure, suggesting that about 1 in 7 cases of new or relapsed asthma in adult life are potentially preventable. Work can exacerbate asthma in several different ways, usually as a consequence of airway hyper-​responsiveness (e.g. exposure to irritant chemicals such as sulphur dioxide or dust particles, inhal- ation of cold air in refrigerators or outdoors, or exertion, particu- larly in an irritant environment). One-​third of patients with asthma report worsening of their symptoms at work. Table 18.7.3  Selected causes of hypersensitivity-​induced occupational asthma by occupational group: high-​ and low-​molecular-​mass agents Occupation Agent(s) High molecular mass Baking and milling Flour (wheat, barley, rye, oat, soya), fungal α-​amylase, egg proteins, milk proteins, storage mites Research science, animal handling, laboratory work Small animal proteins (urine, dander, serum): rats, mice, guinea-​pigs, ferrets, and others; insect proteins: cockroach, locust, housefly, fruit fly, gypsy moth, mealworm, and other animal proteins: latex ‘Biological’ detergent powder manufacture Detergent enzymes (protease, amylase, lipase, cellulase) Food processing (nonbaking/​ milling) Linseed, green coffee bean, castor bean, tea dust, tobacco leaf, rosehip, shellfish proteins, fish proteins, milk proteins, egg proteins, cocoa proteins, proteolytic enzymes Nursing, dentistry, other healthcare work Latex Farming and other agriculture Storage mites, mealworms, spider mite, poultry mite, cow dander, cow β-​lactoglobulin, pig urine, mink urine, insect larvae, poultry feathers, honeybee dust, silkworm larvae, fruit, vegetable and flower pollens, fungi, grain dust, spider mite, vine weevil Floristry, botany Pollens, Ficus elastica, gypsophila Low molecular mass Spray painting Hexamethylene diisocyanate, toluene diisocyanate, dimethylethanolamine, other amines Welding, soldering, electronic assembly Colophony fume, stainless steel welding fume, aminoethylethanolamine, cyanoacrylates, toluene diisocyanate, persulphate salts Woodwork Hardwood dusts (western red cedar, iroko, African maple, mahogany, Mansonia, obeche, and others) Chemical processing Azodicarbonamide, phthalic anhydride, trimellitic anhydride, maleic anhydride, hexavalent chromium Plastics manufacture and processing Diphenylmethane diisocyanate, toluene diisocyanate, monomer acrylates, various amines Food processing (nonbaking/​ milling) Chloramine-​t, metabisulphite Hairdressing Persulphate salts, henna Textile/​fabric work Reactive dyes, gum acacia Pharmaceutical manufacture, pharmacy Psyllium, ispaghula, methyldopa, penicillins, cephalosporins, tetracycline, sulfathiazole, spiramycin, isoniazid, piperazine, cimetidine, dichloramine, ipecacuanha, bromelain, morphine, and other opiates Nursing, dentistry, other healthcare work Glutaraldehyde, formaldehyde, monomer acrylates, antibiotics, psyllium, hexachlorophene, pancreatic extracts, N-​acetylcysteine Metal refining Complex platinum salts, hexavalent chromium, nickel, vanadium, furfuryl alcohol Table 18.7.2  NSAIDs that cross-​react with aspirin in respiratory reactions Type of COX inhibitor NSAID Inhibitors of both COX-​1 and COX-​2a Piroxicam Indomethacin Sulindac Tolmetin Ibuprofen Naproxen Naproxen sodium Fenoprofen Meclofenamate Mefenamic acid Flurbiprofen Diflunisal Ketoprofen Diclofenac Ketorolac Etodolac Nabumetone Poor inhibitors of COX-​1 and COX-​2b Oxaprozin Paracetamol (acetaminophen) Salsalate Selective inhibitors of COX-​2c Celecoxib Rofecoxib (now withdrawn) a On first exposure to the drug, cross-​reactions with low provoking doses. b A small percentage of patients with AIA cross-​react with high dose of these drugs. c In theory should not cross-​react.

18.7  Asthma 4075 Prognosis Knowledge of the outcome of asthma has been hindered by the lack of a clear workable definition of asthma, which includes all cases (sensitive) and excludes noncases (specific), and by the relative paucity of longitudinal data on well-​defined community cohorts including a representative group of cases of asthma and not limited to those coming to medical attention. Nonetheless there is now sufficient information to allow a reasonable view of the outcome of the disease. The relationship between wheezing in preschool children and asthma in school-​age children has been clarified by several overlapping studies. Viral-​induced wheeze in preschool children is common, but fortunately only some children will have persistent problems until school age. Two different pragmatic clinical pheno- types of preschool wheeze have been described:  episodic viral wheeze (wheezing during discrete time periods, often in association with clinical evidence of a coryza, with absence of wheeze between episodes) and multitrigger wheeze (wheezing that shows discrete exacerbations, as with episodic viral wheeze, but also symptoms be- tween episodes). There is a large overlap between the two groups and symptoms vary over time and with treatment. To date there is no single diagnostic test that will predict asthma. The important risk factors for wheezing in children aged less than 2–​3 years are reduced lung function at birth, prematurity or low birth weight, and maternal smoking during pregnancy, which both reduces lung function and alters the baby’s immune responses. The prognosis for such children is good, with remission in most by school age and normal lung function in adult life. ‘Wheezy bronchitis’ in preschool years does not occur more frequently in school-​age children with asthma, whose risk factors are different, suggesting the two disorders are independent. The peak prevalence of asthma occurs between the ages of 5 and 10 years, and is associated with eczema in infancy and evidence of sensitization to common inhalant allergens (identified either by skin test responses or by increased total IgE). The outcome for children who develop asthma has been the subject of several general practice and hospital-​based reports, which of necessity describe the prognosis of more severe cases. The out- come for cases identified in random population samples has been reported from Australia and the United Kingdom. The Australian study found that risk of asthma persisting at ages 21 and 28 years was associated with the frequency of wheezing at ages 7 and 14 years. Children who wheezed infrequently in childhood and adolescence were least likely to have continuing asthma as young adults: more than one-​half of those with asthma before the age of 7 years that had remitted by the age of 14 years remained symptom free aged 21 years. However, less than 20% of those with persistent symptoms in child- hood were symptom free in adolescence, and frequent attacks in this group continued to the age of 28 years. Some two-​thirds of those without symptoms in adolescence remained free of asthma at the age of 28 years. The United Kingdom study described the incidence of wheezing from birth to age 33 years. The incidence of wheezy illness at all ages was related to a history of eczema and hay fever. One-​ quarter of children with a history of asthma or wheezy bronchitis by the age of 7 years continued to have symptoms when aged 33 years. Asthma developing in adult life was strongly associated with cigar- ette smoking and a history of hay fever. In both the United Kingdom and Australian studies, asthma recurred in adult life after a period of remission in adolescence. More than one-​half of those in the United Kingdom study who had wheezed before the age of 7 years and reported wheezing aged 33 years had been free of symptoms for 7 years between the age of 16 to 23 years. Similarly, in the Australian study wheezing had recurred in 30% of those who were free of wheezing aged 21 years. In both studies asthma recurred in some individuals with mild symptoms in childhood that were frequently not recalled, and who would other- wise have been labelled as having ‘adult-​onset’ asthma. Clinical manifestations The symptoms of asthma are nonspecific:  shortness of breath, wheezing, chest tightness, and cough. These are manifestations of airway narrowing, which is usually variable in severity over short periods of time, but can be persistent, and of airway hyper-​ responsiveness. Asthma as the cause of these symptoms is suggested by the variability in their severity and distinguished by their period- icity (e.g. daily, weekly, monthly, or seasonal), their provocation by specific (e.g. allergen) and nonspecific stimuli, and their reversibility with bronchodilators or corticosteroids. Patients with asthma can be categorized, at any one time, by whether their symptoms are intermittent or persistent, and by the severity of their symptoms and underlying airway narrowing (meas- ured by lung function tests). It is important to appreciate that even those with mild intermittent asthma can develop severe exacerba- tions given an appropriate stimulus. • Mild intermittent asthma—​symptoms less than weekly with normal or near normal lung function between episodes • Mild persistent asthma—​symptoms more than weekly but less than daily with normal, or near normal, lung function between episodes • Moderate persistent asthma—​daily symptoms with mild-​to-​ moderate airflow limitation • Severe persistent asthma—​daily symptoms that interfere with normal activities, frequent nocturnal waking, and moderate to severe airflow limitation It is also helpful to distinguish chronic and acute asthma: chronic asthma is asthma requiring maintenance treatment; acute asthma is an exacerbation of underlying asthma requiring additional treatment. Symptoms Symptoms of asthma are typically worse at night, waking the af- fected individual on occasion several times in the early hours of the morning and on first waking in the morning, when chest tightness may be the dominant symptom. Asthmatic symptoms may also be provoked by nonspecific stimuli such as exercise and cold air, and by specific allergens such as domestic animals, particularly cats. In patients allergic to pollens or moulds, asthmatic symptoms occur or worsen during the relevant season (in the United Kingdom tree pollen in the late spring, grass pollen in May and June, and mould spores in the late summer months). In patients with asthma induced by occupational sensitizers, symptoms characteristically increase

section 18  Respiratory disorders 4076 in severity during the working week and improve when away from work on holidays of 1 week or more, if not at weekends. Because occupational causes of asthma are potentially avoidable, all cases of asthma that have occurred or recurred in adult life should be questioned about symptomatic improvement when away from work, and if this is present enquiry should be made about potential causes of asthma in the workplace. The onset of symptoms occurs after a latent interval usually of months or years from the onset of exposure. By contrast, irritant-​induced occupational asthma follows a single identifiable exposure to an irritant chemical in toxic con- centrations causing irritation of eyes, nose, and airways of sufficient severity for the individual to seek medical advice within 24 h of the incident. Respiratory viral infections that occur predominantly in the au- tumn and winter months are the most important precipitating causes of exacerbations of asthma. In some women asthma has a monthly periodicity, becoming increasingly severe during the days before menstruation and improving with its onset. Although breathlessness and wheeze are often considered the most characteristic symptoms of asthma, cough can be the dom- inant and, on occasions, the only symptom of asthma. Nocturnal cough particularly suggests asthma, although in community studies isolated nocturnal cough has been found to be a poor predictor of asthma. ‘Cough-​variant asthma’ is occasionally seen in adults in whom cough and eosinophil-​rich sputum are the only manifest- ations of the disease. The characteristic symptoms of asthma are manifestations of vari- able airway narrowing and airway hyper-​responsiveness. Patients with chronic severe asthma have more persistent airway narrowing, are limited in their day-​to-​day activities by breathlessness, and may have less symptomatic evidence of spontaneous variability of airway narrowing. Patients with acute severe asthma are usually distressed by severe shortness of breath with wheezing, and are unable to sleep or to complete sentences in one breath because of the severity of the airway narrowing. Signs The physical signs of mild or moderate asthma may be limited to ex- piratory polyphonic wheezes audible over the lungs. Because of the variable nature of the airway narrowing some patients have normal lung sounds, although expiratory wheezes are to be anticipated in patients with persistent symptomatic asthma. Patients with chronic persistent asthma can develop hyperinflated lungs. In acute severe asthma patients are usually extremely short of breath, sitting up or leaning forward using their accessory muscles of respiration. Characteristically, with increasingly severe airway narrowing, increasingly prolonged expiration alternates with short inspiratory gasps, impairing speech. Tachycardia and pulsus paradoxus (an exaggeration of the normal fall in systolic blood pres- sure on inspiration to >10 mm Hg) often accompany acute severe asthma, but pulsus paradoxus is not a reliable indicator of severity (because it depends on respiratory effort and is therefore not seen in the patient who is exhausted and may be near death). Airway nar- rowing may become sufficiently severe for no wheeze to be audible and gas exchange sufficiently impaired to cause detectable cyanosis. Patients with asthma of this severity are usually distressed, anxious, apprehensive, and can be confused because of hypoxia. Exhaustion ultimately leads to inadequate ventilation and a rising PCO2, the two cardinal features that indicate the need for transfer to an intensive care unit in the event that assisted ventilation is required. Diagnosis A structured clinical history assessing for wheeze, cough, breathless- ness, and any variation of symptoms throughout 24 hours is essen- tial when diagnosing asthma. The presence of atopy in the patient and/​or family should be recorded, as should trigger symptoms. Although asthma is now defined by characteristic pathological changes in the airways, it is usually identified by its pathophysio- logical manifestations, variable or reversible airway narrowing (air- flow limitation) and airway hyper-​responsiveness. In some patients the presence of eosinophils in sputum, a raised eosinophil count in the blood, or raised levels of FeNO can be valuable diagnostic pointers. Airflow limitation Most typically, asthma is diagnosed by the demonstration of airflow limitation that varies spontaneously over short periods of time, or which reverses after inhalation of a short-​acting β-​agonist or (over a more prolonged period of time) use of a corticosteroid either by inhalation or by mouth. In a few patients provocation tests using exercise or pharmaco- logical agents such as histamine or methacholine can be valuable. Inhalation tests with the specific agent may be indicated in suspected cases of occupational asthma, but inhalation tests with common in- halant allergens are rarely indicated in clinical practice. The most clinically useful and first-​line investigation of meas- urements of airflow limitation is spirometry. A forced expiratory volume in 1 s/​forced vital capacity (FEV1/​FVC) ratio of less than 70% is regarded as a positive test for obstructive airway disease. Reversibility and variability Patients who demonstrate airway obstruction on spirometry (FEV1/​ FVC ratio less than 70%) should be offered a bronchodilator re- versibility test. An improvement in airflow limitation, identified by an increase in FEV1 of 12% or more, together with an increase in volume of 200 ml or more, 15–​20 min after inhalation of a broncho- dilator, usually a short-​acting β-​agonist such as salbutamol 200 µg, is generally regarded as evidence of asthma. However, it is important to appreciate that the absence of a significant improvement in lung function after inhalation of bronchodilator does not exclude a diag- nosis of asthma (i.e. it is a more specific than sensitive test). Rapid re- versibility of airflow limitation is more readily seen in young adults with mild or moderate asthma than in more elderly patients with more severe airflow limitation. Reversibility cannot be tested in a patient whose lung function is normal at the time of testing. Expressing changes in airflow as a proportion of baseline will ex- aggerate the degree of improvement in those with a low initial FEV1 or peak expiratory flow rate. A 20% increase in FEV1 in a patient with a baseline FEV1 of 4 litres is 800 ml, but only 200 ml in a patient whose baseline FEV1 is 1 litre. Studies of short-​term (20 min) vari- ability in FEV1 in patients with airflow limitation have found that the increase in FEV1 needed to exclude natural variability with 95% con- fidence was 160 ml. This value did not differ significantly from the value in normal individuals, in whom an absolute increase in FEV1

18.7  Asthma 4077 of 190 ml was needed to exclude a chance increase with 95% confi- dence. Both in normal individuals and in those with an airflow limi- tation, expression of variability as an absolute difference was similar at all levels of FEV1, whereas when expressed as a percentage change, the degree of variability decreased with increasing FEV1. This means that selecting a specific percentage change in FEV1 to define asthma will necessarily include a greater proportion of patients with lower prebronchodilator FEV1: patients with a higher baseline FEV1 need to achieve a greater absolute increase to fulfil the defined criterion. Expression of variability as an absolute change has more biological and statistical validity: an increase of more than 200 ml in FEV1 has a probability of less than 5% of occurring by chance. However, as with expression of lung function, it is unlikely that the use of results based on absolute values, although biologically more valid, will be adopted. It should be appreciated, however, that in patients with a low FEV1 a 20% increase in FEV1 may have occurred by chance, and in those with a high FEV1 an increase of more than 200 ml is unlikely to have occurred by chance. If there is diagnostic uncertainty, peak expiratory flow rate (PEF) monitoring for a period of 2–​4 weeks can provide helpful informa- tion. Serial measurements of PEF in most (although not all) patients with asthma show spontaneous variability. The most characteristic pattern is of a circadian variation, with airflow limitation most se- vere on waking in the morning (and during the night if awoken) and with improvement occurring during the morning after waking (Fig. 18.7.3). A small circadian variation in PEF or FEV1 is seen in normal individuals; in asthma a difference of 20% or more between the highest and lowest values may be found. Other patterns of variation in severity of airflow limitation may be imposed on the circadian pattern, such as falls in PEF provoked by exercise, exposure to an allergen, or occupational sensitizer, which resolve after avoidance of the stimulus. While variations of 20% or more in FEV1 or PEF are commonly regarded as indicating asthma, in patients with severe airflow limitation and an FEV1 of 1 litre, 20% variability equates to 200 ml, a level of spontaneous variation ob- served in nonasthmatics. Airway inflammation FeNO originates in the airway epithelium as a result of inflam- mation, hence exhaled nitric oxide (NO) may be regarded as an indirect marker of airway inflammation. Patients with asthma tend to have higher levels of NO in their exhaled breath, and this can be lowered by effective asthma treatment with inhaled corticoster- oids. Measuring FeNO in the breath may help in the diagnosis and management in people, who—​after initial clinical examination—​are considered to have an intermediate probability of having asthma. A level of 40 ppb or more in adults is regarded as a positive test. Airway hyperreactivity measures Airway hyper-​responsiveness—​an exaggerated response to non-​ specific provocative stimuli—​is a cardinal feature of asthma. Tests of airway responsiveness to exercise and to inhaled histamine or methacholine, which can provoke acute airway narrowing in a dose-​dependent fashion, can be of value in the diagnosis of asthma, particularly in patients with symptoms suggestive of asthma but in whom lung function when measured is normal or, if abnormal, shows no reversibility with inhaled bronchodilators. These tests are required in only a few patients, and each has its limitations: exercise testing can be insensitive (i.e. false negatives), and tests of airway reactivity to inhaled histamine or methacholine nonspecific (i.e. false positives), although the provocation of a 20% fall in FEV1 by histamine 4 mg/​ml or less (or equivalent) occurs uncommonly in non­asthmatic patients. In general, normal airway responsiveness to exercise, histamine, or methacholine makes a diagnosis of current asthma very unlikely, whereas an abnormal test is diagnostically less helpful. Airway reactivity to inhaled histamine or methacholine Acute airway narrowing can be provoked in a dose-​dependent manner by the inhalation of increasing doses of a bronchoconstrictor, of which histamine or methacholine are the most commonly used. The test consists of tidal breathing of doubling doses of histamine, with measurement of FEV1 6 min after each inhaled dose. The percentage change in FEV1 from a post-​saline baseline after each concentration of inhaled (histamine) can be plotted, with the test terminated when either a 20% or greater fall in FEV1 is provoked or the maximum con- centration (usually 16 or 32 mg/​ml) is reached. The level of airway reactivity is usually expressed as the concentration of histamine that provokes a 20% fall in FEV1 (PC20 histamine), which can be iden- tified by linear interpolation: the lower the PC20, the more reactive the airways. The test is usually repeatable within one doubling dose, but may not be consistent in any individual, PC20 falling for instance after exposure to allergen or occupational sensitizer. In population studies the major determinants of airway reactivity have been atopy (in older children and young adults) and smoking in older adults (probably reflecting reduced FEV1). Airway respon- siveness can be increased in atopic children with rhinitis and in healthy adults after a viral respiratory tract infection. Evidence of measurable airway reactivity is therefore not necessarily evidence of asthma. However, it is uncommon for nonasthmatic individuals to have a PC20 for histamine or methacholine of less than 8 mg/​ml. Measurement of airway reactivity to histamine or methacholine is more sensitive than exercise testing, although a less specific test for asthma. Like exercise testing, its value in clinical practice is pri- marily in symptomatic patients with normal or near normal FEV1, without evidence of spontaneous variability or reversibility. A nega- tive test in a symptomatic patient suggests that current asthma is unlikely to be the cause of their symptoms. 500 400 300 200 100 1 2 3 4 5 6 7 8 9 Days Peak expiratory flow rate (l/min) Fig. 18.7.3  Circadian rhythm in peak expiratory flow rate in a patient with asthma recovering from an acute attack.

section 18  Respiratory disorders 4078 Skin prick testing and serum IgE measures provide information in the assessment of atopy, which may be an aggravating factor driving asthma, but they are not routinely offered in the initial diagnosis of asthma. Imaging Imaging of the chest is not commonly of diagnostic value in asthma, but can be important in identifying its complications. In patients in whom asthma develops over the age of 30 years the chest radiograph is usually normal, but about one-​quarter of children and one-​fifth of adults show changes of hyperinflation. These changes include a low diaphragm (below the sixth intercostal space anteriorly) and an in- creased retrosternal space. In some children with chronic persistent asthma the length of the lung becomes greater than the width of the thorax, with the posterior ends of the ribs becoming more horizontal. A commonly observed radiographic sign in asthma is of thickened bronchial walls due to eosinophilic infiltration of the airways: these are visible on the chest radiograph as parallel lines (‘tram lines’), or as a thick-​walled ring shadow when seen end on. The complications of asthma include pneumothorax, pneumomediastinum, lobar collapse, allergic bronchopulmonary aspergillosis (ABPA), and eosinophilic pneumonia. The physical signs of pneumothorax can be difficult to discern in an acute asth- matic attack, but its detection can be lifesaving. Pneumomediastinum is of less clinical importance. Plugging of the airways by mucus char- acteristically occurs in ABPA, but can occur in asthmatic patients without ABPA: in both it can cause atelectasis, which is usually lobar or segmental. Bronchopulmonary aspergillosis causes fleeting nonsegmental areas of consolidation that are characteristically perihilar, accom- panied by a moderate blood eosinophilia (1–​1.5 × 109/​litre), raised total IgE greater than 1000 IU and positive Aspergillus fumigatus (Af)-​specific IgE levels as well as Af-​precipitins/​Af-​IgG. Less com- monly, lobar, or segmental atelectasis is caused by mucus impaction. With progression the disease characteristically causes bronchiec- tasis that is predominantly proximal, visible both on the chest radio- graph and CT scan, and upper lobe fibrosis. Eosinophilic pneumonia is characterized by consolidation on the chest radiograph accompanied by a raised blood eosinophil count. This can be a manifestation of several conditions, including ABPA, helminth infections, and drug reactions, as well as being of unknown cause—​acute and chronic eosinophilic pneumonia (see Chapter 18.14.2). Of these, ABPA and chronic eosinophilic pneu- monia (which can be a manifestation of Churg–​Strauss syndrome—​ allergic granulomatosis, see Chapter 18.11.5) are the most common causes of eosinophilic pneumonia in patients with asthma. Chronic eosinophilic pneumonia causes fleeting consolidation that is characteristically peripheral in distribution, either in lo- calized areas or more widespread (the ‘photographic negative’ of pulmonary oedema). The blood eosinophil count is usually consid- erably more elevated than in ABPA. If seen as a manifestation of Churg–​Strauss syndrome, a granulomatous vasculitis that develops in patients with rhinitis and asthma, then other features can include pleural and pericardial effusions, dilated cardiomyopathy, vascultic rash, and mononeuritis multiplex. Abnormalities on the chest radio- graph include enlargement of the heart, because of pericardial or myocardial disease, and consolidation due to chronic eosinophilic pneumonia. Diagnosis of occupational asthma The diagnosis of occupational asthma should be considered in any adult who develops asthma or whose asthma has deteriorated in working life. In the case of irritant-​induced asthma the association of the onset of asthma with inhalation of a toxic chemical is usu- ally clear. The association of asthma caused by a specific hypersen- sitivity reaction is often less apparent, and the diagnosis is based on the following: • Exposure to a sensitizing agent at work • A  characteristic history of onset of asthma after an initial symptom-​free period of exposure; and deterioration in symp- toms during periods at work and improvements during absence from work • The results of objective investigations:  lung function tests, im- munological tests, and inhalation tests Lung function tests The most commonly used criterion for diagnosing asthma—​ improvement in airflow limitation (FEV1 or PEF) after inhalation of bronchodilator—​is often not present in cases of occupational asthma because lung function may be normal when the patient is seen away from work and, if present, does not identify a work relationship. The measure of lung function most commonly used to identify work-​related asthma is serial self-​recorded PEF. A patient with sus- pected occupational asthma is asked to record their PEF at intervals of 2–​3 h for a month from waking to sleeping, and at night if awoken, both during periods at and absences from work. The results can be summarized in a graphical display that records the best, worst, and average values for each day, allowing comparison of PEF during days at work with days away from work (Fig. 18.7.4). Comparisons with the results of inhalation testing as the ‘gold standard’ have shown that serial self-​recorded PEF measurements are a sensitive and spe- cific index of work-​related asthma. The main diagnostic difficulties are in patients with evidence of asthma on PEF records without a work relationship, of whom a proportion are eventually shown to have occupational asthma, the commonest reason for such ‘false-​ negative’ responses being insufficient time away from work for sig- nificant improvement to have occurred. Immunological tests The presence of specific IgE antibody, identified either by immediate skin test response to a soluble protein extract or a hapten–​protein conjugate, or by immunoassay in serum, is evidence of sensitiza- tion to a specific agent. Specific IgE can be identified in most, if not all, protein causes of occupational asthma, and in a small number of low-​molecular-​weight chemical causes of asthma, notably com- plex platinum salts, acid anhydrides, and reactive dyes. No reliable immunological test has been developed for sensitivity to other im- portant causes of asthma such as isocyanates and colophony. Specific inhalation testing The objective of an inhalation test is to expose the individual under single-​blind conditions to the putative cause of their asthma in cir- cumstances that resemble as closely as possible the conditions of exposure at work. The different test methods used depend upon

18.7  Asthma 4079 the physical state of the test material, which can be water soluble (most proteins) and inhaled in solution, a volatile organic liquid inhaled as a vapour, or a dust. Any change in lung function, both in airways calibre (usually measured as FEV1 or PEF) and in air- ways responsiveness to inhaled histamine or methacholine (meas- ured as PC20), is compared with results on appropriate control days. The patterns of airways response provoked by specific inhalation tests have been distinguished by their time of onset and duration (Fig. 18.7.5). Immediate asthmatic responses occur within minutes of the test exposure and usually resolve spontaneously within 1–​2 h. Late asthmatic responses develop 1 h or more after the test exposure and can persist for 24–​36 h. Late asthmatic (but usually not im- mediate) responses are accompanied by an increase in nonspecific airways responsiveness 3 h and, less reliably, 24 h after the test inhal- ation. An immediate response followed by a late response has been called a dual response. Inhalation testing allows the investigation of specific causes of asthma in individuals exposed to them. Provided that the agent being tested is not a nonspecific mucosal irritant and does not provoke an immediate asthmatic response in patients with hyper-​responsive airways—​such as sulphur dioxide, histamine, or exercise—​the 30 15 −15 −30 −45 −60 0 % change in baseline FEV1 BL 0 5 10 30 60 2 3 (hours) (mins) Time after challenge Baseline FEV1 3.78 4 5 6 7 8 9 10 11 12 ~ 15 Control Amylase 1% Amylase 0.1% Amylase 2.5% Fig. 18.7.5  Specific inhalation test demonstrating dual asthmatic response in baker with occupational asthma from fungal α-​amylase. 1 2 200 300 400 500 600 650 700 Peak flow (max, mean, min) litre/minute 27 29 23 23 31 32 31 25 25 24 12 10 25 26 22 9 9 9 9 7 5 11 17 14 18 18 4 % variability: Overall mean: 498 litres/minute Predicted mean: 583 litres/minute Completeness: 99% Predicted Mean 550 450 250 350 3 4 5 6 7 8 9 10 11 12 13 14 Days 15 16 17 18 19 20 21 22 23 24 25 No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment No Treatment 26 27 Fig. 18.7.4  The 27-​day serial peak flow record of a baker with occupational asthma from fungal α-amylase.
On each day, represented by a column, the average, maximum, and minimum peak flow measurements are plotted. Blue columns are work days. The boxed figures at the top of each day are measures of diurnal variation (percentage).

section 18  Respiratory disorders 4080 provocation of an asthmatic response by an occupational agent im- plies that it is a cause of asthma. This causal relationship is strength- ened if the agent reproducibly provokes a late asthmatic response and increases nonspecific airways responsiveness. The diagnosis of occupational asthma requires differentiation from work-​exacerbated asthma, which is incidental asthma aggra- vated by nonspecific provocative stimuli encountered at work such as sulphur dioxide, exercise, or cold air, also from other causes of similar respiratory symptoms, in particular chronic airflow limita- tion and hyperventilation. Differential diagnosis Asthma needs to be differentiated from localized airways obstruc- tion, other causes of generalized airways obstruction, and other causes of intermittent breathlessness. Localized airways obstruction Upper airways obstruction of the larynx or trachea causes a mono- phonic inspiratory wheeze (stridor) audible over the trachea, with a characteristic abnormality of the flow–​volume loop showing de- creased inspiratory flow rate. Wheezing in a child can be caused by an inhaled foreign body, which should be suspected particularly if wheeze develops suddenly in a child who is previously healthy. The chest radiograph may show the foreign body if opaque, or distal atelectasis, consolidation, or air trapping on an expiratory film (which may not be possible to obtain in small children), but it can be normal and—​if foreign body inhalation is suspected—​ bronchoscopy should be undertaken to identify and remove it or to exclude the possibility. In adults localized airway narrowing is more likely to be due to a tumour, benign or malignant, which may occa- sionally cause a unilateral monophonic wheeze. The tumour may be visible on the chest radiograph, but definite diagnosis will require bronchoscopy and biopsy. Generalized airways obstruction The main causes of generalized airways obstruction from which asthma needs to be distinguished are chronic bronchitis and em- physema (COPD), although in some cases these may coexist with asthma. Other causes such as obliterative bronchiolitis are less common. In general, COPD causes breathlessness that increases slowly in severity over years and only uncommonly causes breath- lessness before the age of 40 years. Nocturnal waking by respira- tory symptoms is uncommon in COPD, although not universal in asthma. Chronic severe asthma responsive to corticosteroids, but without significant reversibility to inhaled bronchodilators, may have similar radiographic and spirometric abnormalities. In both the lungs may be hyperinflated on the chest radiograph, but in asthma—​unlike emphysema—​there is no associated loss of vascular markings. Lung function tests in both asthma and emphysema can show air- flow limitation with reduced FEV1, reduced FEV1/​FVC ratio, and hyperinflated lungs with increased total lung capacity. However, while factor transfer (TLco) and gas transfer coefficient (Kco) are reduced in emphysema, in asthma Kco is normal or increased. In young children, asthma needs to be differentiated from wheezing episodes associated with viral respiratory tract infections, and in children and adolescents from cystic fibrosis. Cystic fibrosis is suggested by a disproportionate production of (usually discol- oured) sputum, weight loss, and an abnormal chest radiograph. The presence of staphylococci in sputum and the development of nasal polyps in childhood are very suggestive of cystic fibrosis. Other causes of chronic suppurative lung disease in children, such as pri- mary ciliary dyskinesia and severe combined immunodeficiency (SCID), may also need to be excluded. Other causes of intermittent breathlessness Important causes of intermittent breathlessness from which asthma should be differentiated are left ventricular failure, pulmonary emboli, extrinsic allergic alveolitis, hyperventilation, vocal cord dysfunction, and exercise-​induced bronchoconstriction or exercise-​ induced laryngeal obstruction. Hyperventilation Episodes of hyperventilation may be difficult to distinguish symp- tomatically from asthma, and in some cases complicate asthma, which can be very confusing. The diagnosis should be suspected in a patient who complains of breathlessness that occurs without identifiable cause (e.g. while sitting reading), may be associated with pins and needles in the fingers and dizziness (attributable to hypocapnia), and does not disturb sleep, although hyper- ventilation may inhibit the onset of sleep. The symptoms com- plained of can often be reproduced by a short period of voluntary overbreathing: 20 deep breaths are usually sufficient. Various ex- planations for the tendency of some patients to hyperventilate have been suggested, but none are convincing. However, it is important to recognize that asthma is characteristically a variable condition and a diagnosis of hyperventilation should not be made solely on the basis of absent physical signs or normal lung function at the time of consultation, but on the characteristics described earlier. Vocal cord dysfunction Vocal cord dysfunction is easily misdiagnosed as asthma and may coexist with asthma. In vocal cord dysfunction, wheezing is caused by adduction of the anterior two-​thirds of the vocal cords, and does not occur during sleep. The diagnosis is best made by direct examin- ation of the cords during an attack, which shows characteristic para- doxical vocal cord adduction. Other helpful pointers include poorly reproducible spirometry and flow–​volume curves (particularly during the inspiratory phase), and a disproportionate reduction in FEV1 compared to other effort-​independent measures of airflow obstruction, such as specific airways conductance as determined by whole-​body plethysmography. Management can be difficult, but recognition of this not uncommon condition allows high-​dose oral corticosteroid treatment for ‘uncontrolled asthma’ to be avoided. See Chapter 18.5.1 for further discussion. Exercise-​induced breathlessness Although exercise is a well-​known trigger factor that can provoke or exacerbate asthma symptoms, a substantial number of people, in particular older children, adolescents, and athletes, regularly ex- perience respiratory symptoms without necessarily suffering from asthma. Exercise-​induced laryngeal obstruction and exercise-​ induced bronchoconstriction are two possible causes of breathless- ness in conjunction with exercise.

18.7  Asthma 4081 Exercise-​induced laryngeal obstruction describes the phenom- enon of the transient narrowing of the larynx during intense ex- ercise, predominantly due to the antero-​medial in-​folding of the supraglottic or arytenoid structures. An estimated 5–​10% of young people suffer from this condition, with symptoms characteristically improving rapidly after exercise. This is in contrast to symptoms of exercise-​induced asthma, which tend to peak shortly after exercise. Continuous fibreoptic laryngoscopy during exercise is now regarded as the gold standard diagnostic test. Speech therapy, psychotherapy, muscle training, as well as laser supraglottoplasty, are currently available treatment options, but randomized controlled trials are yet to establish evidence-​based treatment schemes. Exercise-​induced bronchoconstriction, a distinct form of airway hyper-​responsiveness, is characterized by temporary narrowing of the airways after exercise and, like exercise-​induced laryngeal ob- struction, is commonly seen in athletes who may or may not suffer from asthma. Training is often performed in harsh environmental conditions; runners are exposed to high levels of allergens or pollu- tants such as pollen, particulate matter, or ozone, whereas swimmers are exposed to chloramines from chlorinated pools. During exer- cise, in particularly high-​level intense training, minute ventilation increases significantly, posing not only a mechanical stress to the airways but further resulting in airway dehydration and increased osmolarity of the fluid layer along the airways. This is believed to activate airway inflammatory cells and smooth muscle cells causing oedema and airway bronchoconstriction. Diagnosing or distinguishing asthma and/​or exercise-​induced bronchoconstriction in athletes can be difficult as expiratory flows can be supranormal. A correct diagnosis may not only prevent im- paired physical performances in athletes but also potentially dele- terious effects of overprescribed asthma therapy. Investigations should ideally be performed during times of training as many ath- letes have normal responses after they stop intense training. Indirect provocation tests such as eucapnic hyperventilation, hyperosmolar challenge tests with saline or mannitol, or laboratory or field exer- cise tests are often a requirement if preventive and treatment-​related medications are to be used in competition. Management—​objectives, treatment selection,
and patient education The objectives of treating patients with intermittent or persistent asthma are to: • Educate the patient about their disease and the objectives of its management • Minimize or eliminate asthma symptoms • Achieve best possible lung function and prevent an accelerated decline in lung function • Prevent exacerbations of asthma • Achieve these objectives with fewest drugs, keeping short-​term and long-​term adverse effects to a minimum These objectives are most likely to be achieved by treatment that reduces airway inflammation, either by avoidance of its inducing cause or by drugs with anti-​inflammatory activity. The risk of side effects of asthma treatment should be appreciated and minimized, and patients’ concerns about the potential side ef- fects of long-​term treatment recognized and relevant informa- tion provided to them. A number of recent studies have compared the level of asthma control, particularly with regard to the frequency of exacerbations and duration of freedom from an exacerbation, in patients with asthma whose management was based on usual clinical criteria (symptom severity, lung function, and bronchodilator require- ments), with management based on a measure of airway inflam- mation, usually sputum eosinophilia but also exhaled NO (FEno). In general these studies have shown that using indices of airway in- flammation to guide treatment reduced the frequency of exacerba- tions and duration of exacerbation-​free interval without an increase in the need for corticosteroid treatment. In one study of 74 patients with moderate or severe asthma followed up for 1 year after random allocation to management by British Thoracic Society (BTS) guide- lines or by maintenance of sputum eosinophils to less than 3%, there were significant fewer exacerbations (35 vs. 109) and hospital admissions (1 vs. 6) in the group managed by maintaining sputum eosinophils less than 3% (Fig. 18.7.6). In a second similar study the exacerbation frequency was reduced overall by one-​half, and by two-​thirds in those with moderate or severe asthma, in patients whose management was controlled on the basis of maintaining sputum eosinophils less than 2% as compared to usual clinical in- dices of symptoms, lung function, and bronchodilator requirement. In a similar comparison study maintaining FE no less than 15 ppb was associated with a nonsignificant reduction in exacerbations by 50% in the year of follow-​up, and a reduction by 40% in overall corticosteroid dosage as compared to a group managed on usual clinical criteria. These studies indicate the value of using an index of airway inflam- mation (at present better demonstrated for sputum eosinophils than for FEno) in patients with moderate and severe asthma. However, these are not currently widely used in clinical practice, and if they are introduced decisions will need to be guided by them in addition to—​not instead of—​the current indices of symptom severity, lung function, and bronchodilator requirements. Treatment selection Randomized controlled trials of asthma treatments have deter- mined the benefit of different treatment interventions in patients with asthma of varying severity. This information has provided a secure basis for deciding which treatment is likely to be most ef- fective in individual patients, with broadening of the indications for the use of inhaled corticosteroids being of particular import- ance, and has informed the published guidelines for asthma man- agement in the United Kingdom, the United States of America, and elsewhere. The objectives for effective asthma control in individual patients are to: • Allow normal daytime activities (e.g. going to work or to school) as well as the ability to enjoy physically demanding activities (e.g. sport). • Permit sleeping through night, without being awoken by respira- tory symptoms. • Achieve a situation where use of ‘rescue’ medication with inhaled β2-​agonists is needed less than once per day.

section 18  Respiratory disorders 4082 • Achieve normal or near normal PEF and FEV1 with less than 20% variability between best and worst values. • Avoid drug side effects. Asthma, except where caused by a dominant and avoidable agent (e.g. a domestic pet or an occupational sensitizer), is not curable, but current treatment offers the great majority of patients the op- portunity to enjoy a normal life. In most cases asthma is mild: in one community survey only 15% of patients had persistent asthma of moderate severity (Step 3 BTS Guidelines or worse—​see next), but some 5% of patients have severe asthma that responds poorly to conventional treatment. These patients suffer most, both from their disease and from the side effects of its treatment, and are at highest risk from hospitalization and death from asthma. Patient education There is clear evidence from a systematic review and additional ran- domized controlled trials for the benefit of patient education to en- able adults to manage their asthma. In comparison to usual care it has been shown that this can reduce the frequency of unscheduled visits to general practitioners, hospital admissions, and time off work. The four important components of effective patient education are: • Information—​provision of information about asthma and its management. • Self-​monitoring—​regular assessment by the patient of symptoms, or peak expiratory flow rate, or both. • Regular medical review—​assessment of asthma control, severity, and treatment. • Written action plan (Box 18.7.1)—​an individualized written plan to allow self-​management of asthma exacerbations that is in- formed by the severity and treatment of the patients’ asthma and includes four essential components: (1) information about when to increase treatment; (2) how to increase treatment; (3) the dur- ation of treatment increase; and (4) when to cease self-​treatment and seek medical help. Management—​prevention and avoidance of asthma attacks Allergen avoidance The identification and, where feasible, the avoidance of relevant al- lergens at home or at work is an essential part of the management of asthma. It enables patients to recognize important causes of their asthma and take responsibility for their avoidance. Allergen avoidance should be regarded as complementary to drug treatment of asthma, with the advantage in some cases (where a single allergen is the dom- inant cause) of providing a cure with avoidance of the potential side effects of drugs. Complete avoidance of exposure to house dust mite, domestic pets, and occupational causes of asthma have been associ- ated with marked improvement in respiratory symptoms, lung func- tion, and airway hyper-​responsiveness. Avoidance of exposure to the house dust mite, Dermatophagoides pteronyssinus, by spending Time (months) 0 0 20 40 60 80 100 120 1 2 3 4 5 6 7 8 9 10 11 12 Number of exacerbations Fig. 18.7.6  Cumulative frequency of asthma exacerbations in BTS management (solid line) vs. sputum management group (dashed line) (see text for details). Reprinted from The Lancet, 360(9347), Green RH et al., Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial, 1715–​21, Copyright © 2002, with permission from Elsevier. Box 18.7.1  Components of written asthma plan • When to increase treatment -​ Symptoms v PEF -​ PEF % predicted vs. personal best -​ Number of action points based on % best PEF • How to increase treatment -​ Increased inhaled corticosteroids to up to 4x normal dose at onset of attack -​ Oral corticosteroid -​ Combination • For how long -​ Duration of treatment increase: continue increased inhaled cor- ticosteroids for up to 14 days to reduce risk of needing oral steroids • When to call for help After Gibson PG, Powell H (2004). Written action plans for asthma: an evi- dence based review of key components. Thorax, 59, 94–​9. Modified to reflect 2019 SIGN/BTS guideline.

18.7  Asthma 4083 several months in the Alps or in a hospital, has been shown to pro- vide symptomatic and functional improvement. However, house dust mites are ubiquitous in many environments, including much of the United States of America, the United Kingdom, and Europe, and elim- ination of mites from the home sufficient to reduce exposure to the relevant allergens (e.g. Der p1) to concentrations that do not continue to induce airway inflammation can be difficult. The issue with house dust mite avoidance is therefore the feasibility of securing an effective intervention, and the utility of routine advice for implementation of house dust mite avoidance strategies in mite-​sensitive adult asthma has been questioned following the results of a recent large random- ized controlled trial of a single intervention of mite-​proof bedding for 12 months, which failed to improve symptoms or PEF rates or reduce asthma medication requirements. Given that effective mite avoidance is both expensive and time-​consuming, more trials involving multiple interventions are needed. Data in favour of mite avoidance is more convincing in mite-​allergic asthmatic children than in adults. Avoidance of exposure is most clearly indicated and usually most feasible when the cause of asthma is an agent inhaled at work. Removal of a pet from the home, particularly a cat, is most effective when accompanied by thorough cleaning and washing of the house to remove residual allergen, which can otherwise persist in concen- trations sufficient to provoke asthma for many months. Occupational asthma Occupational asthma offers a rare opportunity to cure a patient of their disease. In almost all cases of hypersensitivity-​induced asthma there is considerable and often complete resolution of symptoms and accompanying bronchial hyper-​responsiveness once exposure to the causative agent has ceased. However, occupational asthma, whatever its cause, may become chronic and persist for several years, if not indefinitely, even after avoidance of exposure to the causative agent. The only important determinant of chronicity identified to date has been the duration of symptomatic exposure to the initiating cause after the onset of asthma: those who remain exposed to the cause are more likely to develop chronic asthma. Any improvement after avoidance of exposure seems to occur in the first 2 years, sub- sequently reaching a plateau. There is little evidence that pharmaco- logical treatments affect the rate or extent of recovery. Patients who develop ‘hypersensitivity-​induced’ occupational asthma in whom a specific cause is identified should be advised to avoid further exposure to that cause. In this way the risk of developing chronic asthma and airways hyper-​responsiveness is diminished, and the likelihood of significant improvement or cure is enhanced. Immunotherapy Allergen immunotherapy involves the provision of gradually increasing doses of allergen subcutaneously to promote immuno- logical tolerance to future environmental exposures to the specific allergen. This fell into disrepute some 20 to 30 years ago because of reports of anaphylactic reactions, and in a few cases death, fol- lowing allergen injection. More recent studies have demonstrated its efficacy and safety, particularly in seasonal allergic rhinitis with or without peak seasonal wheezing, where there is clear evidence of efficacy and long-​term benefits that may persist for years following its discontinuation. However, subcutaneous immunotherapy should only be undertaken under direct medical observation and supervi- sion, with immediate access to resuscitation facilities. A recent Cochrane review has shown that allergen immuno- therapy is effective in reducing asthma symptoms as compared to placebo, reducing the need for asthma medication and, where measured, improving airway hyper-​responsiveness. The most con- sistent evidence of benefit was found for pollen and mite allergens. However, the risks of systemic side effects of treatment are increased in patients with asthma, and immunotherapy has been shown to be ineffective for asthma in patients with multiple allergies. Thus, al- though immunotherapy for seasonal allergic rhinitis with or without asthma is recommended in patients who fail to respond to usual medication, in view of the increased risks and less benefit, asthma remains a relative contraindication for immunotherapy, at least in the United Kingdom. Exceptions may include asthmatics whose dis- ease is clearly related to a single allergen (with associated elevated allergen-​specific IgE), and where the allergen cannot be avoided, such as occupational exposure to cats in veterinary practitioners. Management—​drug treatments for asthma The ‘stepped’ approach to the treatment of asthma The purpose of treatment of asthma varies in different patients, from the reversal of occasional mild symptoms to the restoration of normal life in a patient with severe disabling ill health. Treatment needs therefore vary greatly between different patients, which is reflected in the ‘stepped’ approach to treatment that is the basis of current guidelines for asthma management, including the British Thoracic Society and Scottish Intercollegiate Guidelines Network guidelines that are regularly updated. In the stepped approach, asthma severity is defined by the treatment step needed to achieve and maintain good control (Table 18.7.4). Inhaled corticosteroids form the mainstay of maintenance treat- ment for most patients, the initial dose being that considered on clinical grounds as most likely to control the disease. Inhaled β2-​ agonists are used primarily for symptomatic relief. There is good evi- dence that regular treatment with short-​acting β2-​agonists alone is less effective than regular inhaled corticosteroids and provides less good control of asthma, both symptomatically and of lung function. Steps 1 to 5 of the BTS guidelines identify the treatment require- ments for asthma of increasing severity. Failure to achieve treatment targets at any step implies the need to increase treatment to a step that provides good control. • Step 1—​patients with mild intermittent asthma whose asthma is controlled by the use of an inhaled shorter-​acting β2-​agonist (e.g. salbutamol or terbutaline) less than once a day. Requirement for more regular treatment implies the need for regular anti-​ inflammatory treatment (i.e. a higher step). Anyone prescribed more than one short-acting bronchodilator inhaler device a month should be identified and have their asthma assessed urgently and measures taken to improve asthma control if this is poor. • Step 2—​patients with mild persistent or intermittent asthma that is of sufficient frequency to require regular anti-​inflammatory treatment. Inhaled corticosteroids are the most effective and com- monly used anti-​inflammatory drugs. Treatment with an inhaled corticosteroid should be started at a dose of beclometasone 400 µg twice daily (or equivalent) in adults and 200 μg twice daily in chil- dren. This dose should be continued for at least 3 months, the

section 18  Respiratory disorders 4084 period when most benefit of the inhaled steroid is obtained, be- fore reducing the dose to the minimum required to maintain good control. This can be achieved by reducing the dose by 25 to 50% every 1 to 3 months. Short-​acting β2-​agonists are used as required for symptomatic relief. • Step 3—​patients with moderate persistent asthma whose disease, despite adherence to treatment and correct inhaler technique, is not controlled. The treatment of choice is the addition of a long-​ acting β-​agonist (LABA), which should be continued if it provides good asthma control. If it provides benefit, but asthma remains inadequately controlled, the dose of inhaled corticosteroid should be doubled (e.g. beclometasone 400–​800 μg/​day). If the LABA provides no benefit, then it should be discontinued and the in- haled steroid dose doubled, and if this does not provide adequate control a trial of other treatments such as a slow-​release theophyl- line or leukotriene antagonist should be instituted. The option of a combination inhaler for maintenance and reliever therapy (MART) should be considered in patients with a history of asthma attacks despite medium dose inhaled corticosteroid or inhaled corticosteroid/LABA. • Step 4—​if asthma control remains poor despite the measures re- commended in Step 3, consideration should be given to increasing further the dose of the inhaled corticosteroid to the equivalent of beclometasone 2000 μg/​day, or to the addition of a fourth drug (e.g. slow-​release theophylline, a leukotriene antagonist, or a long-​ acting antimuscarinic). • Step 5—​patients who fail to respond to these combinations of Step 4 treatments will require the addition of an oral corticosteroid while continuing high-​dose inhaled corticosteroid treatment. The dose of oral corticosteroid should be the lowest to provide adequate control. Patients who require oral corticosteroids for longer than 3 months or need frequent courses of oral corticosteroids are at risk of sys- temic side effects. Children should have their growth monitored and eyes regularly examined for cataracts. There is minimal evi- dence for a steroid-​sparing effect in the treatment of asthma for im- munosuppressants such as methotrexate and ciclosporin. Corticosteroids Corticosteroids are the most effective treatment for asthma. Systemic corticosteroids were introduced for the treatment of asthma in the 1950s, but their use was limited by serious unwanted side effects, which stimulated research into the development of equally ef- fective but safer alternatives. The introduction of topically active corticosteroids—​administered by inhalation and free of the sys- temic side effects of oral corticosteroids at therapeutically effective doses—​revolutionized the treatment of asthma. Corticosteroids suppress airway inflammation, with improve- ment in airway hyper-​responsiveness, lung function, and associated respiratory symptoms. Although their mechanism of action con- tinues to be debated, they inhibit the formation of cytokines relevant to asthmatic inflammation, such as interleukins IL-​4, IL-​5, IL-​13, and GM-​CSF, by lymphocytes and macrophages by inhibition of transcription of cytokine genes. While suppressing inflammation they do not, however, cure the disease: to be effective they must be taken continuously. Oral corticosteroids Oral corticosteroids—​prednisolone and prednisone—​are rapidly ab- sorbed from the gut, achieving peak plasma levels at 1–​2 h. Prednisone is biologically inactive but rapidly and completely converted in the liver to the active form, prednisolone, which has a plasma half-​life of around 2–​3 h. Some 20% of prednisolone is inactivated in the liver by conjugation by first-​pass metabolism, leaving 80% of the oral dose bioavailable. Hepatic enzyme inducers such as rifampicin, barbitur- ates, and phenytoin can reduce the half-​life of prednisolone by 50%. To counter the consequent reduction in anti-​inflammatory activity the dose of oral prednisolone should be doubled in patients concur- rently receiving these treatments. Some drugs, such as itraconazole, reduce the rate of metabolism of corticosteroids, both oral and in- haled, increasing its blood level for a given dose. Oral corticosteroids effect detectable improvement in airflow limitation in patients with asthma within 6–​12 h of administration. In cases of severe asthma maximum improvement can take sev- eral days, probably reflecting the time to reverse the inflammatory changes in the airways. The early use of oral corticosteroids in the treatment of asthma was severely limited by the high risk of unwanted effects, including osteoporosis, hypertension, diabetes mellitus, cataract formation, adrenal suppression, and (in children) growth suppression. The introduction in the 1970s of inhaled corticosteroids allowed local anti-​inflammatory activity without limiting systemic side effects. Inhaled corticosteroids Inhaled corticosteroids are highly lipophilic and rapidly enter cells within the airways. They combine high topical potency with low systemic bioavailability of the swallowed dose and rapid metabolic Table 18.7.4  Steps in the management of chronic asthma Steps Asthma severity Treatment Step 1 Mild intermittent Short-​acting β2 agonist as required Step 2 Mild persistent Low-​dose ICS (BDP or BUD <800 µg/​day, FP <500 µg/​day), or DSG or nedocromil sodium plus short-​acting β2-​agonist as required Step 3 Moderate persistent High-​dose ICS (BDP or BUD >800 µg/​day or FP >500 µg/​day OR low-​dose ICS (as for Step 2) plus long-​acting β2-​agonist OR plus slow-​release theophyllines plus short-​acting β2-​agonist as required Step 4 Severe persistent High-​dose ICS (as for Step 3) plus regular bronchodilator (e.g. long-​acting β2-​agonist or slow-​release theophylline or inhaled antimuscarinic or long-​acting oral β2-​agonists or high-​dose inhaled β2-​agonists) Step 5 ‘Difficult’ (not responsive to maximal inhaled treatment) Regular oral corticosteroids (in single daily dose) plus high-​dose ICS and (as for Steps 3 and 4) long-​acting bronchodilators (as for Step 4) and inhaled bronchodilators as required BDP, beclomethasone; BUD, budesonide; DSG, deoxyspergualin; FP, fluticasone; ICS, inhaled corticosteroids.

18.7  Asthma 4085 clearance of any corticosteroid reaching the systemic circulation, conferring a high benefit:risk ratio. Although 80–​90% of an inhaled dose from a metered dose inhaler is deposited in the oropharynx, swallowed, and absorbed, more than 80% of beclometasone, 90% of budesonide, and 99% of fluticasone is inactivated by first-​pass metabolism in the liver. The 10–​20% of the inhaled dose deposited in the airways is also absorbed from the lungs and misses first-​pass metabolism, as does medication deposited in the oropharynx. For fluticasone and budesonide, devices that increase lung deposition (such as large volume spacer and Turbohaler) therefore increase the dose available for systemic absorption. Five inhaled corticosteroids are generally available at pre- sent: beclometasone dipropionate (BDP), budesonide, mometasone, ciclesonide, fluticasone propionate, and fluticasone furoate, which despite their names are distinct drug substances with distinct prop- erties. Beclometasone and budesonide are equipotent; fluticasone propionate is twice as potent, requiring half the dose to achieve the same benefit as beclometasone and budesonide. Likewise, mometasone and ciclesonide appear to provide equal clinical ac- tivity to BDP and budesonide at half the dosage. Inhaled corticosteroids have a dose–​response relationship for both efficacy and adverse effects: in general most therapeutic benefit is obtained at low to moderate doses; further increases in dosage provide small increases in benefit but a steep rise in the incidence of adverse effects (Fig. 18.7.7). The clinical effects and side effects of inhaled corticosteroids have been the subject of considerable clinical investigation. Systematic re- views of randomized controlled trials and additional randomized controlled trials of 393 adults and adolescents with mild, persistent asthma have shown that low-​dose inhaled corticosteroids improve symptoms and lung function and reduce the need for as-​needed in- haled bronchodilators as compared with placebo. In addition, sev- eral randomized controlled trials have shown that low-​dose inhaled corticosteroids reduce the frequency of exacerbations in this group of patients. The OPTIMA trial, which compared inhaled budesonide 200 μg/​day with placebo in 700 patients with mild persistent asthma who had not previously taken corticosteroids, found a significant re- duction in exacerbation frequency in the budesonide group as com- pared to placebo (0.77 vs. 0.29 exacerbations/​year). The consistently shown benefits of inhaled corticosteroids in mild persistent asthma mean that these are the treatments of choice in this group of patients. Inhaled corticosteroids are also effective in school-​age children with mild and moderate persistent asthma. The Strategic Timing of Antiretroviral Treatment (START) trial compared low-​dose inhaled budesonide with placebo on the progression of asthma in adults and children (aged 5–​11  years) with newly diagnosed mild per- sistent asthma as measured by time to first severe exacerbation re- quiring hospital treatment and decline in postbronchodilator FEV1. By 3 years the frequency of exacerbations (6% vs. 3%) and need for added treatment with inhaled corticosteroids (50% vs. 30%) was greater in the placebo than the budesonide group. Local side effects of inhaled corticosteroids The severe adverse effects of systemic steroids and the widening in- dications for the use of inhaled corticosteroids have led to close scru- tiny of their side effects. Oropharyngeal candidiasis (thrush) and dysphonia are well recognized and dose dependent. Oropharyngeal candidiasis occurs in about 5% of patients but can be problem, par- ticularly in older people. The risk of its development can be reduced by the use of a large volume spacer and rinsing the mouth out after each inhaled dose. Dysphonia is the commonest side effect of in- haled steroids, occurring in at least one-​third of patients. It is be- lieved to be due to a myopathy of the laryngeal muscles and reverses when treatment is stopped. Inhaled corticosteroids do not cause atrophy of the airway epithelium after 10 years of treatment and are not associated with an increased risk of pulmonary infection, including tuberculosis. Systemic side effects of inhaled corticosteroids Concern about systemic side effects of inhaled steroids stems from the need for their regular use for prolonged periods, of several years or decades, in both adults and children. Because many patients who take inhaled corticosteroids also require oral corticosteroids, distinguishing the adverse systemic effects of inhaled corticosteroids can be difficult. Three important risks of inhaled corticosteroids that have been the subject of recent concern are osteoporosis in adults, and growth suppression and acute adrenal failure in children at the time of inter- current infection. Studies that have addressed these outcomes are limited by their relatively short duration as compared to the length of time for which the treatment is usually taken in routine clinical practice. In general, systematic reviews have found that inhaled cortico- steroids are associated with a reduction in bone mineral density related to cumulative dose. In addition there is evidence for an increased risk of hip fracture in older people: a population-​based case–​control study using the United Kingdom General Practice Research Database comparing inhaled corticosteroid use between 16 341 cases of hip fracture and 29 889 control patients matched for age (mean 79 years), sex, and general practice found that the risk of hip fracture was increased by some 25% in those who had taken in- haled corticosteroids, and by some 20% after adjustment for use of oral corticosteroids. Both asthma and oral corticosteroids can impair growth in chil- dren. Several short-​term studies in growth during a 1-​year period have found evidence for growth retardation of approximately 1.5 cm/​ year in children taking inhaled beclometasone 400 μg/​day. However, Effect Dose Adverse effects Beneficial effects Fig. 18.7.7  Schematic dose–​response curve for beneficial and adverse effects of inhaled corticosteroids. The beneficial effects are seen at lower doses and plateau. The adverse effects increase progressively with increasing dose.

section 18  Respiratory disorders 4086 a recent prospective study of children with asthma, followed up for an average of 9.2 years, taking budesonide in a mean daily dose of 412 μg, found the children to attain their expected adult height. Several studies have found a dose-​related reduction in adrenal cortisol secretion with increasing doses of inhaled corticoster- oids. In comparison to the effect of oral prednisolone, 1 mg inhaled budesonide was equivalent to between 3 and 8.7 mg prednisolone, and 1 mg fluticasone to about 8.5 mg prednisolone. A number of cases of acute adrenal failure were recently reported in patients in United Kingdom taking inhaled corticosteroids. The risk of adrenal failure is also increased in patients taking itraconazole for ABPA, which inhibits hepatic corticosteroid metabolism. The evidence for side effects caused by inhaled corticosteroids, particularly osteoporosis and adrenal suppression, is now suffi- cient to imply that the lowest dose of inhaled corticosteroid that is clinically effective should be prescribed in both children and adults, and particularly in patients taking topical corticosteroids by other routes (e.g. nose or skin), and the dose tapered to the min- imum necessary when symptomatic and functional improvement is achieved. However, in general current evidence indicates that in- haled corticosteroids do not cause important side effects in doses of beclometasone and budesonide of up to 400 µg/​day in children and 800 µg/​day in adults. The side effects that may occur at higher doses—​ more with beclometasone than with budesonide or fluticasone—​can be reduced by the use of a spacer with metered dose inhalers, and by rinsing the mouth after inhalation of a dry powder inhaler, which should be recommended when doses of 400 µg per day or more in children and 800 µg per day or more in adults are prescribed. β2-​Adrenoreceptor agonists The β-​agonists are sympathomimetic amines that include catechol- amines, both naturally occurring (adrenaline, noradrenaline, and dopamine) and synthetic (isoprenaline), and noncatecholamines, both short acting (e.g. salbutamol and terbutaline) and long-​acting (salmeterol and formoterol). Catecholamines have been replaced in the treatment of asthma by β2-​selective noncatecholamines, which have a longer half-​life than catecholamines because they are not subject to catecholamine uptake mechanisms and not broken down by catechol-​O-​methyl transferase. This means that the duration of bronchodilatation after inhalation of noncatecholamines is longer, salbutamol and terbutaline persisting for 3–​6 h and salmeterol and formoterol for up to 12 h. The actions of β-​agonists in asthma are the result of stimulation of β-​adrenoreceptors that are located in the airways, on airway epi- thelium, submucosal glands, airway, and vascular smooth muscle. β-​Receptors in the airways are entirely β2, with the exception of some β1 receptors on submucosal glands. β2-​Agonists can influ- ence airways function through several mechanisms:  relaxation of bronchial smooth muscle by direct effect on β2 receptors; in- hibition of mast cell mediator release; and enhanced mucociliary clearance. Inhalation of a β2-​agonist by a patient with asthma increases airway calibre and reduces airway hyper-​responsiveness. β2-​Agonists also cause tachycardia and increased cardiac output, systemic vasodila- tation, and increased muscle blood flow. The tachycardia and in- creased cardiac output are the results of both stimulation of cardiac β adrenoreceptors and a reflex response to peripheral vasodilation. In addition, β2-​agonists cause tremor and have metabolic effects, of which hypokalaemia is probably the only one of clinical importance. Inhaled selective, short-​acting β2-​agonists reverse mild acute airway narrowing and are sufficient treatment, alone, for mild inter- mittent asthma causing occasional symptoms (Step 1 of the BTS guidelines: Table 18.7.4). Regular vs. as-​needed inhaled β2-​agonists Studies in patients with asthma not taking inhaled corticosteroids comparing regular with as-​needed inhaled β2-​agonists have shown that regular treatment confers no benefit over as-​needed inhalation and can have adverse consequences. A randomized controlled trial in 255 patients with mild intermittent asthma, comparing salbu- tamol taken as needed with regular treatment, found no difference at 16 weeks in respiratory symptoms, airway function, or frequency of exacerbations. However, those taking regular salbutamol took more salbutamol, showed more variability in peak flow rates, and had increased airway responsiveness to inhaled methacholine. Short-​ acting β2-​agonists should, in general, be reserved to provide reversal of acute airway narrowing, taken as-​needed, and prior to exercise in patients with exercise-​provoked asthma. Safety of inhaled β-​agonists Two epidemics of asthma deaths, the first in the 1960s in six coun- tries following the introduction of isoprenaline forte, the second in the mid-​1970s in New Zealand after the introduction of fenoterol, led to concerns about the safety of inhaled β-​agonists. Case–​control studies have also identified an association between asthma deaths and overuse of inhaled β2-​agonists. However, it is difficult to distin- guish cause and effect from confounding in these studies: overuse of β2-​agonists to treat frequent symptoms is more likely to occur in patients with severe uncontrolled asthma who are at high risk of a fatal attack. The evidence for cause and effect in asthma epidemics is stronger: the increased death rates that followed the introduction of the particular inhaled β-​agonists fell rapidly after recognition of the association and no other plausible explanation has been advanced. Isoprenaline is a nonselective β-​agonist and fenoterol is less se- lective than salbutamol and terbutaline. Both drugs were marketed in high dose and are cardiotoxic in the presence of hypoxia, hence the two epidemics may have been due to the acute cardiac effects of β-​agonists inhaled in high dose by hypoxic patients with acute severe asthma. The evidence that selective β2-​agonists formulated in lower doses have a similar cardiotoxic effect and cause asthma deaths outside these epidemics is limited to associations in case–​ control studies, from which it is not possible to infer cause and effect. Long-​acting β2-​agonists A systematic review and additional randomized controlled trials have shown that the addition of long-​acting β2-​agonists (LABAs) improved respiratory symptoms and lung function with reduced re- quirement for ‘rescue medication’ as compared to doubling the dose of inhaled corticosteroid in patients with asthma poorly controlled by inhaled corticosteroids alone. The OPTIMA study investigated the addition of the LABA formoterol to the inhaled corticosteroid budesonide in patients with mild persistent asthma. In 700 pa- tients with mild persistent asthma who had not previously used in- haled corticosteroids, the frequency of exacerbations was reduced in those taking budesonide 200 μg alone as compared with placebo (0.77 vs. 0.29 exacerbations per patient per year). The addition of formoterol provided no further benefit in this group of patients with

18.7  Asthma 4087 mild persistent asthma. In contrast, the addition of formoterol in patients with moderate persistent asthma already using inhaled cor- ticosteroids provided significant benefit in exacerbation frequency, indicating that combination treatment is indicated in patients with moderate persistent asthma insufficiently controlled by low doses of inhaled corticosteroids (Fig. 18.7.8). LABAs are intended for regular use with 12-​h duration of action. Of the two currently used, salmeterol has a slower onset of action than formoterol. Ultra-​long-​acting LABAs allow for once-​daily dosing and are currently licensed for asthma as combination in- halers LABA/​inhaled corticosteroids (ICS; vilanterol/​fluticasone furoate). One systematic review and several additional randomized con- trolled trials have shown that in patients with moderately severe asthma, not controlled by low-​dose inhaled corticosteroids, the addition of a LABA improved symptoms and lung function and re- duced the need for rescue medication as compared to increasing the dose of inhaled corticosteroid. Several randomized controlled trials have shown that the addition of a LABA to an inhaled cor- ticosteroid improved lung function as compared to the addition of a leukotriene antagonist. However, treatment with LABAs (both salmeterol and formoterol) has been associated with an increased frequency of exacerbations of asthma requiring hospitalization, of life-​threatening exacerbations in both adults and children, and of asthma-​related deaths. The Strategies for Management of Asthma Therapy (SMART) study, which followed more than 26 000 par- ticipants for 6  months, found a fourfold increase in the risk of asthma-​related deaths in those taking salmeterol, which equated to two asthma-​related deaths per 1000 patient years of salmeterol usage. Those most at risk of asthma-​related deaths were African Americans, which might reflect an increase in asthma severity in this population and a high proportion taking salmeterol without an inhaled corticosteroid. A  recent meta-​analysis of the results from 19 trials with 33 826 participants found, as compared to pla- cebo, a 2.6-​fold increased risk of exacerbations requiring hospital- ization, a 1.7-​fold increased risk of life-​threatening exacerbations; the risk of asthma-​related deaths was also significantly increased. Furthermore, the risk for asthma exacerbations requiring hospi- talization was increased twofold in patients taking salmeterol with concomitant inhaled corticosteroids. To put these findings into context, the addition of a LABA to low-​dose inhaled corticosteroids in patients with moderately se- vere asthma has been shown to provide greater improvement in symptoms and lung function than doubling the dose of inhaled corticosteroid. What is clearly important is not to prescribe a LABA without a concurrent inhaled corticosteroid, not to add a LABA unnecessarily in a patient with mild asthma adequately controlled on low-​dose inhaled corticosteroids, and to discontinue a LABA in those patients with moderately severe asthma in whom it is not providing benefit. Corticosteroids and LABAs are often prescribed as combination inhalers and although efficacy studies have shown no difference in giving inhaled corticosteroids and LABA in combination or in sep- arate inhalers, the former is recommended to improve patients’ in- haler adherence and to guarantee that a LABA is not taken without inhaled corticosteroids. Long-​acting muscarinic antagonists Muscarinic receptors in the lungs are present on airway smooth muscle and on the nerves that control airway smooth muscle. Stimulation of the vagus nerve releases acetylcholine (ACh) from postganglionic cholinergic fibres, which activates muscarinic re- ceptors resulting in bronchoconstriction and mucus secretion. Muscarinic receptor blockade is one of the oldest treatments for asthma. A short-​acting anticholinergic, ipatropium bromide, is—​on rare occasions—​used for the few adult patients who experience side effects with short-​acting β2-​agonists. However, they are not as ef- fective as short-​acting β2-​agonists and a 10-​year Cochrane review found no evidence to support their use in the treatment of chronic asthma. In the acute setting, the addition of ipatropium bromide to regular short-​acting β2-​agonists has a small but significant additive effect on bronchodilation and its use is therefore recommended for the treatment of an acute asthma attack (see next). There are five muscarinic receptor subtypes (M1–​M5). Tiotropium has similar affinity for all muscarinic receptor subtypes, but is functionally selective for M3 receptors, which are predominantly expressed on airway smooth muscle cells, and M1 receptors on sub- mucosal glands. It dissociates slowly from M3 and M1 receptors but more rapidly from cardiac M2 receptors. Tiotropium has a pro- longed duration of action allowing for once-​daily dosing. Studies with tiotropium are suggestive of superior efficacy to doubling the dose of ICS in patients with ongoing symptoms and to result in im- proved lung function and reduced exacerbation rates when added to pre-​existing therapy with ICS-​LABA combination. It also appears to allow for a reduction in the dose of inhaled corticosteroids while maintaining lung function. Methylxanthines Theophylline is the pharmacologically active methylxanthine most usually employed in clinical medicine, because of its greater (a) 1 (b) 0.8 0.6 0.4 0.2 0 Placebo Budesonide 200 µg/day Budesonide 200 µg/day Budesonide 400 µg/day Budesonide 200 µg/day + Formoterol 9 µg/day Budesonide 400 µg/day + Formoterol 9 µg/day Fig. 18.7.8  Frequency of exacerbations—​the OPTIMA Study. (a) In mild asthma frequency is reduced in patients taking budesonide 200 μg/​day as compared to placebo, but there is no additional benefit from additional formoterol 9 μg/​day. (b) In moderate asthma frequency is reduced in patients taking budesonide 400 μg/​day and formoterol 9 μg/​day as compared to budesonide 200 μg/​day and budesonide 400 μg/​day. After O’Byrne P, et al. (2001). Low dose inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA Randomised Trial. Am J Respir Crit Care Med, 164, 1392–​7.

section 18  Respiratory disorders 4088 bronchodilator activity, less erratic absorption, and longer half-​ life than other methylxanthines. More predictable theophylline absorption can be obtained by slow-​release formulations, and the addition of ethylene diamine to theophylline (aminophylline) pro- vides the increased solubility required for intravenous administra- tion. Nonetheless, theophylline has a relatively narrow ‘therapeutic window’ for a safe and effective dose, with wide differences between individuals in its metabolism, which can also be adversely affected by several extrinsic factors to cause clinically important side effects (Table 18.7.5). The most common side effects are ‘caffeine-​like’ an- orexia, nausea, and vomiting, followed by headache and insomnia. It increases the force and rate of heart contraction and causes vaso- dilatation, and in toxic doses it can cause arrhythmias that may be fatal. It is also a central nervous system stimulant causing increased alertness and—​in toxic doses—​confusion, irritability, and fits. Theophylline relaxes bronchial smooth muscle and, like β-​ agonists, is a functional agonist that does so irrespective of the con- strictor stimulus. Anti-​inflammatory activity in ‘subtherapeutic’ concentrations (i.e. <10 μt/​ml) has been suggested as a possible mechanism of action in asthma. Theophylline is metabolized to inactive products by cytochrome P450-​dependent pathways in the liver. The variation between indi- viduals is large and the half-​life for theophylline can vary between 4 and 24 h. This may in part reflect the wide range of exogenous factors that influence hepatic metabolism of the drug. The half-​life of theophylline is increased by several drugs—​cimetidine (but not ranitidine), erythromycin, ciprofloxacin, and oral contraceptives—​ and decreased by rifampicin, barbiturates, and carbamazepine (Table 18.7.5). Bronchodilatation increases linearly with increase in serum theo- phylline concentration. Toxic effects show a similar linear relation- ship, but at higher concentrations, although there are considerable differences between individuals in the serum concentration at which side effects occur. Serum concentrations of between 10 and 20 µg/​ ml combine substantial bronchodilatation with a low risk of side ef- fects. Safe, effective theophylline treatment requires monitoring of plasma concentration at the start of treatment to ensure a concen- tration within the therapeutic window, and subsequently to ensure its maintenance. Theophyllines are used as an additional treatment in patients whose asthma is inadequately controlled by inhaled corticoster- oids. Comparison in a randomized controlled trial of budesonide 400 µg twice daily and theophylline (250 or 375 mg twice daily) with budesonide 800 µg twice daily for 3 months in 62 patients whose asthma was not controlled by the lower dose of inhaled steroid, found the combination of low-​dose inhaled corticosteroid and theophylline provided the greater improvement in lung function, peak flow variability, and β2-​agonist use. In those receiving it, me- dian theophylline concentration was 8.7 µg/​ml. The additive effect was similar to that provided by inhaled salmeterol, suggesting that oral theophylline at doses lower than the conventional therapeutic dose can be an appropriate alternative to the addition of inhaled salmeterol where this does not provide adequate control at Stage 3 of the BTS guidelines. Antileukotrienes Antileukotrienes are classes of anti-​inflammatory drugs that in- hibit leukotriene synthesis (5-​lipoxygenase inhibitors) or antag- onize leukotriene receptors (leukotriene receptor antagonists). The 5-​lipoxygenase inhibitor zileuton inhibits the conversion of arachidonic acid into 5-​hydroperoxyeicosatetraenoic acid (5-​ HPETE) prior to its transformation into cysteinyl-​leukotriene A4. The leukotriene receptor antagonists (montelukast, pranlukast, and zafirlukast) block the receptors for the cysteinyl-​leukotrienes C4, D4, and E4. Anti-​leukotrienes are used in the treatment of asthma as either single or combined therapy with inhaled corticosteroids. In general, systematic reviews of their efficacy as single therapy suggest they are safe but less effective than inhaled corticosteroids in preventing asthma exacerbations. Beclometasone 400 μg/​day and fluticasone 200 μg/​day are superior in efficacy to montelukast 10 mg/​day and zafirlukast 20 mg twice daily. However, in patients whose asthma is not sufficiently controlled with beclometasone 400–​800 μg/​day (or equivalent), the addition of a leukotriene antagonist in usual doses has been found to provide some improvement in asthma control, but although the addition of a leukotriene antagonist may be an alterna- tive to doubling the dose of inhaled corticosteroids, in adults with moderate persistent asthma both are less effective than the addition of a long-​acting β2-​agonist in improving asthma control. Antileukotrienes are generally safe at usual licensed doses, but increasing the licensed dose two-​ to fourfold—​although associ- ated with increased efficacy—​is not recommended because of the two-​ to fourfold increased risk of abnormal liver function tests. Churg–​Strauss syndrome has been reported with all marketed antileukotrienes, with one systematic review identifying 25 such cases, although the total number of patients taking antileukotrienes in whom these cases occurred was not stated. It has been suggested that starting patients on leukotriene receptor antagonists with con- current withdrawal of systemic steroids may result in the possible unmasking of an underlying autoimmune pathology. However, in some cases the association between montelukast and Churg–​Strauss syndrome seems causal, and more accurate epidemiological studies are needed to discover risk factors favouring montelukast-​associated adverse events. Other treatments Patients whose symptoms remain poorly controlled on high doses of inhaled corticosteroids plus LABA and an additional drug (patients on Step 4/​5 of the BTS guidelines) benefit from referral to a spe- cialist centre. A systematic evaluation of their disease will determine whether their asthma is genuinely therapy refractory, or whether Table 18.7.5  Factors influencing the half-​life of theophylline Increase half-​life Decrease half-​life Liver disease Cigarette smoking Heart failure Alcohol Virus infection Drugs Cimetidine Rifampicin Erythromycin Barbiturates Clarithromycin Phenytoin Ciprofloxacin Carbamazepine Oral contraceptives

18.7  Asthma 4089 their symptoms are aggravated by comorbidities or inadequate treat- ment adherence. Therapies beyond Step 5 of the BTS treatment guidelines have focused on the immunological nature that drives airways hyperreactivity and smooth muscle hypertrophy in asthma. Anti-​IgE therapy Atopic asthma is strongly associated with allergen-​specific IgE. Omalizumab is a humanized IgG1k monoclonal antibody that spe- cifically binds to free human IgE but not to IgE that is already bound by the high affinity IgE receptor (FcεRI) on the surface of mast cells, basophils, and antigen-​presenting dendritic cells. Steric hindrance by the receptor means the receptor is not accessible to omalizumab binding, thus averting anaphylaxis. Omalizumab significantly im- proves asthma-​related symptoms, allowing for reduction in cortico- steroid and rescue inhaler use. A review of 25 studies involving over 6000 patients concluded that it reduced exacerbations by about 40% and improved health related quality of life scores. It appears that most benefit is obtained by patients with blood eosinophilia, high levels of exhaled nitric oxide, and high levels of serum periostin. Treatment (in the UK) is currently restricted based on the presence of peren- nial atopy, serum IgE levels and the patient’s body weight, criteria that are not necessarily associated with therapy response. Treatment with anti-​IgE does not affect IgE production and patients have to at- tend for omalizumab injections regularly and on a long-​term basis. Future research addressing this and the role of anti-​IgE therapy in nonatopic asthma might increase its availability and effectiveness. Bronchial thermoplasty The airways of patients with asthma demonstrate both airways smooth muscle hypertrophy and, particularly in the most severe types of disease, cell hyperplasia. Inhaled β2 agonist therapy allevi- ates symptoms via muscle relaxation and bronchodilation, whereas inhaled corticosteroids counteract mechanisms that cause airway obstruction via inflammation, but neither of these treatments are curative. Applying radiofrequency energy to subsegmental airways has been shown to reduce muscle mass at the site of thermoplasty. A four-​armed basket electrode is introduced into the airways using a bronchoscopic catheter, expanded to make contact with the airway wall, and then used to deliver radiofrequency energy in order to warm the airway wall to a target temperature of 65°C. Therapy involves three bronchoscopy procedures, and patients are at considerable risk of exacerbations of asthma immediately thereafter. Sham-​controlled trials have demonstrated a reduction in the number of severe asthma exacerbations and improvement in asthma –​specific quality of life. A recent study found no adverse events after a five-​year follow-​up period. Although guidelines recommend bronchial thermoplasty for adults with severe asthma that is not controlled on inhaled cortico- steroids and long-​acting β2-​agonists (LABA), it is currently unclear which phenotypes respond best to the treatment, and long-​term safety outcomes remain uncertain. Immune suppressive treatments Methotrexate, an antimetabolite that antagonizes folate metab- olism, is a well-​established anti-​inflammatory and corticosteroid sparing drug used in various autoimmune diseases. In patients with severe asthma whose symptoms remain uncontrolled despite op- timal therapy, methotrexate has been shown to be of some benefit; placebo-​controlled, randomized, double-​blind, parallel-​group studies reported a marginal reduction in glucocorticosteroid use. Methotrexate in low doses (usually 5–​15 mg weekly, administered on a single day) has been used with generally infrequent and minor side effects. Increasing doses may be accompanied by more severe side effects including leukopenia (which is unpredictable and can be life-​ threatening), acute liver injury, pulmonary toxicity (acute pneumon- itis and insidious interstitial fibrosis), and opportunistic infections such as Pneumocystis carinii pneumonia, pulmonary cryptococcosis, and nocardiosis. Patients on methotrexate require close monitoring and treatment should only be initiated in specialist centres. Antimicrobial treatments Macrolides are a group of drugs with a macrocyclic lactone ring. The group consists of a variety of agents including antibiotics, antifungal drugs, prokinetics, and immunosuppressants. Macrolides have been shown to attenuate proinflammatory cytokine production, cell proliferation, and mucin secretion in the airways. Studies suggest that patients with neutrophil predominant severe asthma or with documented Mycoplasma or Chlamydia infection tend to benefit most from treatment by showing a decline in exacerbation rate, im- proved peak expiratory flows, and improved quality of life. However, chronic antimicrobial use is associated with the risks of population resistance, and treatment should be restricted to a carefully selected patient group who remain symptomatic despite optimal asthma management. Itraconazole is an antifungal agent used for the treatment of ABPA, a frequently seen complication in severe asthma. Two randomized controlled studies demonstrated a benefit compared with placebo in terms of eosinophilic airway inflammation and corticosteroid re- quirements, but the effect on lung function has been less convincing. Severe asthma with fungal sensitization, a disorder closely related to ABPA, is a specific phenotype of asthma characterized by severe asthma and evidence of fungal sensitization after exclusion of ABPA. In patients with this condition itraconazole has been shown to sig- nificantly improve asthma quality of life in a placebo-​controlled study over a 32 week period. Azoles such as itraconazole are strong inhibitors of the CYP3A4 enzymes that metabolize inhaled corticosteroid in the liver to in- active metabolites. Concomitant administration of itraconazole and budesonide, for example, has been associated with a more than 4-​fold increase in plasma concentrations of inhaled budesonide re- sulting in increased systemic absorption and corticosteroid related side effects requiring close monitoring and (if necessary) dose ad- justment. Whether the benefits of itraconazole is due to primarily a pharmacokinetic effect on corticosteroid bioavailability will need to be addressed in future trials. Voriconazole and posaconazole are antifungal agents used in patients who are intolerant of itraconazole or in itraconazole failures, although studies to date suggest that their effectiveness might not be as good as itraconazole. Future treatments The identification of novel bioactive molecules that contribute to the pathophysiology of asthma has been a predominant focus of asthma research in the last decade. Several biologics that target the Th2 cyto- kines involved in asthma pathogenesis, such as anti-​IL5, anti-​ IL-​13

section 18  Respiratory disorders 4090 and combined anti-​IL-​4/​13 antibodies, have had promising results in clinical trials so far. Anti-​IL-​5 antibodies The first randomized controlled study with anti-​IL-​5 antibodies was conducted in patients with mild-​to-​moderate asthma. A single dose of the anti-​IL-​5 antibody mepolizumab reduced sputum and blood eosinophil counts but failed to show a clinically significant benefi- cial effect in terms of lung function and symptom control. However, after selectively targeting patients with severe disease and evidence of airway eosinophilia, anti-​IL-​5 treatment has been shown to sig- nificantly reduce exacerbation rates and oral corticosteroid doses re- quired to control symptoms. In this study (DREAM—​dose ranging efficacy and safety with mepolizumab in severe asthma) treatment with mepolizumab reduced asthma exacerbations by 50%, although the effect on asthma symptoms, quality of life, or lung function was limited. In a subsequent study the investigators selected patients with high blood eosinophilia and exacerbation rates (at least two per year) and found clear evidence for improved symptom control and a percentage reduction from baseline in the corticosteroid dose of 50%. Measuring of sputum eosinophilia is not readily available but the study identified blood eosinophil counts as a good predictive biomarker for treatment response. Aside from mepolizumab, studies have also tested the anti-​ interleukin-​5 antibody reslizumab, which showed promising re- sults in patients with asthma and nasal polyps. The humanized monoclonal antibody targeting the interleukin-​5 receptor (Rα) benralizumab led to lower exacerbation rates in patients with eo- sinophilic asthma and to improved quality of life and lung function. Mepolizumab, reslizumab and benralizumab may be appropriate treatments for patients with a high oral corticosteroid burden, but (because of funding restraints) are not widely available. Inhibitors of cytokines IL-​4 and IL-​13 Various approaches to inhibiting the cytokines IL-​4 and IL-​13 have been developed. Pitrakinra is an IL-​4 mutein, which binds to the IL-​4Rα subunit and prevents the inflammation induced by IL-​4 and IL-​13. It has been shown to reduce allergen induced airway re- sponses when given in inhaled or subcutaneous form in a study of mild asthmatics, and to reduce exacerbation rates in those with eo- sinophilia. The investigators also found a reduction in FeNO levels after four weeks of treatment, which underpins FeNO as a valuable biomarker for Th2 directed therapies. Other groups have tested the fully human monoclonal IL-​4R-​α antibody dupilumab and found improved lung function, symptoms, and exacerbation rate in moderate—​severe asthma. During the study patients reduced first their LABA’s and secondly their inhaled corticosteroids. Patients on dupilumab had significantly fewer ex- acerbation rates after withdrawal as compared to the placebo group. In the study exacerbation was defined as the need for systemic cor- ticosteroids or doubling of the ICS dose, whereas most studies would use more than 3 days of oral corticosteroids as definition. Treatment also improved lung function and asthma quality of life. Lebrikizumab is a humanized monoclonal antibody against IL-​ 13, which induces bronchial epithelial cells to secrete periostin, a matricellular protein involved in airway hyper-​responsiveness, mucus production, and airway remodelling. A  study with lebrikizumab found a small but significant improvement in FEV1 in patients with moderate—​severe asthma. The effect was most substantial in pa- tients with above the median serum periostin concentrations, making periostin not only a reliable biomarker but also a predictor of re- sponse to a targeted therapy. Another IL-​13 monoclonal antibody, tralokinumab, also showed a beneficial effect on lung function. Inhibitors of cytokines IL-​17 Treatments for patient with a Th2 low inflammatory signal have so far been more difficult to achieve clinical benefits and the reason for this might stem from the fact that Th2-​low asthma remains poorly understood and largely identified by the absence of Th2 biomarkers. Patients with severe asthma are found to have higher levels of the proinflammatory cytokine IL-​17A in sputum and airways, and the severity of airway hypersensitivity correlates with airway neutrophilia and levels of IL-​17A. In a randomized controlled trial the human anti-​IL-​17 receptor monoclonal antibody brodalumab, which blocks receptor binding of IL-​17A and IL-​17F, and also the Th2 associated IL-​17E/​IL-​25, was not effective compared to placebo. Inhibitors of TNFa Tumour necrosis factor-​alpha (TNF​α), a proinflammatory cytokine released by mast cells, eosinophils, epithelial cells, and T cells, con- tributes to airway inflammation by stimulation of adhesion mol- ecules, accounting for the increased accumulation of neutrophils and eosinophils in the lungs. TNF​α also contributes to airway re- modelling by stimulating the production of extracellular matrix glycoproteins and goblet cell metaplasia and by activating fibro- blasts. It is present in higher concentration in the airways of patients suffering from asthma, particularly severe asthma. Targeting TNF​α has proven successful in several inflammatory conditions, generally involving neutrophils, including rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. In asthma, the anti-​TNF​α antibody etanercept has been tested in severe asthma, and while a small study found that it increased lung function and decreased bronchial hyperresponsiveness compared to placebo, a larger follow-​up study showed only minimal effect on asthma symptom control and no effect on other outcomes measured. Infliximab, another monoclonal antibody against TNF​α, has been tested in moderate symptomatic asthmatics and resulted in reduced exacerbation rates. However, the effect ceased as soon as the drug was discontinued. The fully human anti-​TNF-​antibody golimumab did not have any clinical benefit, but resulted in an increase in re- spiratory infections and malignancies leading to an early discon- tinuation of the trial. Vitamin D supplementation Deficiency in serum vitamin D has been linked to chronic inflam- matory lung disease such as asthma and viral respiratory infections, with higher rates of hospital admissions for respiratory diseases. Multiple epidemiological studies have shown a positive correlation between vitamin D deficiency and asthma prevalence, severity, and corticosteroid requirements. This led to a variety of supplementa- tion studies. A small study in children observed reduced exacerbation rates in those treated with ICS and vitamin D, as compared to ICS and pla- cebo. Other studies in children from Japan and Mongolia noticed a reduction in respiratory infections, an important cause of asthma exacerbations. The Vitamin D Assessment (VIDA) trial, a study in

18.7  Asthma 4091 over 400 adults with poorly controlled asthma, reported no effect on asthma exacerbation rates but noted that patients treated with vitamin D were able to reduce the dose of ICS significantly more than the placebo group. By contrast, several placebo-​controlled intervention studies failed to show any significant effect on asthma symptom control, exacerbation rates, or lung function. Overall, no clear conclusion has emerged from trials of vitamin D. A reason for this might be the heterogeneity in trial designs so far, with different groups using different molecular forms and dosing regimens of vitamin D. It further remains unclear whether all in- dividuals would benefit from vitamin D treatment, or only those with profound low serum levels, or certain asthma endotypes such as patients with asthma that is less steroid responsive. Future trials need to address two important questions. Firstly, does vitamin D supplementation affect the development of asthma. The Vitamin D Antenatal Asthma Reduction Trial has been designed to determine whether prenatal supplementation can prevent the development of asthma and allergies in women’s offspring. Secondly, well-​ conducted, randomized controlled trials need to address whether vitamin D supplementation has a role in improving asthma severity. Severe and difficult-​to-​treat asthma Most cases of asthma in the community are mild—​Steps 1 and 2 of the BTS guidelines; ‘difficult’ asthma, requiring treatment equivalent to Step 5, constitutes less than 5% of cases. A community study of five large general practices in South Nottinghamshire, England (a population of 38 865) found patients with diagnosed asthma were either not receiving treatment (8%) or receiving treatment equiva- lent to Steps 1 and 2 (76%); 11% were on Step 3 and some 5% on Steps 4 and 5. The authors endeavoured to assess the effectiveness of asthma treatment in this population by measuring the proportion of patients who during a 1-​year period required oral corticosteroid courses or were prescribed 10 or more short-​acting β2-​agonist in- halers:  12.5% patients not taking them regularly had been pre- scribed one or more courses of oral corticosteroids, 1.6% on three or more occasions; 13.6% patients had been prescribed 10 or more short-​acting β2-​agonist inhalers; both outcomes were more frequent in patients on Steps 3 or higher of the BTS guidelines. However, be- cause only a few patients (15%) were in these categories, more than one-​half of the patients who required either oral corticosteroids or 10 or more β2-​agonist inhalers were on Steps 1 or 2, indicating con- tinuing significant morbidity among some cases of asthma receiving either low dose or no anti-​inflammatory treatment. Severe asthma is asthma that is not controlled by maximum doses of inhaled treatment, including inhaled corticosteroids in doses of beclometasone of up to 2000 µg/​day (or equivalent), along with add- itional treatment such as long-​acting β2-​agonists. It is uncommon, af- fecting around 5–​10% of asthmatics, but important. The severity of disease and associated disability is considerable: the risks of near-​fatal and fatal asthma are high, and the adverse consequences of treatments are severe and tolerable only if these are demonstrably effective. Assessment of a patient presenting with recurrent episodes of wheezing, chest tightness, and/​or cough requires a careful history focusing on symptoms, exacerbating triggers including occupa- tional as well as environmental factors, and current treatment re- gimes. Assessment aims to differentiate severe asthma (Box 18.7.2) from difficult-​to-​treat asthma (Box 18.7.3), which is aggravated by poorly controlled comorbidities or inadequate treatment adherence and/​or inhaler technique. With the correct diagnosis established, systematic evaluation has the potential to identify up to half of pre- viously deemed severe asthmatics as difficult-​to-​treat asthmatics. In a prospective study of 286 patients with severe asthma a system- atic assessment within a dedicated Difficult Asthma Service in the United Kingdom led to significant improvements in quality of life, reductions in hospital admissions, and steroid dose required to con- trol symptoms. In 2013, the international ERS/​ATS guidelines classified severe asthma as a disease that requires treatment with high-​dose inhaled corticosteroids and/​or systemic corticosteroids to prevent it from becoming uncontrolled, or which remains uncontrolled despite this therapy. Symptoms are assessed with the help of the Asthma Control Questionnaire (ACQ) and the Asthma Control Test (ACT). Asthma Control Questionnaire Patients are asked to recall their experiences during the previous week and answer six questions related to night-​time waking, Box 18.7.2  Features of severe asthma 1 Consistently poor symptom control: ACQ consistently more than 1.5 or ACT less than 20. 2 Frequent severe exacerbations requiring at least two courses of oral corticosteroids for a minimum of three days in the previous year. 3 One or more hospitalizations, intensive care unit admission or invasive ventilation in the previous year. 4 FEV1 less than 80% predicted (with FEV1/​FVC reduced to less than the lower limit of normal). Box 18.7.3  Difficult asthma—​why is it failing to respond? 1 Does patient have asthma? • Is there evidence of significant response to bronchodilators/​ steroids? • Have other relatively common causes of similar symptoms been excluded? −​ COPD (irreversible airflow limitation) −​ Localized obstruction −​ Left heart failure −​ Pulmonary thromboembolic disease −​ Vocal cord dysfunction • Have other relatively uncommon causes of similar symptoms been excluded? −​ Vasculitis—​Churg–​Strauss syndrome 2 Is prescribed treatment reaching the airways? • Is patient taking the treatment (inhaled and oral) • Is inhaler technique satisfactory? 3 Are there any unrecognized provoking factors? • Domestic allergens—​particularly cats • Occupational agents • Drugs (e.g. aspirin, NSAIDs, β-​blockers) • Upper airway disease—​rhinitis/​sinusitis • Gastro-​oesophageal reflux −​ Fungal sensitization −​ Obstructive sleep apnoea −​ Obesity 4 Are there significant psychological and social factors?

section 18  Respiratory disorders 4092 symptoms on waking, activity limitation, shortness of breath, wheeze and rescue short-​acting β2-​agonist use. They respond to each on a seven-​point scale (0 = no impairment; 6 = maximum im- pairment). In addition their FEV1% predicted prebronchodilator is scored on a similar seven-​point scale. The items are equally weighted and the ACQ score is the mean of the seven items, ranging between 0 (totally controlled) and 6 (severely uncontrolled). A score below 1.0 indicates adequate control and a score above 1.0 inadequate control. Asthma Control Test Patients are asked to answer five questions: in the past four weeks: (1) How much of the time did your asthma limit you from getting as much done at work, school, or home as you wanted? (2) How often have you had shortness of breath? (3) How often did asthma symptoms wake you at night or earlier than usual in the morning? (4) How often have you used your rescue inhaler or nebulizer medi- cation? (5) How would you rate your asthma control? Each question is answered on a five-​point scale, leading to a total score ranging from 5 (poor control) to 25 (complete control). Box 18.7.2 shows the features of severe asthma, with any of the criteria listed qualifying a patient as having ongoing symptoms and therefore severe asthma. Management of severe and difficult-​to-​treat asthma Having confirmed the diagnosis of asthma, it is important to en- sure good inhaler technique and adherence to prescribed treat- ment, failure to take treatment properly being a common reason for failure to respond. This may reflect lack of understanding that pre- ventive treatment needs to be taken regularly and not ‘as needed’, or poor inhaler technique. Patients may take preventive treatment irregularly because, unlike short-​acting β2-​agonists, it does not pro- vide immediate symptomatic relief. Others may be inappropriately concerned about potential side effects or resent the need to take regular inhaled treatment. In patients taking oral corticosteroids blood eosinophil count is markedly reduced and often reported as zero. Failure to take prednisone can be confirmed by demonstrating its absence in serum. One study, using a computerized timing device in a dry powder inhaler, found only 18% of patients took inhaled steroids as pre- scribed, but in routine clinical practice adherence to inhaled treat- ment is difficult to monitor. Poor treatment adherence may be suspected as a cause of difficult asthma in patients whose asthma im- proves when treatment, although unchanged, is supervised. Patient understanding of the effectiveness of regular treatment may also be reinforced by this means. Allergens Unidentified provoking factors include allergens, commonly do- mestic pets (in particular cats), whose allergens can be present in suf- ficient concentrations to cause asthma for several months after the animals have left the home. Sensitizing agents encountered at work can also cause asthma that is poorly controlled by inhaled treatment. Early identification and avoidance of the cause is important to min- imize the risk of development of chronic asthma. Aspirin, NSAIDs, and β-​blockers can also be important provoking factors. Severe asthma is associated with fungal and/​or mould sensitivity, with up to a quarter of patients with persistent symptoms testing positive on skin tests for Aspergillus or other fungi such as Candida, Penicillium, and Curvularia species. Fungi can cause damage to the host either by acting as an aeroallergen or by causing infection. ABPA is a hypersensitivity reaction to Aspergillus fumigatus and can be found in 10–​25% of patients with severe asthma. It is character- ized by peripheral blood eosinophilia, elevated specific serum IgE levels, positive skin prick testing to Aspergillus, and fleeting pul- monary opacities on the chest X-​ray. Symptoms tend to respond well to treatment with oral corticosteroids and antifungals. Patients with evidence of fungal sensitization who do not meet the criteria for ABPA are characterized as suffering from severe asthma with fungal sensitization. Rhinitis Rhinitis commonly accompanies asthma, and its treatment can be associated with improvement in asthma and airway hyper-​ responsiveness. The explanation for this association is unclear but may be a consequence of inflammatory mediators in postnasal drip increasing airway responsiveness and provoking cough. Similarly, gastro-​oesophageal reflux can provoke cough and worsen asthma, and a trial with a proton pump inhibitor such as omeprazole should be instituted when this is suspected to an exacerbating factor, al- though objective improvement in asthma with such treatment is uncommon. Other factors Snoring, observed apnoea, and poorly controlled asthma are closely linked and patients with obstructive sleep apnoea and nocturnal asthma may have similar clinical presentations. Treatment with continuous positive airway pressure has the potential to improve asthma-​related quality of life, lung function, and to reduce short-​ acting β-2 agonist requirements Uncommonly asthma may be a manifestation of systemic dis- ease, particularly a systemic vasculitis—​Churg–​Strauss syndrome—​ when asthma, which can be difficult to control, is accompanied by a high blood eosinophil count (usually >1.5 × 109/​litre). Other mani- festations include eosinophilic pneumonia, pleural and pericardial effusions, and mononeuritis multiplex. Effective treatment requires high-​dose oral corticosteroids and in some cases other immunosup- pressant treatment. Nocturnal asthma can persist in some patients despite treatment with inhaled corticosteroids that provides good daytime control. This may be improved by the addition of a long-​acting β2-​agonist or slow-​release theophylline. Premenstrual deterioration of asthma is not uncommon, and in some women can be severe and unresponsive to corticosteroid treatment. Characteristically symptoms increase and PEF falls 2–​5 days before the menstrual period, improving with the onset of menstruation that coincides with the fall in progesterone secre- tion and increase in oestrogen:progesterone ratio. Some patients are improved by treatment with intramuscular, but not oral, pro- gestogen during the week before menstruation. Patients with se- vere premenstrual exacerbations can require hospital admission, in some cases ventilation, and may only be improved by surgical removal of the ovaries. There is also now the option of inducing a short-​term chemical menopause with GnRH analogues prior to surgery.

18.7  Asthma 4093 Corticosteroid-​resistant asthma Patients with corticosteroid-​resistant asthma, which is very un- common, show no response to oral corticosteroids, even in high dose, although they do show spontaneous variability of peak flow and reversibility with inhaled bronchodilators. They probably form the end a spectrum of resistance to the anti-​inflammatory activity of corticosteroids, which also includes the very few patients with ‘corticosteroid-​dependent asthma’ whose disease is only controlled with continuous oral corticosteroids, often in high doses, with re- duction in dose being followed by worsening of asthma. A variety of definitions have been used to describe corticosteroid resistance, with the most widely one being that of persistent airways obstruction with an increase of less than 15% in FEV1 following two weeks of oral corticosteroid treatment. Steroid resistance is attributable to genetic disease specific and environmental factors. Gene expression studies have linked gene modification, for example, in p50 (a component of NF-​κB), FKBP51, a glucocorticosteroid receptor (GR) chaperone protein or corticotrophin releasing hormone receptor-​1, with the degree of responsiveness of asthmatics to steroids. Steroid resistance is also associated with an increased expression of the transcriptionally inactive glucocorticoid receptor β (GR-​) ß and defects in gluco- corticoid receptor binding. Cigarette smoke has been implicated in steroid resistance; oxidative stress has been shown to impair nuclear translocation of GR and to increase proinflammatory transcription factors such as NF-​κB and AP-​1, and to reduce histone deacetylase (HDAC2), a protein suppressing proinflammatory genes. Blood mononuclear cells from smoking asthmatics also have an elevated GR-​β to GR-​α ratio. Allergen exposure decreases the binding af- finity of GR, and viruses and bacteria have been shown to impair GR nuclear translocation. Steroid resistance has also been associ- ated with airway remodelling: TIMP-​1 is a tissue inhibitor protein of the matrix metalloproteinases (MMPs), which degrade collagen. MMP-​9 and TIMP-​1 have both been shown to be increased in asth- matic patients, but steroid resistant patients express a higher ratio of MMP-​9/​TIMP-​1 because of an inability of steroids to enhance TIMP-​1 production. A better understanding of the molecular mechanisms of corticosteroid-​resistant asthma will pave the way for future, steroid-​ sparing treatments. Therapy with antibodies including anti-​IgE and anti-​IL-​5 have been proven safe and effective, and a variety of novel biologics continue to be developed. In vitro studies suggest a role for vitamin D in improving the therapeutic response to corticosteroids and clinical studies addressing the role of vitamin D in this defined patient group will clarify these findings. Acute asthma attacks Asthma attacks are episodes of progressively worsening airway narrowing associated with increasing shortness of breath, cough, wheezing, and chest tightness, or some combination of these. They can vary in severity from episodes in which patients are able to manage themselves by following an agreed treatment plan, to severe and potentially life-​threatening episodes that require medical atten- tion and hospital admission. Severe attacks can vary in their speed of onset from deterioration over days to episodes that progress rapidly and can become life-​threatening within minutes or hours. In about one-​half of cases of fatal asthma the attack lasted more than 24 h, in one-​quarter less than one hour. Fatal or near-​fatal attacks of asthma are associated with: • Patients who have previously required hospital admission for se- vere asthma and who require regular oral steroid treatment • Failure to recognize severity of asthma by the patient: those with long-​standing asthma can become accustomed to their symptoms and not appreciate an important increase in their severity that may persist for days or weeks, sometimes associated with psychosocial problems and poor adherence to treatment • Failure to recognize the severity of asthma by the doctor, the risk of which can be minimized by making appropriate objective measurements of respiratory, heart, and peak flow rates to assess severity • Undertreatment or inappropriate treatment:  failure to use oral corticosteroids in adequate doses early in an exacerbation is prob- ably the single commonest remediable factor; the use of sedatives or anxiolytics to reduce the anxiety or agitation that can often ac- company acute severe asthma is absolutely contraindicated Many of these problems can be overcome by improved patient understanding, allowing them to have control over their illness sup- ported by a jointly agreed management plan. Moderate asthma attacks Exacerbations of asthma with increased symptoms, both during the daytime and at night, frequently follow a viral infection or allergen exposure in allergic individuals (or both), or a reduction in anti-​ inflammatory treatment. The increase in symptoms, associated with deterioration in peak flow, is often treated adequately by the patient increasing the frequency of inhaled short-​acting bronchodilators, doubling the dose of inhaled steroids, or taking a short course of oral steroids. Several studies have shown that early treatment with oral corticosteroids taken at the start of an acute exacerbation re- duces the need for hospital admission, the frequency of relapse, and the need for β2-​agonists. One recent overview of seven randomized controlled trials in 320 patients found that systemic corticosteroids, taken at the onset of an acute exacerbation, reduced hospital admis- sions in both children and adults by 65% in the first week compared with placebo, an effect maintained for 21 days. No difference was observed between the use of oral and intramuscular corticoster- oids. Oral corticosteroids continued for a short period after hos- pital discharge reduce the risk of early relapse, which occurs in some 10–​15% of patients following discharge after emergency treatment. A Cochrane review of seven trials comparing oral corticosteroid treatment with placebo following discharge found a two-​thirds re- duction in relapse rate in those taking oral corticosteroids and a re- duced need for β2-​agonists at 1 and at 3 weeks after discharge. Severe asthma attacks Acute severe asthma is a potentially life-​threatening increase in the severity of asthma that can develop over minutes, hours, or days, and which has often failed to respond to conventional inhaled broncho- dilator treatment. It is usually the outcome of airways increasingly narrowed by the consequences of chronic inflammation to cause increasing resistance to airflow identified as a reduction in PEF and

section 18  Respiratory disorders 4094 FEV1, hyperinflated lungs, ventilation–​perfusion inequality, and hypoxia, which is the most serious consequence of severe asthma. Initially these stimulate alveolar hyperventilation with a reduction in PCO2, but—​with increasing airway narrowing and exhaustion—​ arterial PO2 continues to fall while arterial PCO2 rises to normal, and subsequently increases steeply with the development of alveolar hypoventilation. In general, PCO2 rises into the normal range when FEV1 is some 25% and PEF 30% of predicted normal values. Enquiries into asthma deaths in the United Kingdom concluded that many patients who died had received inadequate treatment. One reason for this may be a lack of awareness among doctors and patients on the severity of their disease. The clinical features of importance in identifying acute severe asthma and assessing its severity are shown in Box 18.7.4. Patients are usually extremely breathless and unable to complete sentences in one breath. A rapid respiratory rate and heart rate are good markers of severity of asthma and hypoxia. Although anxiety and increased use of β2-​ agonists can increase heart rate, a rapid heart rate should not be ignored by attributing it to these factors. An objective measure of airflow should be obtained because the severity of limitation is difficult to assess clinically. Although PEF is an effort-​dependent measurement, it is usually possible to obtain a reading from pa- tients with severe asthma: a value of less than 50% of predicted, or of the recent best value in an adult aged less than 50 years, usually indicates severe asthma; a value of less than 33% indicates a poten- tially life-​threatening attack. Arterial blood gas analysis should be performed in adults seen in hospital as an important guide to the severity of asthma; children can often be managed safely by measurement of oxygen saturations alone. Most patients admitted to hospital with acute severe asthma are hypoxic, of whom about one-​third will have PO2 less than 8 kPa (60 mm Hg). PCO2 is reduced in patients with moderately severe asthma, but with increasingly severe airways obstruction and fatigue PCO2 subsequently rises in parallel with a falling PO2. A normal PCO2 in a hypoxic patient with acute severe asthma indicates impending hypoventilation, with a rapidly increasing PCO2, falling PO2, acidosis, narcosis, and death. Management The aims of the treatment of acute severe asthma are to reverse the hypoxia, airflow limitation and airway inflammation with oxygen, bronchodilators, and corticosteroids (Box 18.7.5). Criteria for admission to hospital Patients with any features of acute severe asthma that persist after initial treatment should be admitted to hospital. Admission is also appropriate in patients whose symptoms improved but where there are concerns about treatment adherence, psychological problems, physical disability, and uncontrolled comorbidities or learning dif- ficulties. Patients who present at night, who are pregnant, or who suffered an attack despite being on adequate treatment, should be admitted for observation. Patients who have PEF measurements below 75% of their personal best or predicted have a substantial risk of early relapse and readmission and are at a high risk of mor- bidity and mortality. Oxygen Oxygen relieves the hypoxia that is present in most people with an acute severe asthma attack. The aim is to give controlled oxygen therapy with flow rates adjusted as necessary to achieve target sat- urations of 94–98%. Bronchodilators The purpose of bronchodilator treatment in acute severe asthma is to reverse the airway narrowing due to smooth muscle contraction, before the onset of the anti-​inflammatory action of corticosteroids that usually takes 6–​12 h from administration. Inhaled bronchodilators Inhaled high-​dose β2-​agonists (salbutamol, terbutaline) admin- istered by spacer or nebulizer are used as initial treatment. The benefit of a nebulizer is that it allows inhalation of bronchodilator to be driven by a high flow of oxygen, which can be important in Box 18.7.4  Acute severe asthma: assessment of severity Features of acute severe asthma • Unable to complete sentences in one breath • Respiration rate more than 25 breaths/​min • Pulse rate more than 110 beats/​min • Peak expiratory flow rate 33–​50% predicted or best Life-​threatening features • PEF less than 33% predicted or best • Silent chest • Bradyarrhythmia or hypotension • Exhaustion, confusion, or coma SpO2 less than 92% PO2 less than 8 kPa Normal PCO2 (4.6–​6 kPa) Markers of near-​fatal asthma • High PCO2 • Severe hypoxia: PO2 less than 8 kPa (60 mm Hg) • Low pH or high (H+) Box 18.7.5  Treatment of acute severe asthma Initial treatment • Oxygen to maintain SpO2 94–​98% • Nebulized salbutamol 2.5–​5 mg or terbutaline 5–​10 mg (driven by oxygen via nebulizer) • Oral prednisolone 40–​50 mg or intravenous hydrocortisone 400 mg daily (100 mg six-​hourly) If poor response to initial treatment after 15–​30 min • Continue oxygen • Repeat nebulized salbutamol 5 mg after 15 min • Add ipratropium 0.5 mg to nebulized β-​agonist • Consider intravenous magnesium sulphate 1.2–​2 g over 20 min • Investigations: -​ Chest radiograph to exclude pneumothorax, pneumomediastinum, and lobar collapse -​ Monitor serum K + (risk of hypokalaemia with high-​dose β-​agonist) • Consider intravenous salbutamol (see text) • Consider intravenous aminophylline (see text) If poor response within 1 h • Admit to intensive care for possible intubation and ventilation

18.7  Asthma 4095 severe and life-​threatening asthma as β2-​agonists may increase ventilation–​perfusion inequality and consequent arterial hypoxia, hence β2-​agonists should not be administered without oxygen to those who are hypoxic. Continued nebulization has been proven to be more effective than bolus dose administration. Nebulized salbutamol (5 mg) or terbutaline (10 mg) driven by 6 litres/​min oxygen can be given safely by trained ambulance crews during transfer to hospital. However, nebulizers are inefficient and widely variable in their performance, which has led to the suggestion that large volume spacers be used as alternative delivery systems. In adults and children with severe but not life-​threatening asthma, inhalation of β2-​agonist by nebulizer has not been found to pro- vide additional bronchodilatation as compared to inhalation of a metered dose inhaler via a spacer, and the latter is associated with fewer side effects. However, it should be appreciated that the studies on which these observations are based are of patients with moderately severe asthma who did not require hospital admission. Spacers do not easily allow concurrent administration of oxygen and require patient cooperation, which can be difficult in severely breathless patients. Intravenous bronchodilators The intravenous bronchodilators used in clinical practice are β2-​ agonists and theophylline. The theoretical advantage of giving β2-​agonists intravenously rather than by inhalation is access to peripheral airways so narrowed that they cannot be reached by in- halation, although inhaled salbutamol is rapidly absorbed from the lungs, reaching a peak concentration within 10 min of inhalation. Although some study results suggest that a bolus of intravenous sal- butamol may reduce symptoms and hasten recovery, the evidence base for intravenous β2-​agonists remains limited. The major dis- advantage of intravenous β2-​agonists, in comparison to inhalation, is the greater frequency of systemic side effects including a dose-​ related risk of developing diastolic hypotension and lactate acid- osis. For this reason intravenous β2-​agonists should be reserved for patients in whom inhaled therapy cannot be used reliably and for whom close monitoring is available. The use of intravenous aminophylline in the treatment of acute asthma has decreased with the recognition that it does not provide additional benefit to repeated or continuous nebulized β2-​agonist bronchodilators in the initial hours of emergency treatment. This, together with its narrow therapeutic window, need for drug moni- toring, and interactions with other drugs, has led to its replace- ment as first-​line bronchodilator treatment of asthma by inhaled β2-​agonists. However, it is recommended as additional therapy for patients not responding to initial treatment with inhaled β2-​ agonists and corticosteroids and as initial treatment in the very se- verely ill patient with a normal or high PCO2. In patients who have not been taking theophylline prior to admission, a loading dose of 5 mg/​kg body weight over 20 min should be followed by a main- tenance dose of 0.5 mg/​kg body weight per hour until a serum level of 10–​20 µg/​litre is obtained. The loading dose should be omitted in those currently taking theophyllines, in whom the serum con- centration should be measured. The infusion rate should be de- creased in patients with liver or heart failure, or in those taking cimetidine, macrolide, or quinolone antibiotics. Toxic side effects are increasingly common in patients whose serum level exceeds 25 µg/​litre, ranging from gastrointestinal symptoms to fits and car- diac arrhythmias. Antimuscarinics The purpose of antimuscarinic treatment is to reverse airway nar- rowing caused by increased vagal tone that is not responsive to high-​dose inhaled β2-​agonists. Several studies have suggested the addition of a nebulized antimuscarinic provides additional benefit in the treatment of acute severe asthma, both in children and in adults. A Cochrane review in children found that multiple doses of ipatropium bromide in addition to a β2-​agonist significantly increased FEV1 and reduced the risk of hospital admission in comparison to a β2-​agonist alone in moderate and severe exacerbations of asthma. A Cochrane review of similar combination therapy in adults found consistent evi- dence for similar improvements in FEV1 and reduction in hospital admissions. Systematic reviews have confirmed the benefits of using inhaled ipatropium bromide in combination with a β2-​agonist in the treatment of patients with moderate to severe acute asthma. Magnesium Systematic reviews have shown that intravenous magnesium sul- phate is a safe and effective treatment in patients with exacerbations of severe asthma. A Cochrane review found that in severe asthma the addition of magnesium sulphate to a β2-​agonist and intravenous corticosteroids improved lung function and reduced the need for hospitalization, without causing adverse effects. Nebulised magne- sium sulphate is ineffective and should not be used. Corticosteroids Systemic corticosteroids are given in acute severe asthma to re- verse the underlying airway inflammation, such anti-​inflammatory action requiring 6–​12 h from administration for demonstrable bronchodilatation to occur. Within 1 h of their administration, ster- oids may also reverse β2 receptor desensitization induced by regular β2 inhalation. The value of corticosteroid treatment in acute severe asthma was first demonstrated in a randomized controlled trial in 1956 and has since been generally accepted. Corticosteroids are usually given by intravenous administration, but other than in life-​threatening asthma and in patients vomiting or unable to swallow, there is no demonstrable advantage of intravenous over oral administration. When indicated, intravenous doses initially of 100 mg hydrocor- tisone 4–​6 hourly can be followed by oral prednisolone in a dose of 40–​50 mg/​day. The duration of treatment with oral prednisolone will depend on the severity of and rate of recovery from the acute episode. In general, oral prednisolone should be continued until resolution of the acute episode with return to usual daytime activ- ities, resolution of nocturnal symptoms, and PEF within 80% of the patient’s predicted or best values. Short courses of oral cortico- steroids (taken for <2 weeks) do not need to be tapered provided patients are taking an appropriate dose of inhaled corticosteroid. Although some studies in patients with relatively mild exacerba- tions of asthma (PEF >60% predicted or best) have suggested that high-​dose inhaled steroids are an effective alternative to oral cor- ticosteroids, these results should not to extrapolated to acute se- vere asthma where the recommended guideline is that all patients should be given systemic corticosteroid treatment.

section 18  Respiratory disorders 4096 Intensive care and intermittent positive-​pressure ventilation Most attacks of acute severe asthma respond to treatment with con- trolled oxygen therapy, systemic corticosteroids, and inhaled β2-​ agonists. However, this treatment is insufficient in a few cases, which require intensive care and—​on occasion—​intermittent positive-​ pressure ventilation (IPPV). This need arises in two particular situations: patients who have a catastrophic hyperacute attack, and those whose asthma progressively increases in severity despite max- imal bronchodilator and corticosteroid treatment. The indications for intensive care and IPPV are given in Box 18.7.6. Patients with increasing drowsiness or who lose consciousness with hypoxia and worsening hypercapnoea require IPPV, as do those who suffer a re- spiratory arrest. However, because of the high inflation pressures needed to overcome the high airway resistance and hyperinflated lungs and chest wall, IPPV in acute severe asthma can be difficult and hazardous. High inflation pressures can cause barotrauma with pneumomediastinum and, on occasion, pneumothorax. In addition, up to one-​third of patients develop clinically significant hypoten- sion, requiring inotropic support. Follow-​up Follow-​up arrangements must be made for every patient attending the emergency department with an asthma attack. A review with the patient’s general practitioner or asthma nurse should be ar- ranged within two working days. Treating healthcare profes- sionals ought to encourage self-​management. There is evidence for better asthma control in patients with personal asthma action plans, which should include individual trigger factors, guidance on how to step up treatment and when to seek advice in the case of symptom deterioration. Every patient admitted to hospital with an asthma attack should have a structured review by a member of a specialist respiratory team before discharge. Patients who have been admitted to hospital or who have presented to medical services with two or more asthma attacks in the previous 12 months should be referred for specialist opinion. FURTHER READING Adcock IM, Barnes PJ (2008). Molecular mechanisms of cortico- steroid resistance. Chest, 134, 394–​401. Barnes PB (1998). Current issues for establishing inhaled corticoster- oids as the anti-​inflammatory agents of choice in asthma. J Allergy Clin Immunol, 101, 5427–​33. Barnes PJ, Pederson S, Busse WW (1998). Efficiency and safety of in- haled corticosteroids. Am J Resp Crit Care Med, 157, 551–​3. Baxter PJ, Aw TC, Cockcroft A (eds) (2010). Hunter’s diseases of occu- pations, 10th edition. Taylor & Francis, London. Berry MA, et al. (2006). Evidence of role of tumour necrosis factor α in refractory asthma. N Engl J Med, 354, 697–​708. Brehm JM, et al. (2009). Serum vitamin D levels and markers of se- verity of childhood asthma in Costa Rica. Am J Respir Crit Care Med, 179, 765–​71. Busse WW, et al. (2013). Randomized, double-​blind, placebo-​controlled study of brodalumab, a human anti-​IL-​17 receptor monoclonal anti- body, in moderate to severe asthma. Am J Respir Crit Care Med, 188, 1294–​302. Castro M, et  al. (2010). Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, ran- domized, double-​blind, sham-​controlled clinical trial. Am J Respir Crit Care Med, 181, 116–​24. Choi JH, Kim MA, Park HS (2014). An update on the pathogenesis of the upper airways in aspirin-​exacerbated respiratory disease. Curr Opin Allergy Clin Immunol, 14, 1–​6. Chung KF, et al. (2014). International ERS/​ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J, 43, 343–​73. Corren J, et al. (2011). Lebrikizumab treatment in adults with asthma. N Engl J Med, 365, 1088–​98. Denning DW, O’Driscoll BR, Hogaboam CM, Bowyer P, Niven RM (2006). The link between fungi and severe asthma: a summary of the evidence. Eur Respir J, 27, 615–​26. Desai D, et al. (2013). Elevated sputum interleukin-​5 and submucosal eosinophilia in obese individuals with severe asthma. Am J Respir Crit Care Med, 188, 657–​63. Drazen JM, et al. (1996). Comparison of regularly scheduled with as needed use of albuterol in mild asthma. Asthma clinical research network. New Eng J Med, 335, 841–​7. Evans DJ, et al. (1997). A comparison of low dose inhaled budesonide plus theophylline and high dose inhaled budesonide for moderate asthma. New Engl J Med, 337, 1412–​18. Garbelt JF, et  al. (1997). Nebulised salbutamol with and without ipratropium bromide in the treatment of acute asthma. J Allergy Clin Immunol, 100, 165–​70. Gibson PG (2013). Obesity and asthma. Ann Am Thorac Soc, 10(Suppl), S138–​42. Gibson PG, Powell H (2004). Written action plans for asthma: an evi- dence based review of key components. Thorax, 59, 94–​9. Green RH, et al. (2002). Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet, 360, 1715–​21. Greening AP, et al. (1994). Added salmeterol versus higher dose cor- ticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet, 344, 219–​24. Grimaldi-​Bensouda L, et al. (2013). Does omalizumab make a differ- ence to the real-​life treatment of asthma exacerbations? Results from a large cohort of patients with severe uncontrolled asthma. Chest, 143, 398–​405. Haahtela T, et al. (1991). Comparison of a β2 agonist terbutaline with an inhaled corticosteroid budesonide in newly detected asthma. New Engl J Med, 325, 388–​92. Haahtela T, et  al. (1994). Effects of reducing or discontinuing in- haled budesonide in patients with mild asthma. New Engl J Med, 331, 700–​5. Box 18.7.6  Acute severe asthma Indications for intensive care • Hypoxia (PaO2 <8 kPa) despite high flow oxygen • Hypercapnoea (PaCO2 >6 kPa) • Exhaustion with feeble respiration • Confusion or drowsiness • Unconsciousness • Respiratory arrest Indications for intermittent positive-​pressure ventilation • Hypoxia (PaO2 <8 kPa) despite high flow oxygen • Increasing hypercapnoea • Drowsiness or unconsciousness • Respiratory arrest

18.7  Asthma 4097 Heaney LG, et al. (2003). Predictors of therapy resistant asthma: out- come of a systematic evaluation protocol. Thorax, 58, 561–​6. Jayaram L, et al. (2006). Determining asthma treatment by moni- toring sputum cell counts: effect on exacerbations. Eur Respir J, 27, 483–​94. Julien JY, et  al. (2009). Prevalence of obstructive sleep apnea-​ hypopnea in severe versus moderate asthma. J Allergy Clin Immunol, 124, 371–​6. Laviolette M, et al. (2013). Effects of benralizumab on airway eosino- phils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol, 132, 1086–​96 e5. Ledford DK, Lockey RF (2013). Asthma and comorbidities. Curr Opin Allergy Clin Immunol, 13, 78–​86. Lipworth B (1999). Systemic adverse effects of inhaled corticosteroid therapy. A systematic review and meta-​analysis. Arch Intern Med, 159, 941–​55. Mallia P, Johnston S (2006). How viral infections cause exacerbations of airway disease. Chest, 130, 1203–​10. Marquette CH, et al. (1992). A 6 year follow up study 145 asthmatic patients who underwent mechanical ventilation for near-​fatal attack of asthma. Am Rev Respir Dis, 146, 76–​81. Moore WC, et al. (2010). Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med, 181, 315–​23. Mortimer KJ, Tattersfield AE (2005). Benefit versus risk for oral in- haled and nasal glucocorticosteroids. Immunol Allergy Clin North Am, 25, 523–​39. Nicholson PJ, et  al. (2005). Evidence based guidelines for the pre- vention, identification, and management of occupational asthma. Occup Environ Med, 62, 290–​9. Niven R, et al. (2019). European consensus meeting/statement on bronchial thermoplasty—who? where? how?. Respir Med, 150, 161–4. Nowak D (2006). Management of asthma with anti-​immunoglobulin E:  a review of clinical trials of omalizumab. Respir Med, 100, 1907–​17. O’Byrne P, et al. (2001). Low dose inhaled budesonide and formoterol in mild persistent asthma. The OPTIMA Randomised Trial. Am J Respir Crit Care Med, 164, 1392–​7. Pauwels RA, et al. (1997). Effect of inhaled formoterol and budesonide on exacerbations of asthma. New Engl J Med, 337, 1405–​11. Pauwels RA, et al. (2003). Early intervention with budesonide in mild persistent asthma:  a randomised double-​blind trial. Lancet, 361, 1071–​6. Pavord ID, et al. (2012). Mepolizumab for severe eosinophilic asthma (DREAM):  a multicentre, double-​blind, placebo-​controlled trial. Lancet, 380, 651–​9. Robinson DS, et al. (2003). Systematic assessment of difficult-​to-​treat asthma. Eur Respir J, 22, 478–​83. Scottish Intercollegiate Guidelines Network, British Thoracic Society (2019). British guideline on the management of asthma: a na- tional clinical guideline. https://www.brit-thoracic.org.uk/quality-
improvement/guidelines/asthma/ Tattersfield AE, Postma DS, Barnes PJ (1999). Exacerbations of asthma. A descriptive study of 425 severe exacerbations. Am J Respir Crit Care Med, 160, 594–​9. ten Brinke A, et al. (2005). Risk factors of frequent exacerbations in difficult-​to-​treat asthma. Eur Respir J, 26, 812–​18. Todd GRG, et al. (2003). Survey of adrenal crisis associated with inhaled corticosteroids in the United Kingdom. Arch Dis Child, 87, 457–​61. Walsh LJ, et al. (1999). Morbidity from asthma in relation to regular treatment: a community based study. Thorax, 54, 296–​300. Wechsler ME, et al. (2013). Bronchial thermoplasty: long-​term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol, 132, 1295–​302. Wenzel SE (2012). Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med, 18, 716–​25. Wenzel SE, et al. (2007). IL4R alpha mutations are associated with asthma exacerbations and mast cell/​IgE expression. Am J Respir Crit Care Med, 175, 570–​6. Wenzel S, et al. (2013). Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med, 368, 2455–​66. Wenzel S, et al. (2007). Effect of an interleukin-​4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: re- sults of two phase 2a studies. Lancet, 370, 1422–​31. Woodruff PG, et al. (2009). T-​helper type 2-​driven inflammation de- fines major subphenotypes of asthma. Am J Respir Crit Care Med, 180, 388–​95. Woolcock AJ, et al. (1996). Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med, 153, 1481–​8.

18.8 Chronic obstructive pulmonary disease 4098 Ni

18.8 Chronic obstructive pulmonary disease 4098 Nicholas S. Hopkinson

ESSENTIALS Definition Chronic obstructive pulmonary disease (COPD) is a lung condi- tion caused by the inhalation of noxious materials, principally to- bacco smoke, and characterized by airflow limitation that is not fully reversible. Key features are cough, sputum production, and breathlessness. There are chronic progressive symptoms and acute exacerbations. The term COPD incorporates several pathological processes, present to a variable extent in any given individual, involving both the airways (chronic bronchitis) and the lung paren- chyma (emphysema). Most COPD patients will have one or more other long-​term conditions. COPD is the third leading cause of death worldwide. COPD should be considered in those over the age of 35 who have (1) exposure to risk factors, usually, but not exclusively, tobacco smoke; (2) a history of chronic progressive respiratory symptoms; (3) airflow limitation that is not fully reversible. Aetiology Cigarette smoking is the single most important identifiable risk factor. Worldwide, biomass smoke exposure from domestic heating, cooking, and lighting is also a major contributor. Other risk factors include early life disadvantage, childhood asthma, and occupations with exposure to dust, fumes, and chemicals. There is significant familial risk, but apart from α1-​antitrypsin deficiency other genetic causes of COPD remain to be established. Pathology and pathophysiology Inflammation, protease/​antiprotease imbalance and oxidative stress all have a role in producing chronic bronchitis, obstructive bron- chiolitis, or small airways disease, and emphysema, which can be centrilobular (centriacinar) or panlobular (panacinar). The characteristic physiological impairment is a decrease in maximum expiratory airflow that limits the level of ventilation that can be achieved. This is caused by destruction of and damage to airways, combined with a loss of lung elastic recoil due to paren- chymal damage. To avoid early airway closure and gas trapping, operating lung volumes rise, increasing the load on the respiratory muscles which are simultaneously at a mechanical disadvantage. Unequal ventilation of lung units leads to ventilation–​perfusion (V/​Q) mismatch which can cause hypoxia. Destruction of the pul- monary capillary bed can lead to pulmonary hypertension. Lung hyperinflation can also impair cardiac function. Skeletal muscle impairment associated with physical inactivity and loss of fitness also contributes to symptoms of breathlessness, as may coexisting cardiac disease. Clinical features History—​Breathlessness is chronic, though there may be some day-​to-​day variation. Cough and sputum vary between individ- uals and over time. Smoking status, tobacco, and nontobacco, is essential as well as details of any childhood chest disease and previous and present occupations, particularly exposure to dust, fumes, and chemicals. Exacerbation frequency can be assessed by patient recall. Comorbidities should be actively sought. Use a health status measure such as the COPD assessment test (CAT) routinely. Examination—​Signs of airflow limitation may not be present until there is significant impairment of lung function, but the breathing pattern in COPD is often characteristic, with a prolonged expiratory phase, and there may be signs of overinflation of the chest. Breath sounds are typically quiet. Pulmonary crackles suggest infection or coexistent bronchiectasis. Seek evidence of pulmonary hyperten- sion (oedema, raised venous pressure, tachycardia). Pulse oximetry should be performed routinely. Investigation Spirometry—​A post-​bronchodilator forced expiratory volume in
1 s/​forced vital capacity (FEV/​FVC) ratio less than 0.70 confirms the presence of airflow limitation that is not fully reversible and is a diagnostic criterion for COPD. The severity of airflow limitation can be graded according to the Global Initiative for Obstructive Lung Disease (GOLD) as mild (≥80% predicted), moderate (50–​79% pre- dicted), severe (30–​49% predicted), or very severe (<30% predicted). Further categorization is based on breathlessness and exacerbation frequency. Lung function tests—​Static lung volumes can be measured to assess the degree of overinflation and gas trapping. Gas transfer measures give evidence of the extent of emphysema. 18.8 Chronic obstructive pulmonary disease Nicholas S. Hopkinson

18.8  Chronic obstructive pulmonary disease 4099 Arterial blood gases—​Confirm the degree of hypoxaemia and hypercapnia in stable patients with oxygen saturations below 93%, or those with clinical signs of respiratory or right heart failure or features of sleep-​disordered breathing. Exercise testing—​The incremental shuttle walk test or 6-​min walk provide objective evidence of exercise capacity, give prognostic in- formation, and may also be used to evaluate the need for ambulatory oxygen. Imaging—​(1) Chest X-​ray may appear normal or show signs of overinflation, pulmonary vascular abnormalities, or other coexisting pathologies. (2) CT scanning can be used to quantify and identify the pattern of emphysema present as well as detecting coexisting bron- chiectasis or pulmonary fibrosis. Other tests—α1 ​antitrypsin levels and phenotype can be measured, especially in patients who have become symptomatic at an early age or with a strong family history. Prevention Stopping smoking is the most effective measure. Action on indoor and outdoor air quality and to address child poverty and early life dis- advantage are also important. Physical activity is probably protective. Management Stable COPD—​treatment is based on an assessment of symptoms, severity of airflow limitation, and the risk of exacerbations. As well as being a preventive measure, the highest value treatment for COPD is smoking cessation. All patients should receive influenza and pneumococcal vaccination. Pulmonary rehabilitation, a supervised programme of exercise and education, reduces breathlessness, improves exercise toler- ance and health related quality of life, and reduces exacerbation frequency and should be offered to all patients who are limited by breathlessness. It is also highly effective, reducing hospital readmis- sion, when applied post exacerbation. Pharmacologic therapy—​inhaled bronchodilators (β2-​agonists and/​ or antimuscarinic agents) are central to symptom management. Short-​acting bronchodilators are prescribed on an as needed basis, but long-​acting bronchodilators usually in combination are given if symptoms are persistent. Inhaled corticosteroids are indicated in patients having two or more exacerbations/​year or in people with more severe airflow obstruction, when they act synergistically with long-​acting bronchodilators. Inhaled therapies do not alter the nat- ural history of the disease. Oral theophyllines are less effective and less well tolerated than long-​acting bronchodilators, but can provide additional symptom relief when added to long-​acting bronchodila- tors. Long-​term azithromycin is effective in some patients with fre- quent exacerbations. Palliative measures—​These include hand-​held battery-​powered fans and low dose oral morphine for breathlessness. Discussions about end of life and establishing a ceiling of care are important in people with severe COPD. Long-​term oxygen therapy (>15 h per day) given to patients with chronic respiratory failure (PaO ≤7.3 kPa or PaO2 <8.0 kPA if pul- monary hypertension is present) improves survival. Other interventions—​Lung volume reduction surgery improves survival in carefully selected patients (upper lobe emphysema, poor exercise capacity but condition not too severe for safety). The evidence for benefit from endobronchial valve placement is also growing. Lung transplantation can be considered in patients with very advanced COPD but is often inappropriate because of comorbidity. Acute exacerbations of COPD (AECOPD) can be caused by various factors, the commonest being viral or bacterial respiratory tract infections. Most can be managed in the community (many patients are able to self-​manage) with short courses of antibiotics and oral corticosteroids. Severe AECOPD are a common reason for admission to hospital, especially in frail individuals or if there is respiratory failure. Treatment includes: (1) controlled oxygen therapy to achieve Pa greater than 8 kPa (60 mm Hg) or Sa 88–​ 92%, without inducing significant CO2 retention; (2) nebulized bronchodilators; (3)  antibiotics—​if there is increased sputum purulence with increase in dyspnoea and/​or increase in sputum volume; (4)  corticosteroids—​prednisolone 30–​40 mg daily for 7 days; and (5) ventilatory support—​usually noninvasive, if pH is less than 7.35. Introduction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. It is defined in the joint American Thoracic Society and European Respiratory Society Guidelines as ‘a preventable and treatable disease state characterized by air- flow limitation that is not fully reversible. The airflow limitation is usually progressive and is associated with an abnormal inflamma- tory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Although COPD affects the lungs, it also produces significant systemic consequences’. The key clinical features of COPD are breathlessness, cough and sputum production, limitation of daily physical activities and the occurrence of acute exacerbations. The presence of airflow obstruc- tion is required as part of the clinical definition of COPD. The se- verity of COPD has conventionally been classified according to the severity of airflow obstruction, defined as a reduction in the forced expiratory volume in one second (FEV1), but this captures only one aspect of the condition. The term COPD, first introduced in 1965, encompasses several pathological processes which may affect the large and small air- ways, the lung parenchyma, and the pulmonary vasculature to a varying extent in any individual. This gives rise to a wide range of possible disease phenotypes (Fig. 18.8.1). In the large airways, chronic bronchitis is defined as the presence of a chronic productive cough on most days for 3 months in at least two consecutive years. Chronic bronchitis is characterized by mucus hypersecretion and may occur by itself in the absence of airflow obstruction, particu- larly in smokers. Conversely, airflow obstruction can occur in the absence of chronic bronchitis. Small airways are destroyed through a process of obliterative bronchiolitis. This, together with emphy- sema, the destruction of lung parenchyma and consequent loss of lung elastic recoil, produces airflow obstruction. COPD can be as- sociated with flare ups or acute exacerbations which are distressing and can be life-​threatening, and are a major burden to patients and health services.

section 18  Respiratory disorders 4100 The characteristic lung function abnormality is airflow obstruc- tion measured, by spirometry, as the ratio of the FEV1 to the vital capacity (VC). A ratio below 70% is usually taken to be required for the diagnosis to be made. The most effective treatment for COPD is smoking cessa- tion. Pulmonary rehabilitation, a combination of supervised ex- ercise and education, also has a strong evidence base for benefit. Pharmacotherapy can reduce symptoms and exacerbation fre- quency, but existing therapies have so far demonstrated little ef- fect on the natural history of COPD. For selected individuals with severe emphysema, lung volume reduction surgery can improve prognosis. Long-​term oxygen therapy improves survival in hypoxic individuals For most patients, COPD is only one of several long-​term con- ditions. Around 80% of individuals with COPD have an additional diagnosis. Patient management needs to reflect this multimorbidity as well as following a rational approach to the specific COPD pheno- type of each individual. The lungs are at the cutting edge of the social determinants of health. Social class gradients in smoking, together with occupations that expose individuals to dust, fumes, and chemicals, as well as exposure to biomass smoke and an adverse early life environment which impacts on lung development, all mean that the prevalence of COPD increases with increasing poverty. Aetiology COPD is caused by the individual’s response to the inhalation of noxious materials. This depends on a combination of host factors and exposure. The major risk factor is smoking, but COPD is also associated with occupations where individuals are exposed to dust, fumes, or chemicals (Table 18.8.1). Genetic predisposition, airway hyperreactivity or asthma, and a failure of lung growth are key sus- ceptibility factors. Fletcher and Peto first demonstrated, in an 8-​year study of working men, that smoking was associated with impaired lung function. Prospective life course data, such as from the Framingham study, now show clearly that tobacco smoking is associated with an increased rate of lung function decline (Fig. 18.8.2). There are individual variations in susceptibility to tobacco smoke which are poorly understood but which appear to be heritable to an extent. COPD is a progressive condition so its prevalence increases with age. Lung function at any given point in time will depend on the rate of decline but also on the peak lung function achieved from which this decline is occurring. Lung function usually peaks around the age of 20 and early life factors are therefore crit- ical. Maternal or paternal asthma, childhood asthma, maternal smoking and childhood respiratory infections are significantly associated with lower FEV1 in adult life and have been defined as Table 18.8.1  Risk factors for COPD Exposures Tobacco smoking Major cause of COPD worldwide Biomass smoke exposure Smoke from domestic cooking and heating Occupational exposures Mining, industrial occupations, cleaning Poor nutrition Lead to impaired lung growth Passive and in utero smoke exposure Susceptibility factors Airways hyperreactivity
and asthma Recurrent bronchopulmonary infections Genetic factors Gene polymorphisms influence lung function decline, specific COPD phenotypes, and avidity of nicotine receptors α-1 antitrypsin deficiency Female sex May increase susceptibility to the effects of smoke Chronic bronchitis Emphysema COPD Airflow obstruction Asthma 1 11 2 5 3 6 8 7 4 10 9 Fig. 18.8.1  Nonproportional Venn diagram of chronic obstructive pulmonary disease (COPD) produced by the American Thoracic Society. The subsets comprising COPD are shaded. Subset areas are not proportional to the actual relative subset sizes. Asthma is by definition associated with reversible airflow obstruction although, in variant asthma, special manoeuvres may be necessary to make the obstruction evident. Patients with asthma whose airflow obstruction is completely reversible (subset 9) are not considered to have COPD. Because in many cases it is virtually impossible to differentiate patients with asthma whose airflow obstruction does not remit completely from persons with chronic bronchitis and emphysema who have partially reversible airflow obstruction with airway hyperreactivity, patients with unremitting asthma are classified as having COPD (subsets 6, 7, and 8). Chronic bronchitis and emphysema with airflow obstruction usually occur together (subset 5), and some patients may have asthma associated with these two disorders (subset 8). Individuals with asthma who have been exposed to chronic irritation, as from cigarette smoke, may develop chronic productive cough, which is a feature of chronic bronchitis (subset 6). Persons with chronic bronchitis and/​or emphysema without airflow obstruction (subsets 1, 2, and 11) are not classified as having COPD. Patients with airway obstruction due to diseases with known aetiology or specific pathology such as cystic fibrosis or obliterative bronchiolitis (subset 10) are not included in this definition. Reproduced from Thorax, Marsh SE et al., 63(9), 761–​7, copyright © 2008 BMJ Publishing Group Ltd and the British Thoracic Society, with permission from BMJ Publishing Group Ltd.

18.8  Chronic obstructive pulmonary disease 4101 ‘childhood disadvantage factors’. People with these factors have permanently reduced lung function, a more rapid decline in lung function, and a substantially increased COPD risk. Importantly, the impact of childhood disadvantage is as large as that of heavy smoking. In utero exposure through maternal smoking is associ- ated with low birth weight and subsequent impaired lung func- tion. It also increases asthma severity symptoms and an increased risk of wheezy illness. Smoking is itself an addiction mostly starting in childhood. For example, in the United Kingdom 200 000 11–​15  year olds start smoking every year. In Pakistan 40% of smokers report that they started before they were 10 years old. The effects of smoking are thus first experienced by people while their lungs are still growing. Although smoking has been accepted as the major cause of COPD, biomass smoke exposure from wood, charcoal, dried twigs and grass, crop residues, and animal dung cakes burnt for cooking or heating, is also extremely important. Three billion people are ex- posed to biomass smoke and worldwide it is responsible for about 35% of cases of COPD. To underline its importance, in 2010 the three leading contributors to global disease burden expressed as disability adjusted life years were high blood pressure (7.0%[95% uncertainty interval 6.2–​7.7] of DALYs), tobacco smoking including second-​hand smoke (6.3% [5.5–​7.0]), and household air pollution from solid fuels (4.3% [3.4–​5.3]). Exposure to outdoor air pollution also contributes to impaired lung development, the development of COPD, and exacerbation of COPD symptoms. Illicit drug use is a risk factor, including inhaled marijuana but also heroin and crack cocaine. Occupation COPD is more common in people exposed to dust, fumes, or chem- icals through their occupation. Confirmation of these links for spe- cific occupations can be confounded by the effects of smoking and depends on accurate data about exposure over time. In the United Kingdom, evidence for an association between coal dust exposure and the development of COPD has led to the establishment of COPD as a disease that is considered for compensation in miners. Exposure to welding fumes has been shown to be associated with the development of COPD in a study of shipyard workers, and workers exposed to cadmium have an increased risk of emphysema. More recently it has been recognized that exposure to products used in cleaning work also increases the risk of COPD. 100 (a) (b) 75 50 25 0 10 20 30 40 Age (years) FEV1 (% of value at age 25) 50 60 70 NS NS CS* CS* 90 80 100 75 50 25 100 75 50 25 0 10 20 30 40 Age (years) FEV1 (% of value at age 25) 50 60 70 80 90 100 75 50 25 Fig. 18.8.2  Mean FEV1 values (expressed as percent of its value at the age of 25) by age, for healthy never-​ smokers (NS), and continuous smokers (CS). (a) Data for males and (b) for females. The mean FEV1 decline value (and 95% confidence intervals) for males was 38.2 ml (33.9–​42.6) and for females 23.9 ml (20.9–​27.0), with a p value less than 0.001 (*p <0.05 versus healthy never-​smokers). Reproduced from Kohansal R, et al. (2009). The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med, 180(1), 3–​10.

section 18  Respiratory disorders 4102 Diet Undernutrition in childhood can impact on lung development and thus increase the risk of COPD in later life. Data on specific dietary components is less clear. There is some evidence that low vitamin D levels may accentuate the effects of smoking on the lung and they have been found to be associated with lung function impairment, though there are potential problems with reverse causation. Several studies have reported associations between fre- quent or high consumption of cured meats and increased risk of developing COPD. Gender Although historically COPD had a male preponderance, there has been a rapid increase in the prevalence, morbidity, and mortality of COPD in women, largely due to increases in their tobacco con- sumption. There is evidence that women may be more susceptible to the effects of inhaling smoke and that they are more likely to de- velop a chronic bronchitis phenotype. The factors underlying this remain to be established. Airway hyperresponsiveness and asthma The relationship between asthma and COPD is complex. Traditional descriptions have stressed clearly defined differ- ences between the two conditions. However, it is now clear that both diagnostic terms encompass a range of phenotypes and shared pathologies and that these may overlap and evolve over an individual’s lifetime. Bronchial hyperactivity in childhood as well as a diagnosis of asthma are both powerful predictors of the presence of COPD in later life. This may in part be because chronic inflammation in asthma eventually causes reversible airway obstruction to become fixed, but there is also an increased risk of smokers with asthma developing emphysema, suggesting some common or synergistic inflammatory pathways in the two conditions. Studies in middle-​aged smokers with a degree of im- pairment of lung function show a positive correlation between ac- celerated decline in FEV1 and increased airway responsiveness to either methacholine or histamine. Epidemiology Prevalence The prevalence of COPD increases with age. Data from the Burden of Lung Disease study (Fig. 18.8.3) suggest that about 10% of individuals over the age of 40 have COPD; 10.1% (SE 4.8) overall, 11.8% (7.9) for men, and 8.5% (5.8) for women. It is now the third leading cause of death worldwide, a position achieved partly through smoking habits and partly as a consequence of increased life expectancy as other cause of death such as com- municable diseases become less prevalent. In environments with high biomass smoke exposure, COPD can be more prevalent at younger ages. For example, the FRESH AIR study in rural Uganda found that in people aged 30–​39 years, 38% of men and 40% of women had COPD. Fig. 18.8.3  Global age-​standardized mortality rate for COPD. Institute for Health Metrics and Evaluation (IHME). COD Visualization. Seattle, WA: IHME, University of Washington, 2014. Available from http://​ihmeuw.org/​3r9k (accessed 2nd June 2015).

18.8  Chronic obstructive pulmonary disease 4103 There is a marked disparity between the prevalence of diagnosed COPD and that predicted from epidemiological surveys. For ex- ample, the diagnosed prevalence of COPD in England in 2011 was 765 000 compared to an expected prevalence of 1.4 million (Fig. 18.8.4). This underdiagnosis is likely to reflect normalization of symptoms, where patients attribute breathlessness to normal ageing and dismiss cough and sputum production as normal. In addition, there is evidence that numerous opportunities to make the diagnosis of COPD are missed in primary care before it is finally identified. In the 2014 Royal College of Physicians (RCP)/​British Thoracic Society (BTS) COPD audit of 13 414 patients admitted to hospital with an acute exacerbation of COPD (AECOPD), 7% had no prior diagnosis of the condition. Prevalence also depends on the spirometric definition chosen. Airflow obstruction is the characteristic feature of COPD and a ratio of FEV1/​VC less than 70% has been adopted in most na- tional and international guidelines, and severity of disease can be classified according to the severity of airflow limitation (Table 18.8.2). Because lung elasticity declines with age the FEV1/​VC ratio tends to fall in healthy individuals, which means that a fixed ratio definition tends to underestimate the prevalence of COPD in younger people and overestimate it in older individ- uals. Having a variable lower limit of normal has been proposed as a more accurate approach. For epidemiological studies this is important, but for diagnosis in an individual presenting with symptoms it is less so, and the added complexity of a variable vs. fixed ratio means that the latter is preferred. In addition, evidence suggests that mild airflow obstruction (an FEV1 between 80 and 100% predicted) in the absence of symptoms of cough sputum or breathlessness does not predict the development of subsequent lung disease. Mortality COPD has become, based on data from the 2010 Global Burden of Disease study, the third leading cause of death worldwide (after stroke and ischaemic heart disease) and the ninth leading cause of life years lost (Fig. 18.8.5). This is due in large part to increased longevity, which increases the impact of diseases that London inset COPD observed over expected prevalence qiutiles, by local authority (n) 0.01–0.20 (71) 0.21–0.31 (70) 0.32–0.40 (70) 0.41–0.50 (70) 0.51–0.87 (70) N Fig. 18.8.4  Diagnosed vs. estimated COPD prevalence by Local Authority area in England Heat map compares expected and observed prevalence of COPD. Darker colours indicate that a higher proportion
of cases have been identified. From Nacul L, et al. (2011). COPD in England: a comparison of expected,
model-​based prevalence and observed prevalence from general practice data.
J Public Health (Oxf), 33(1), 108–​16, by permission of Oxford University Press. Table 18.8.2  Classification of the severity of airflow limitation in COPD (based on post-​bronchodilator spirometry) COPD stage FEV1 (In patients with FEV1/​FVC <0.70 or
<5th percentile) Stage 1: Mild ≥80% predicted Stage 2: Moderate 50–​79% predicted Stage 3: Severe 30–​49% predicted Stage 4: Very severe <30% predicted Median % change (95% UI) 2010 Mean rank (95% UI) 1990 Mean rank (95% UI) 1.0 (1–1) 2.0 (2–2) 3.4 (3–4) 3.6 (3–4) 5.8 (5–10) 6.4 (5–8) 6.7 (5–9) 8.4 (5–11) 9.0 (7–11) 10.1 (8–13) 10.3 (6–13) 14.4 (12–18) 35% (29 to 39) 27% (14 to 32) –7% (–12 to 0) –18% (–24 to–11) 51% (24 to 61) 395% (323 to 465) –42% (–49 to –34) 95% (68 to 102) –17% (–35 to –3) –29% (–39 to –17) 20% (–9 to 56) 46% (18 to 86) 1.0 (1–2) 2.0 (1–2) 3.0 (3–4) 4.0 (3–4) 5.0 (5–5) 6.1 (6–7) 7.3 (7–9) 8.6 (7–12) 9.4 (7–13) 10.4 (8–14) 15.8 (13–19) 35.3 (28–40) 1 Ischemic heart disease 2 Stroke 3 Lower respiratory infections 4 COPD 5 Diarrheal diseases 6 Tuberculosis 7 Preterm birth complications 8 Lung cancer 9 Malaria 10 Road injury 15 Diabetes 35 HIV/AIDS 1 Ischemic heart disease 2 Stroke 4 Lower respiratory infections 3 COPD 7 Diarrheal diseases 10 Tuberculosis 15 Preterm birth complications 5 Lung cancer 11 Malaria 8 Road injury 9 Diabetes 6 HIV/AIDS Communicable, maternal, neonatal, and nutritional disorders Noncommunicable diseases Injuries Fig. 18.8.5  Global causes of death 1990 to 2010. Institute for Health Metrics and Evaluation (IHME). GBD Compare. Seattle, WA: IHME, 2013. Available from http://​vizhub.healthdata.org/​irank/​arrow.php. (accessed 5th June 2015).

section 18  Respiratory disorders 4104 occur in older age, combined with changes in smoking habits. In the European Union and in what is defined as the ‘developed world’, it is the fourth leading cause of death (after lung cancer as well). It is fifth in North America (where Alzheimer’s disease is also a more common cause of death; see Fig. 18.8.6). Mortality rates have fallen in men but risen in women, reflecting later smoking uptake in women. There is a strong association between COPD mortality and de- privation, which is not completely explained by smoking habits (Fig. 18.8.7). Possible explanations include persisting effects of early life disadvantage, greater exposure to pollution, fuel poverty (meaning poorer individuals are more likely to live in cold damp homes), as well as difficulties in accessing healthcare, particularly in healthcare systems where access is based on ability to pay. Prevention COPD is preventable, but its prevention requires political will to implement tobacco control measures fully. Smoking is an ad- diction that usually starts in childhood and is predicted to kill one billion people in the 21st century. The global social burden is estimated to be $2.1 trillion a year. The means to prevent this harm are set out clearly in the World Health Organization’s 2003 Framework Convention on Tobacco Control and the associated MPOWER policy framework (Monitor tobacco use and preven- tion policies, Protect people from tobacco smoke, Offer help to quit tobacco use, Warn about the dangers of tobacco, Enforce bans on tobacco advertising, promotion, and sponsorship, and Raise taxes on tobacco). Countries that have implemented these meas- ures most comprehensively and effectively have seen the greatest falls in smoking rates. Further actions are suggested in the 2015 report from Action on Smoking and Health (ASH) ‘Smoking still kills’. In particular, prevention needs to focus on specific groups where smoking remains high. These include those in poverty, people with mental illness, the homeless, prisoners (the smoking rate for inmates in the United Kingdom is 80%) and the LGBT community. Ensuring every child has a good start in life, one of the principles from the 2010 Marmot Review ‘Fair Society, Healthy Lives’, includes 0 0 25 50 75 50 100 150 200 250 300 350 400 450 Heart disease Cancer Stroke Year of death Accidents Diabetes melitus 1970 1974 1978 1982 1986 1990 Chronic obstructive pulmonary disease 1994 1998 2002 Year of death 1970 1974 1978 1982 1986 1990 1994 1998 2002 Rate per 100000 population Rate per 100000 population 500 550 Fig. 18.8.6  US trends in age-​standardized death rates for the six leading causes of death in the United States. From Jemal, et al. JAMA 2005; 294: 1255–​9. Copyright © 2005, American Medical Association. All Rights reserved.   0 10 20 30 per 100 000 England average Most deprived decile Second most deprived decile Third more deprived decile Fourth more deprived decile Fifth less deprived decile Fourth less deprived decile Third less deprived decile Second less deprived decile Least deprived decile Fifth more deprived decile 40 50 40.4 42.0 43.7 47.0 52.0 55.0 60.4 65.9 74.2 72.6 England, 2011–13 Deaths from chronic obstructive pulmonary disease 60 70 80 Fig. 18.8.7  Mortality rates for COPD in England by decile of deprivation. Available from Public Health England, http://​www.tobaccoprofiles.info/​profile/​tobacco-​control/​data#gid/​1000110/​pat/​6/​ ati/​101/​page/​1/​par/​E12000007/​are/​E09000002 (accessed 3rd June 2015).

18.8  Chronic obstructive pulmonary disease 4105 ensuring healthy lung development both in utero and subsequently, as well as action to reduce inequalities, improve nutrition, and re- duce exposure to biomass smoke. Pathology COPD occurs as a result of a range of pathological mechanisms occurring in response to inhaled material. Principal among these are inflammation, oxidative stress, and proteolysis. Autoimmune processes may also be involved as well as accelerated senescence and cell death. Effects include destruction and remodelling of lung tissues with impacts at the alveolar, small, and large airway level. The pulmonary vasculature is also damaged which can lead to sec- ondary impacts on the heart. Systemic effects of COPD are common and can be difficult to distinguish from comorbidities, which are the norm rather than the exception in COPD. Key pathological fea- tures are outlined in Table 18.8.3. Chronic bronchitis The pathological basis of the hypersecretion of mucus in chronic bronchitis is an increase in the volume of the submucosal glands, and an increase in the number and a change in the distribution of goblet cells in the surface epithelium (Fig. 18.8.8). Submucosal mucus glands are confined to the bronchi, decreasing in number and in size in the smaller, more peripheral bronchi, and are not present in the bronchioles. In chronic bronchitis, there is mucus gland hypertrophy in the larger bronchi with infiltration of the glands with inflammatory cells. In healthy subjects who have never smoked, goblet cells are pre- dominantly seen in the proximal airways and decrease in number in more distal airways, being absent normally in the terminal or respiratory bronchioles. By contrast, in smokers, goblet cells not only increase in number but mucus metaplasia means that they ex- tend more peripherally, hence mucus is produced in greater quan- tities in peripheral airways where the mucociliary escalator is less developed. Mucociliary function is also decreased in smokers. Mucus concen- tration changes with a greater proportion of solid material, making it harder to clear via the muco-​ciliary escalator. Cigarette smoke has also been shown to produce cilia shortening and ciliophagy, impairing mucus clearance. Bronchial biopsies in patients with chronic bronchitis reveal that activated T lymphocytes are prominent in the proximal airway walls. However, in contrast to asthma, macrophages also feature, and the CD8 suppressor T-​lymphocyte subset (rather than CD4) predominates (Table 18.8.4). Increased numbers of neutrophils are present, particularly in the glands, which become even more prom- inent as the disease progresses. Bronchial biopsies from limited studies in patients during exacerbations of chronic bronchitis show increased numbers of eosinophils in the bronchial walls, although their numbers are small compared with exacerbations of asthma Table 18.8.3  Pathological changes in COPD Proximal airways (trachea and cartilaginous airways >2 mm diameter) Submucosal bronchial gland enlargement, glands, and goblet cell metaplasia—​resulting in excessive mucus production or chronic bronchitis; cellular infiltrates (neutrophils, lymphocytes) also occur in bronchial glands Increased macrophages, CD8 + T lymphocytes (cytotoxic T cells); few neutrophils or eosinophils, but neutrophils increase as the disease progresses Airway wall changes include squamous metaplasia of the airway epithelium, ciliary dysfunction, and increased smooth muscle and connective tissue Peripheral airways (noncartilaginous airways <2 mm internal diameter) Bronchiolitis is present at an early stage of the disease. Luminal and inflammatory exudates that are increased in inflammatory response; exudates correlate with the disease severity Pathological extension of goblet cells and squamous metaplasia in peripheral airways Increased macrophages, T lymphocytes, CD8 + > CD4+, increased B lymphocytes, lymphoid follicles, fibroblasts; few neutrophils or eosinophils Peribronchial fibrosis and airways narrowing as the disease progresses Parenchyma (respiratory bronchioles and alveoli) Emphysema-​defined as abnormal enlargement of air spaces distal to terminal bronchioles Alveolar wall destruction, apoptosis of epithelial and endothelial cells Centrilobular emphysema—​dilatation and destruction of respiratory bronchioles; commonly seen in smokers; predominant in upper zones Panacinar emphysema—​destruction of the whole of the acinus; commonly seen in α1-​antitrypsin deficiency; more common in the lower lung zones Microscopic emphysema in the early stages of the disease, progressing to macroscopic lesions or bullae (defined as an emphysematous space >1 cm diameter) Increased macrophages, CD8 + T lymphocytes Pulmonary vasculature Increased thickening of the intima; endothelial dysfunction early in the course of the disease Increased vascular smooth muscle occurs later Increased macrophages and T lymphocytes Collagen deposition, emphysematous destruction of the capillary bed, in later stages Structural changes can eventually lead to pulmonary hypertension and right ventricular dysfunction (cor pulmonale)

section 18  Respiratory disorders 4106 and—​unlike those in asthma—​these cells do not appear to have degranulated. Patients with chronic bronchitis have increased intraluminal and air space inflammation, with or without airways obstruc- tion, with predominantly neutrophils and macrophages in the bronchoalveolar lavage studies. There is also evidence that air space inflammation in patients with chronic bronchitis continues fol- lowing smoking cessation if the production of sputum persists. Emphysema Emphysema is defined as enlargement of the airways distal to the terminal bronchioles, due to destruction of their walls without obvious fibrosis. Three major types are recognized, according to the distribution of enlarged air spaces within the acinar unit (Fig. 18.8.9), the acinus being that part of the lung parenchyma supplied by a single terminal bronchiole: • Centriacinar (or centrilobular) emphysema, in which enlarged air spaces are initially clustered around the terminal bronchiole. • Panacinar (or panlobular) emphysema, where the enlarged air spaces are distributed throughout the acinar unit. • Paraseptal (paralobular or distal acinar) emphysema describes enlarged air spaces along the edge of the acinar unit, but only where it abuts against a fixed structure such as the pleura or a vessel. Centrilobular emphysema is more common in the upper zones of the lung and is the common type in COPD. Panlobular emphysema may be found anywhere in the lungs, but is more prominent at the bases, and is the typical pattern associated with α1-​antitrypsin deficiency. The different types of emphysema can occur alone or in combination in a patient with COPD. There is still debate over whether centrilobular and panlobular emphysema represent different disease processes, and hence have different (a) Gland Cartilage Muscle Muscle Glands Cartilage Gland duct (b) (c) Fig. 18.8.8  A central bronchus from the lungs of a cigarette smoker with normal lung function (a) shows small amounts of muscle present in subepithelium and small epithelial glands. In a patient with chronic bronchitis (b) the muscle appears as a thick bundle and the bronchial glands are enlarged. At a higher magnification (c) these glands show evidence of a chronic inflammatory process involving polymorphonuclear leucocytes (arrow head) and mononuclear cells, including plasma cells (arrow). Reproduced from the GOLD Workshop Report with the kind permission of Professor James C. Hogg. Table 18.8.4  Inflammatory cells in COPD Neutrophils—​increase in sputum and distal air spaces in smokers, with a further increase in COPD related to disease severity. These are important in the secretion and release of proteases Macrophages—​increase in number in airways, lung parenchyma, and in bronchoalveolar lavage fluid. These produce increased inflammatory mediators and proteases T lymphocytes—​increase in the peripheral airways and within lymphoid follicles, possibly as a response to chronic infection of the airways. Both CD4 and CD8 cells increase in airways and in lung parenchyma, with an increase in CD8:CD4 ratio. There is an increase in TH1 and TC1 cells that produce interferon-​γ. CD8 + cells may be cytotoxic, causing alveolar wall destruction Eosinophils—​increase in airways walls, with increased eosinophil proteins in sputum, in some exacerbations of the disease

18.8  Chronic obstructive pulmonary disease 4107 aetiologies, or whether panlobular emphysema is a progression from centrilobular emphysema. Cigarette smoking has a clearer association with centrilobular emphysema than with panlobular emphysema. Smokers with centrilobular emphysema have more small airways disease than those patients with predominantly panlobular emphysema. In the early stages of the disease, emphysematous lesions are microscopic (<1 mm diameter); they may progress to macroscopic lesions or bullae. Bullae are conventionally considered to be areas of emphysema that is distended to more than 1 cm in size. Bullous disease can also occur in the absence of COPD. Normal bronchioles and small bronchi are supported by at- tachments to the outer aspect of their walls of adjacent alveolar walls, an arrangement which maintains the tubular integrity of the airways. Loss of these attachments in emphysema leads to loss of the elastic recoil of the lungs and hence distortion and irregularity of airways, which results in airflow limitation (Fig. 18.8.10). The inflammatory cell profile in the alveolar walls and the air spaces is similar to that described in the airways and persists throughout the course of the disease, even after smoking cessa- tion. Although absence of fibrosis is a prerequisite in the most recent definition of emphysema, fibrosis does occur in the ter- minal or respiratory bronchioles as part of a respiratory bron- chiolitis in COPD patients. Furthermore, there is an increase in collagen in the lung parenchyma in smokers compared with nonsmokers. Bronchiolitis/​small airways disease Increased flow resistance in the lungs in patients with COPD largely occurs in the small airways (<2 mm diameter) at the periphery of the lungs. This was demonstrated mathematically in 1965 by Malcolm Green and directly measured in 1968 by Hogg, Macklem, and Thurlbeck in studies using a retrograde catheter. Inflammation in the small airways is among the earliest changes to be found in asymptomatic cigarette smokers and considerable changes in these airways can occur without giving rise to symptoms or alterations in spirometry. Several pathological changes are found in small air- ways (Fig. 18.8.11), including inflammatory infiltrate in the airway wall, mucus and cells in the lumen, goblet cell hyperplasia, fibrosis in the airway wall, squamous-​cell metaplasia, mucosal ulceration, increased amount of muscle, and pigmentation. Bronchiolitis is present in the peripheral airways at an early stage of the disease. The inflammatory cells in the airway wall and air spaces are similar to those in the larger airways. Studies using resected lung specimens, and those obtained during lung volume reduction surgery, have shown changes in inflammatory response as the disease progresses which are thought to represent innate and adaptive immune responses to long-​term exposure to noxious par- ticles and gases. Fig. 18.8.9  Patterns of emphysema. (a) Normal respiratory bronchiole and alveolar structure. (b) Centrilobular emphysema. (c) Pan lobular emphysema. Reproduced from the GOLD Workshop Report with the kind permission of Professor James C. Hogg.

section 18  Respiratory disorders 4108 Fig. 18.8.10  Pathological changes in emphysema. Cross-​section of a normal small peripheral bronchiole, showing a circular outline supported by adjacent alveolar walls (left panel). A small bronchiole at the same magnification in a patient with very early macroscopic emphysema: the loss of alveolar supporting walls results in an elliptical airway (right panel). Reproduced from the GOLD Workshop Report with the kind permission of Professor James C. Hogg. Fig. 18.8.11  Histological sections of peripheral airways. (a) Section from a cigarette smoker with normal lung function, showing a nearly normal airway with some inflammatory cells in the airway wall. (b) Section from a patient with small airways disease, showing inflammatory cells in the wall and inflammatory exudate in the lumen of the airway. (c) A more advanced case of small airways disease, with narrowed lumen, structural reorganization of the airway wall, increased smooth muscle, and deposition of peribronchiolar connective tissue. Images reproduced with the kind permission of Professor James C. Hogg, University of British Columbia.

18.8  Chronic obstructive pulmonary disease 4109 Recent work, using micro CT, has shown that loss of terminal bronchioles precedes the development of emphysema, highlighting the importance of the small airways. This approach has also allowed linkage of pathological processes to macroscopic structure. Genes increasing in expression with increasing emphysematous destruc- tion included those involved in inflammation, such as the B-​cell receptor signalling pathway, while genes decreasing in expression were involved in tissue repair processes, including the transforming growth factor β (TGFβ) pathway, actin organization, and integrin signalling. A further feature in the later stages of the disease is the presence of an increase in B lymphocytes and lymphoid follicles around the bronchioles. The cause of these changes is not known, but it is possible that they represent an autoimmune or adaptive immune response to chronic lower respiratory infection. As the disease pro- gresses there is fibrosis and increased deposition of collagen in the small airway wall. Pulmonary vasculature Pathological changes in the pulmonary vasculature occur early in the course of the disease. The initial changes are characterized by thickening of the vessel wall and endothelial dysfunction. These are followed by increased vascular smooth muscle and infiltration of the vessel walls by inflammatory cells, including macrophages and CD8 + lymphocytes. In the later stages of the disease there is col- lagen deposition and emphysematous destruction of the capillary bed in the alveolar walls. These structural changes can eventually lead to pulmonary hypertension and right ventricular dysfunction (cor pulmonale). Pathogenesis Inflammation is present in the lungs of all smokers, and amplifica- tion of this is a major factor in the development of COPD. The pre- cise mechanisms of this amplification are not well understood, but the abnormal inflammatory response in COPD leads to increased tissue destruction, impairment of defence mechanisms that limit such destruction, and impairment of the repair mechanisms. In general, the inflammatory and structural changes in the airways in- crease with disease severity and persist even after smoking cessation. However, in addition to inflammation, other processes are involved in the pathogenesis of COPD: • Imbalance between proteases and antiproteases • Imbalance between oxidants and antioxidants (oxidative stress) • Immune dysfunction and impaired bacterial clearance • Fibrosis or disordered lung remodelling in small airways • Accelerated senescence and cell death • Mitochondrial dysfunction and mitophagy These processes interact through a range of mechanisms (Fig. 18.8.12), so their division into categories is somewhat artificial. Inflammatory cells and mediators The inflammatory cellular response which characterizes COPD consists of increased numbers of neutrophils, macrophages, and T lymphocytes (CD8 more than CD4) in the lungs (Fig. 18.8.13). These inflammatory cells are activated to release a variety of cytokines Fibrosis (Small airways) Alveolar wall destruction (Emphysema) Mucus hypersecretion Neutrophil elastase MMP-9 Th1 Tc1 Th17 Neutrophill Macrophage CXCL1 CCL2 Monocyte CXCL11 CXCR3 CXCR2 CCR2 CXCL10 Fibroblast CTGF TGFβ Epithelial cells Cigarette smoke (and other irritans) CXCL9 CXCL8 IL-23 PROTEASES PROTEASES Fig. 18.8.12  Cigarette smoke—​pathways of harm in COPD. Image provided courtesy of Professor Peter Barnes, Imperial College London.

section 18  Respiratory disorders 4110 and mediators, by bacteria and in response to apoptotic cells leading to airway damage which promotes persistent colonization in a posi- tive feedback loop. A wide range of inflammatory mediators have been shown to be increased in COPD and to amplify the inflamma- tory process (Table 18.8.5). Protease/​antiprotease imbalance Important to understanding the pathogenesis of COPD were the ob- servations of an association between α1-​antitrypsin deficiency and the development of early-​onset emphysema, and the development of emphysema following instillation of the proteolytic enzyme pa- pain into rat lungs. These observations form the basis of the pro- tease/​antiprotease hypothesis of the pathogenesis of emphysema, which states that under normal circumstances the release of proteo- lytic enzymes from inflammatory cells that migrate to the lungs to fight infection does not cause lung damage because of inactivation of these proteolytic enzymes by an excess of inhibitors. However, in conditions of excessive enzyme load, or where there is an absolute or a functional deficiency of antiproteases, an imbalance develops between proteases and antiproteases in favour of proteases, leading to uncontrolled enzyme activity and degradation of lung connective tissue such as elastin in alveolar walls, resulting in emphysema. Oxidative stress The oxidative burden is increased in COPD as a result of oxidants from cigarette smoke and reactive oxygen and nitrogen species re- leased from inflammatory cells. There may also be a reduction in endogenous antioxidant responses due to a reduction in the tran- scription factor Nrf2 that regulates many antioxidant genes. Both factors contribute to oxidant–​antioxidant imbalance and hence oxi- dative stress, many markers of which are increased in stable COPD and further increased during acute exacerbations. Oxidative stress can lead to inactivation of antiproteases, stimulation of mucus pro- duction, and activation of proinflammatory genes. Amplification of inflammation can result from oxidative stress enhanced transcrip- tion factor activation (such as NF-​κB) by oxidants, and may also re- sult from a decrease in histone deacetylase activity in lung cells of patients with COPD with consequent increased gene expression of inflammatory mediators. Oxidative stress-​induced mitochondrial dysfunction appears to be an important driver of inflammation and airway smooth muscle remodelling in patients with chronic ob- structive pulmonary disease. Immune dysfunction The fact that inflammation persists in people with COPD after they quit smoking has raised the question of what sustains the process. The persistence of bacterial colonization in COPD patients sug- gests impaired immune function, with evidence that this involves both the innate and acquired immune responses. Bacterial clearance by macrophages is impaired in COPD, which perpetuates the in- flammatory response. Neutrophils are also aberrant, with increased survival and motility, but lack direction which could lead to more widespread destruction during migration. Accelerated ageing Lung function decrease is a feature of normal ageing. A gradual loss of lung elasticity leads to age-​related decline in FEV1. Additional processes in COPD include destruction of the alveolar walls and fi- brosis of peripheral airways, but it is increasingly recognized that people with COPD display a range of exaggerated ageing-​associated processes, including an increase in cellular senescence, stem cell exhaustion, mitochondrial dysfunction contributing to increased oxidative stress, defective autophagy, alteration in the extracellular matrix, and a reduction in endogenous antiageing molecules such as sirtuins. Pathophysiology Airflow obstruction Expiratory airflow obstruction is a cardinal feature of COPD (Fig. 18.8.14 and 18.8.15). Expiratory flow rate is lung volume de- pendent and depends on two factors: (1) the driving pressure pro- duced by the respiratory muscles and elastic properties of the lungs and chest wall; (2) the resistance to airflow of the system. Airflow resistance increases during expiration as airways narrow and the elastic recoil of the lung falls. In COPD, resistance is increased by destruction of small airways as well as epithelial damage and mucus. This is further aggravated by loss of elastic airway attach- ments though emphysema. The latter process causes airways to 120 100 84 55 67 54 66 73 92 25 33 29 32 Acute inflammatory cells PMNs Macrophages Eosinophils 100 80 60 40 20 0 Airways with measurable cells (%) GOLD stage 0 GOLD stages 2 and 3 GOLD stage 1 GOLD stage 4 Fig. 18.8.13  The extent of the airway inflammatory response, as measured by the percentage of the airways containing CD4 cells, CD8 cells, and B cells, among patients in each GOLD stage of COPD. Reproduced from Hogg JC, et al. (2004). The nature of small-​airway obstruction in chronic obstructive pulmonary disease. New England Journal of Medicine, 350(26), 2645–​53. Copyright © 2004 Massachusetts Medical Society. Table 18.8.5  Inflammatory mediators in COPD Leukotriene B4—​a neutrophil and T-​cell chemoattractant that is produced by macrophages, neutrophils, and epithelial cells Chemotactic factors—​e.g. the CXC chemokines IL-​8 and growth-​related oncogene α—​produced by macrophages and epithelial cells; attract cells from the circulation and amplify proinflammatory responses Proinflammatory cytokines—​e.g. TNFα, IL-​1β, IL-​6 Growth factors—​e.g. TGFβ—​which may cause fibrosis in the airways either directly or through release of another cytokine, connective tissue growth factor

18.8  Chronic obstructive pulmonary disease 4111 narrow both by reducing radial traction which pulls airways open from outside and reduces the driving pressure within the airway itself. This leads to premature airway closure and gas trapping. Lung volumes and hyperinflation Lung volumes are increased in COPD because of two processes. The first is a change in the balance between the elastic recoil of the lung and the tendency of the chest wall to spring outwards. The point where these are matched determines functional residual capacity (FRC), which in health is the volume of air in the lung at the end of a quiet tidal breath. Emphysema makes lungs more compliant so that this point is higher leading to static hyperinfla- tion (Fig. 18.8.16). The second process is that early airway closure, because of the mechanisms described here, means that expiration ends before the lungs have emptied. In health, increased ventilatory requirements are met by increasing respiratory rate and tidal volume. In the presence of flow limitation it is necessary to increase operating lung volumes (Fig. 18.8.17). This process is called dynamic hyperinflation. Although this allows a higher flow rate (and therefore minute volume) it has several adverse consequences (Table 18.8.6 and Fig. 18.8.18). As lung volumes increase the load on the respiratory muscles increases and their capacity to meet this load decreases. A key concept in dynamic hyperinflation is that because total lung capacity does not change, there is a limit to the increases in end Radial traction Reduced radial traction Pleural pressure +

Pleural pressure Normal alveolar pressure Reduced alveolar pressure Fig. 18.8.14  Mechanisms of airflow limitation in COPD. The image on the left shows normal pattern with elastic recoil of the lung contributing to alveolar pressure and elastic attachments helping to pull airways open. On the right, reduction in these in COPD leads to airway closure.  8 6 Expiratory flow (l/s) 1 Volume (l) 0.25 s 4 2 0 3 0.50 s 0.75 s 1 s 2 s 3 s 2 0 0.25 s 0.50 s 0.75 s 1 s Fig. 18.8.15  Maximum flow volume curves in a healthy subject (FEV1 2.4 litres) and a subject with COPD and airways obstruction (FEV1 0.8 litres). The development of convexity of the expiratory curve in mild obstruction is characteristic, as is the relative preservation of peak expiratory flow in the patient with COPD. Timepoints in second(s) are plotted on the flow volume curves. 8 6 Static transpulmonary pressure (cmH2O) Volume (litres) 10 4 2 0 20 30 40 60 7 5 1 3 Normal Emphysema 0 Fig. 18.8.16  Static expiratory pressure volume curves of lungs in a subject with severe emphysema compared with a normal subject. The broken lines represent extrapolation of the curve—​to infinite pressure and to the volume axis at zero pressure. Normal Pressure pressure Volume TLC EELV RV 0 20 40 60 80 100 120 Lung volume (% predicted TLC) 140 Volume RV ∆P ∆V ∆IC ∆P ∆V ∆IC IC IC COPD RV ERV 1RV Fig. 18.8.17  Pressure volume curve of the lung in health and COPD. Reduced elastic recoil and airway closure leads to increased residual volume (RV), end expiratory lung volume (EELV) and total lung capacity (TLC). This impacts on inspiratory and expiratory reserve volume (IRV and ERV, respectively). From Langer D, et al. (2014). Lung hyperinflation in chronic obstructive pulmonary disease: mechanisms, clinical implications and treatment. Expert Review of Respiratory Medicine, 8, 731–​49.

section 18  Respiratory disorders 4112 expiratory lung volume and tidal volume that can be accommodated. The O’Donnell Threshold describes the inspiratory reserve volume at which patients experience intolerable dyspnoea in the face of the ventilatory demand of exercise. It is this parameter, rather than the end expiratory lung volume (EELV) per se, which forms a limit to exercise capacity. During acute exacerbations (Table 18.8.7) there is increased airway inflammation, mucus, and smooth muscle contraction, so airways become narrower or completely occluded. This in- creases flow limitation, driving an increase in operating lung volumes and breathlessness. Ventilation inequality increases meaning that ventilation is less efficient, which may cause hyp- oxia and hypercapnia. Gas exchange Gas exchange is impaired in COPD because of ventilation/​perfusion inequality reflecting airway disease as well as alveolar and capillary bed destruction. Impaired cardiac output, due to hyperinflation as well as cardiac comorbidities, increases hypoxia as mixed venous oxygen saturations are lower. As COPD worsens there is also an in- crease in the proportion of each breath which is dead space ventila- tion, reducing ventilatory efficiency. Respiratory muscles Maximum inspiratory pressures are reduced in patients with COPD. The diaphragm is the main inspiratory muscle. At a microscopic level this shows evidence of a training effect, with an increase in slow twitch endurance fibres, but because lung hyperinflation causes the diaphragm to be shortened it is at a less favourable position on Table 18.8.6  Consequences of dynamic hyperinflation Increased load The lungs move onto the upper, flatter part of the pressure volume curve increasing the work needed to expand them At high volumes, tendency of chest is to recoil inwards creating additional threshold load Early airway closure creates positive end expiratory pressure Impaired capacity The respiratory muscles become mechanically disadvantaged. The diaphragm is shortened and flattened, moving it away from the optimum length tension relationship for the muscle Increased intrathoracic pressures and increased volume of the lungs impair cardiac function Respiratory muscle ‘steal’—​blood flow is diverted away from limb muscles which may accelerate fatigue Tidal volume constraint—​total lung capacity cannot be increased so increased end expiratory lung volume is accompanied by a restriction in inspiratory reserve volume in turn constraining tidal volume (Fig. 18.8.18) Table 18.8.7  Mechanisms of impact of acute exacerbation of COPD Inflammation and mucus narrow and occlude airways Ventilation/​perfusion matching impaired. Increased dead space –​ hypoxia –​ hypercapnia Increased airflow limitation leads to dynamic hyperinflation –​ respiratory muscles less efficient –​ ventilation less efficient –​ cardiac function compromised –​ increased work of breathing Increased lung volumes impair cardiac function Systemic inflammatory mediators Hypoxia and sympathetic activation drive fluids retention/​oedema Corticosteroids –​ effects on skeletal muscle –​ metabolic derangement 4.0 Vol (T) (I) Vol (T) (I) 3.0 2.5 2.0 1.5 1.0 0.5 0.0 –0.5 –1.0 –1.5 –2.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 4.0 3.0 2.5 2.0 1.5 1.0 0.5 0.0 –0.5 –1.0 –1.5 –2.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Fig. 18.8.18  Volume time curves at beginning and end exercise in COPD. The image on the left shows 30 seconds of quiet tidal breathing in a COPD patient at rest. Inspiratory flow is downwards and the red section represents an inspiratory capacity manoeuvre where the patient is asked to take a maximum breath in at the end of their next normal breath out. The image on the right shows the same manoeuvre at the end of exercise: respiratory rate and tidal volume have increased, and the inspiratory capacity (the amplitude of the red trace) is reduced, reflecting an increase in end expiratory lung volume. Author’s data.

18.8  Chronic obstructive pulmonary disease 4113 the length tension curve, reducing its capacity to generate force. Adjusting for lung volume, diaphragm strength is normal in COPD. Flattening also reduces the zone of apposition, reducing the trans- mission of pressure to expand the lower ribcage. Accessory inspira- tory muscles are also activated. In health, expiration is passive at rest, relying on lung elastic recoil. In COPD the abdominal muscles are recruited to counter expira- tory flow limitation. The diaphragm is relatively fatigue resistant in COPD patients, whereas the abdominal muscles have been shown to fatigue after maximal exercise. Abdominal muscle recruitment and increased intrathoracic pressures may impair cardiac output and may also cause or aggravate gastro-​oesophageal reflux. Limb muscles Skeletal muscle impairment is present in about a third of people with COPD, assessed either in terms of reduced fat-​free mass or in terms of lower limb strength. Upper limb muscles tend to be relatively well preserved, though patients often report difficulties with upper limb activities of daily living. This may in part be because shoulder muscles are used as accessory respiratory muscles. Hand strength is generally found to be preserved, particularly if nonvolitional tests are used to assess it. The quadriceps muscle has been studied extensively in COPD. There is typically reduced bulk and a switch away from a slow twitch, endurance phenotype leading to reductions in both strength and endurance. The main cause of quadriceps impairment is physical inactivity, and these both occur early in COPD, not merely as ‘end-​ stage’ phenomena. Other proposed contributors to skeletal muscle impairment in COPD include systemic inflammation (though little inflammation has been observed in muscle biopsy samples), hyp- oxia, corticosteroids, and sympathetic activation. COPD patients often have poor nutritional status, which can be reflected in muscle loss, and often have low levels of anabolic hor- mones. An inability to gain weight with nutritional supplementation is associated with a poor prognosis. Clinical features The key symptoms which should suggest the presence of COPD are breathlessness, cough, and sputum production occurring in an in- dividual, usually over the age of 35, with a history of exposure to tobacco smoke or other noxious inhaled material. Physical activity limitation is often an early feature. Physical examination may be un- remarkable in early disease, but as COPD becomes more advanced signs of thoracic hyperinflation may appear. Objective evidence of airflow obstruction, obtained by spirometry, is essential for diagnosis. Symptoms Breathlessness on exertion is a cardinal symptom of COPD. The onset of breathlessness can be insidious and it is often misattributed to normal ageing. A typical history will describe several years of limi- tation and progressive avoidance of exertion (e.g. participation in leisure time activities and hobbies). Breathlessness at rest or in bed at night is unusual except in very severe disease and an additional ex- planation should be sought. Breathlessness in COPD is intertwined with fitness, because exertional breathlessness is a feature of lack of physical fitness and the two processes therefore interact. In addition, physical activity levels are reduced even in early COPD, with evi- dence linking physical inactivity with accelerated lung function de- cline. Anxiety symptoms can also modify or confuse presentation with breathlessness. Breathlessness can be evaluated using instruments such as the Medical Research Council (MRC) dyspnoea score (Table 18.8.8) (a modified ‘mMRC’ score with similar categories but rated 0–​4 in- stead of 1–​5 is also commonly used). There is a strong association between breathlessness and health status as well as exercise capacity and survival in COPD, so it is incorporated into most composite staging systems. Cough is also a frequent symptom of COPD. Cough occurs com- monly in smokers and is a feature of bronchitis which may be present in the absence of airflow obstruction. The cough may be productive of sputum. Normalization of the symptom as a ‘smoker’s cough’ may cause patients with COPD to delay presentation, leading to a later diagnosis at a more severe stage. Nocturnal cough does not appear to be increased in stable COPD. Paroxysms of coughing in the presence of severe airway obstruction generate high intrathoracic pressures, which can sometimes produce syncope and cough fractures of the ribs. Cough incontinence may also be a problem. Wheeze may also occur due to turbulent airflow in large airways, but it is important to recognize that the absence of wheeze does not exclude a diagnosis of COPD. Because of increased lung volumes, patients with COPD may experience chest tightness, particularly on exertion. Although expiratory rather than inspiratory airflow obstruction is the pri- mary physiological impairment, high operating lung volumes mean patients frequently report a sensation of difficulty breathing in. Chest discomfort may also be present because of changes to the conformation of the ribcage and thoracic spine and in some individuals because of osteoporotic disease affecting the thor- acic spine and ribs. A pleuritic pattern of pain suggests an add- itional diagnosis such as infection, pulmonary embolism, or a pneumothorax. The most important symptoms associated with COPD have been formally established through the development of a patient-​ reported outcome tool, the COPD assessment test (CAT) score (Fig. 18.8.19). This includes eight questions answered 0–​5, giving a total score 0–​40 with increments of 10 representing mild (0–​10), mod- erate (11–​20), severe (21–​30), and very severe (31–​40) symptom burden. Routine assessment of health status in this way can help to ensure that important areas are covered and, as the measure can be used in any clinical setting (e.g. primary or secondary care and as an outcome measure for pulmonary rehabilitation), it is Table 18.8.8  The MRC dyspnoea score Grade Degree of breathlessness related to activities 1 Not troubled by breathlessness except on strenuous exercise 2 Short of breath when hurrying or walking up a sight hill 3 Walks slower than contemporaries on the level because of breathlessness, or has to stop tor breath when walking at own pace 4 Stops for breath after walking about 100 m or after a few minutes on the level 5 Too breathless to leave the house, or breathless when dressing or undressing

section 18  Respiratory disorders 4114 helpful for integrating care. Other health status measures include generic scores such as the SF-​36 or respiratory specific tools such as the St George’s Respiratory Questionnaire (SGRQ), the Clinical COPD questionnaire (CCQ), and the Chronic Respiratory Disease Questionnaire (CRDQ). Physical activity limitation Physical activity limitation is an important feature of COPD and one of the main symptomatic complaints. Although activity levels fall with increasing disease severity, it is also a feature of early disease (Fig. 18.8.20), with reduction is step count seen even in GOLD stage I  individuals. Physical activity is most strongly associated with measures of hyperinflation (Fig. 18.8.21). The EU PROactive COPD project has developed a patient-​ reported outcome tool for assessing physical activity in COPD. Physical activity is influenced by both physical capacity and behav- ioural factors and is considered in two domains—​difficulty with activities and amount of activities. The PROa tools incorporate a both a questionnaire and direct physical activity monitoring to address the patient experience completely. Fig. 18.8.19  The COPD assessment test score. The COPD assessment test was developed by a multidisciplinary group of international experts in COPD supported by GSK. GSK activities with respect to the COPD Assessment Test are overseen by a governance board that includes independent external experts, one of whom chairs the board. COPD Assessment Test and the CAT logo is a trademark of the GlaxoSmithKline group of companies. It is available in more than 60 languages via http://​catestonline.org/​ © 2009 GlaxoSmithKline. All rights reserved.  

18.8  Chronic obstructive pulmonary disease 4115 Clinical questions and approach When assessing a patient with COPD, the following considerations are of particular relevance: • Smoking history—​are they a current smoker? If not, when did they quit? What age did they have their first cigarette. Calculate pack per year smoke exposure. Is there any smoking of nontobacco drugs? • Effort intolerance can be assessed using the MRC dyspnoea scale. In COPD there is usually only modest day to day variability. Do they do any regular exercise? Have they taken part in pul- monary rehabilitation? • Sputum production—​is this daily or only with exacerbations? What colour or volume? Is it difficult to clear? Has there been haemoptysis? • Impact of disease on patient’s life—​including limitation of activ- ities, economic impact, well-​being, sexual activity, depression, and anxiety. • History of exacerbations and hospitalizations. Have they ever required ventilatory support? • Multimorbidity—​the presence of multiple long-​term conditions is the norm rather than the exception in COPD. • Heartburn—​gastro-​oesophageal reflux is common in COPD and associated with greater exacerbation risk. • Weight loss—​may be a feature of COPD or comorbidity. Loss of appetite, difficulty swallowing, and breathlessness during meals may be present. • Social and family support—​social isolation is common in COPD patients. Are they in contact with patient support groups (e.g. in the United Kingdom, the British Lung Foundation runs ‘Breathe Easy’ groups)? • Nocturnal symptoms—​is there any evidence of sleep-​disordered breathing? Breathlessness, paroxysmal nocturnal dyspnoea, orthopnoea, morning headaches. Prominent nocturnal symptoms may indicate another diagnosis such as asthma or cardiac failure. • Ankle swelling—​this may represent cor pulmonale or coexisting congestive cardiac failure. • Fatigue—​is a common but nonspecific symptom. • Exposure to risk factors—​smoking, occupational and en- vironmental exposures, childhood history of chest disease or prematurity. • Family history—​of COPD or other chronic respiratory diseases. • Past history—​asthma, eczema, or hay fever suggesting a back- ground of atopy. Allergies, respiratory infections in childhood, or prematurity. And finally, and very importantly: • Likely prognosis—​if, after completing your assessment of a pa- tient, you would not be surprised if they died in the next year, then this should prompt discussion about end-​of-​life care. An overall clinical approach is described in Fig. 18.8.22. Physical signs In early COPD there may be few or no abnormal physical signs, with the diagnosis based on history and spirometry. Breathlessness may 25000 20000 15000 10000 Daily physical activity (steps) Controls I II III p<0.0001 p<0.0001 p<0.0001 p<0.0001 IV 5000 0 GOLD Stage Fig. 18.8.20  Physical activity, assessed as step count using an accelerometer, decreases as COPD progresses, but is reduced even in early disease. Figure courtesy of Dr Dinesh Shrikrishna.  15000 10000 5000 0 40 60 RV/TLC ratio r = 0.6, p<0.0001 80 Daily physical activity (steps) Fig. 18.8.21  Gas trapping, assessed as the proportion of residual volume to total lung capacity (RV/​TLC), is inversely correlated with daily physical activity assessed as step counts measured using a triaxial activity monitor. Figure courtesy of Dr Dinesh Shrikrishna. Breathing SPACE – an approach for every breathless patient Smoking – smoking cessation support for all Pulmonary disease – offer prompt spirometry – prioritize high value care Cardiac disease – dual diagnoses are common Anxiety – identify and support psychosocial problems – don’t undertreat Exercise – pulmonary rehabilitation – encourage physical activity Fig. 18.8.22  The breathing SPACE approach.

section 18  Respiratory disorders 4116 not be apparent at rest, but increased work of breathing with re- cruitment of accessory muscles occurs when walking and dressing/​ undressing. Some patients adopt a pattern of pursed lip breathing during expiration, which generates a positive expiratory pressure acting to splint airways open and delay lung emptying. A similar phenomenon at the laryngeal level can give rise to audible expira- tory wheeze and transmitted upper airway sounds on auscultation of the chest. Clubbing is not a feature of COPD, so if observed other causes such as chronic sepsis, pulmonary fibrosis, or malignancy should be considered. There may be nicotine staining due to smoking or a smell of smoke on clothes or hair. Forearm bruising is also common due to age-​related loss of connective tissue supporting capillaries, exacerbated by the use of inhaled corticosteroids. As COPD progresses and lung volumes increase patients may de- velop a hyperinflated, barrel-​shaped chest, and an increase in the space in front of the trachea. Hoover’s sign, an in-​drawing of the lower ribs during inspiration as opposed to the normal expansion, is also characteristic of hyperinflation. Lung hyperinflation can lead to increased resonance on chest percussion with a loss of hepatic and cardiac dullness. The cardiac apex beat may be difficult to palpate and a more prominent liver edge, which should not be confused with hepatomegaly, may be palpable because the diaphragm is pushed down. The abdomen is often generally prominent for this reason. Chest auscultation may be normal but will characteristically re- veal quiet breath sounds with a prolonged expiratory phase. Wheeze may be present. A monophonic wheeze which does not clear with coughing should raise the possibility of a focal obstructive lesion such as a tumour. Crepitations which do not clear with coughing are not typical of stable, uncomplicated COPD. They may represent acute lung infec- tion, but if occurring in a stable patient they may represent an area of bronchiectasis or an additional or alternative diagnosis such as pulmonary oedema or pulmonary fibrosis. A focused examination of the patient with COPD should look for evidence of pulmonary hypertension and cor pulmonale, including parasternal heave, a loud or split second heart sound, raised jugular venous pressure, and peripheral oedema. Tachycardia is common in COPD, as are atrial arrhythmias. Central cyanosis may be apparent in patients who are hypoxic, particularly if there is accompanying polycythaemia. If hypercapnia is present there may be a bounding pulse and a coarse flapping tremor, known as asterixis. Body mass index should be recorded as both over-​ and under- weight are common in COPD. The latter increases the possibility of coexistent sleep-​disordered breathing (see Chapter 18.5.2). Clinical investigations Pulse oximetry This should be performed routinely in COPD patients to help clas- sify disease severity and as a screening test to identify patients who may benefit from supplemental oxygen during exercise or at rest. Desaturation during exercise, particularly in patients with relatively mild airflow obstruction, may indicate the presence of pulmonary hypertension or pulmonary fibrosis. Measurement of arterial blood gases should be considered in patients with oxygen saturation 92% or less and in patients with symptoms suggestive of sleep-​disordered breathing. Spirometry Spirometry is the most important test for the definition of COPD, and also for evaluating the severity of lung function impairment (Fig. 18.8.23 and Table 18.8.2). It is important that this is carried out in a way that meets published standards such as those of the ATS/​ ERS. Spirometry is dependent on patient effort and coordination. The manoeuvre requires the individual to take a maximum breath in to total lung capacity and then breathe out as hard as they can to residual volume. Older bellows devices transcribed a trace onto paper; newer ones are electronic. The display should be large enough to see if the pattern of the trace is correct, does not stop abruptly, and is continuous without interruptions for breath or coughing. Spirometry should be performed seated. A good mouth fit is im- portant and a nose clip is recommended. It is important to ensure that a full inspiration and maximum effort has been achieved. Three attempts should be made, and for reproducibility the FEV1 should vary by less than 170 ml between manoeuvres. To avoid the effect of airway collapse in patients with COPD during forced expiration, it is suggested that VC should be estimated by a slow or relaxed measurement, which allows patients to exhale at their own pace. The slow VC is often 0.5 litres greater than the FVC. This difference is itself an index of gas trapping. It is important that a volume plateau is reached when performing the FEV1, which can take 15 s or more in patients with severe airways obstruction: if this manoeuvre is not carried out the FVC can be underestimated. The normal forced expiratory time is about 1 second per decade of age (i.e. roughly 5 seconds in a 50-​year-​old). Spirometric measurements are evaluated by comparison of the results with appropriate reference values based on age, height, sex, and race. The presence of a post-​bronchodilator FEV1/​FVC ratio less than 0.70 confirms the presence of airflow limitation that is not fully reversible, which is an essential criterion for the diagnosis of COPD. As discussed earlier, there is debate about the use of a fixed ratio vs. the lower limit of normal. When considering a symptomatic indi- vidual in clinical practice, the fixed value is usually preferred. See Chapter 18.3.1 for further discussion. Many electronic devices allow inspiration as well as expiration to be recorded to produce a flow volume loop (Fig. 18.8.24). In air- flow obstruction the expiratory limb is concave upwards or ‘scal- loped’. The measurement of flow volume loops produces several other metrics that can be calculated to assess the degree of airflow obstruction. Expiratory flow rates at 75% or 50% of vital capacity 0 1 2 3 4 5 6 7 Time (seconds) Obstructive Normal Volume (Litres) FVC FEV1 0 1 2 3 4 Fig. 18.8.23  Spirometry volume time curve in health and COPD. Author’s data.

18.8  Chronic obstructive pulmonary disease 4117 have been used as a measure of airflow limitation. These measure- ments are less reproducible than FEV1, such that values must fall to below 50% of the predicted level to be regarded as abnormal. Flows at lung volumes less than 50% of vital capacity were pre- viously considered to be an indicator of small airways function, but probably provide no more clinically useful information than measurements of FEV1. Peak flow rate is used to monitor lung function in asthma. The flow volume curves illustrate why peak flow rate may underesti- mate the physiological impairment in COPD. In COPD the peak flow rate achieved may be relatively preserved as the larger airways empty quickly, but there is then a rapid fall in flow rate due to dy- namic airways collapse. Reversibility testing For classification of the severity of COPD, testing should be per- formed after the administration of bronchodilators to measure the extent of fixed airflow obstruction. As many patients are on long-​ acting bronchodilator medications anyway, this may simply trans- late into testing them on their usual medication. Reversibility testing is performed specifically to evaluate the response to treatment so differs from ‘post-​bronchodilator’ testing. A large improvement in FEV1 (>400 ml) may indicate the presence of asthma. This can be evaluated after acute administration of bronchodilation or after a trial of oral corticosteroids (e.g. 30 mg prednisone for two weeks). Reversibility testing is however a poor predictor of response to treat- ment. The ISOLDE study showed that there was no link between the response to two weeks of oral prednisone and subsequent re- sponse to inhaled corticosteroids. Likewise, bronchodilators may improve small airway function, reduce gas trapping, and thus re- duce operating lung volumes and breathlessness without the FEV1 changing significantly. This means that an absence of broncho- dilator response does not necessarily mean that the treatment will be ineffective and formal bronchodilator testing to guide treatment is no longer recommended. Reversibility varies from day to day as different degrees of bron- chial smooth muscle constriction can lead to different classification of reversibility status depending on the day of testing. Thus, when airway smooth muscle tone is higher, and thus FEV1 is lower, a re- sponse to bronchodilators may be more likely to be achieved than when muscle tone is lower and FEV1 is higher. Gas transfer measurement A low carbon monoxide transfer coefficient (Kco) and transfer factor (TLco) are present in many patients with COPD and broadly reflect the degree of emphysema. The Kco is the measured rate of uptake of CO, and the Tlco is equal to this value multiplied by the alveolar volume (VA). The VA is measured by helium dilution. The process of gas trapping in emphysema means that the VA under- estimates actual alveolar volume and in addition slow lung unit emptying means that the simple two compartment model that the calculation is based on is inaccurate. Accepting these limitations, Tlco is the lung function parameter most strongly associated with survival in COPD and is also most closely associated with systemic effects, including loss of skeletal muscle bulk. The commonly used method is the single-​breath technique, which uses alveolar volume calculated from helium dilution during the single-​breath test. It requires a vital capacity of 1.5 litres and the ability to breath-​hold for 10 seconds. A steady state technique is also in use in some lung function labs. Gas transfer is also reduced in pulmonary fibrosis and in pul- monary hypertension. These should be considered particularly in individuals with a disproportionately reduced gas transfer com- pared to the extent of airflow obstruction (e.g. an FEV1 of 60% with a Tlco of 30%). However, the possible combinations of airflow ob- struction, ventilation inequality, and emphysema mean that a wide range of lung function patterns are possible without any additional diagnosis being necessary. Lung volumes The helium dilution technique used to assess alveolar volume for gas transfer measurements provides a measure of lung volumes including total lung capacity (TLC), residual volume (RV), and func- tional residual capacity (FRC). However, because of airway closure the helium does not mix with trapped gas and thus underestimates volume. Body plethysmography uses Boyle’s law to calculate lung volumes from changes in mouth and sealed body box pressures. This does measure trapped air within the thorax, including poorly ven- tilated areas, and therefore gives higher readings for lung volumes than the helium dilution technique. Plethysmography is therefore preferred in COPD, especially where these measurements are used to guide treatment decisions such as eligibility for lung volume re- duction procedures. Arterial blood gases Arterial blood gases are used to investigate possible hypoxaemia and hypercapnia in patients with COPD. This test is usually per- formed in stable patients with an FEV1 less than 50% predicted or in those with clinical signs suggestive of respiratory failure or right heart failure. Respiratory failure is defined as a Pao2 less than 8 kPa (60 mm Hg) while breathing air. This is referred to as Type 1 or 6 5 4 3 2 1 0 –1 –2 –3 –4 5 4 VOLUME (L) TLC RV Healthy normal FLOW (L/s) 3 2 IC Rest Exercise COPD 8 6 4 2 0 –2 –4 –6 7 6 5 4 3 2 VOLUME (L) FLOW (L/s) IC Rest Exercise Predicted Rest Exercise Fig. 18.8.24  Flow volume loops in health and COPD. The innermost trace is resting tidal breathing, the middle represents breathing during exercise and the outer the maximum flow volume loop. Reprinted from Chest, 117(2), O’Donnell DE, Assessment of bronchodilator efficacy in symptomatic COPD is spirometry useful?, 42–​7S, Copyright © 2000, with permission from The American College of Chest Physicians.

section 18  Respiratory disorders 4118 hypoxic respiratory failure if PaCO2 is not elevated and Type 2 or hypercapnic respiratory failure if the PaCO2 is more than 6.5 kPa (50 mm Hg). It is essential that the inspired oxygen concentration is speci- fied when reporting blood gas results. It may take at least 30 min to reach a steady state after the inspired oxygen concentration is changed because of long time constants for alveolar gas equilibra- tion in COPD. Acid–​base status can also be assessed from the arterial pH (hydrogen ion concentration) and the bicarbonate. Increases in PaCO2, which can occur rapidly, can be compensated by renal con- servation of bicarbonate ions, which is a relatively slow process. Acid–​base status, particularly mixed respiratory and metabolic dis- turbances, can be characterized by plotting values on an acid–​base diagram (Fig. 18.8.25). Exercise tests Impairment of functional exercise capacity is a key feature of COPD and can be evaluated in several ways. The purposes of testing may include diagnosis, evaluation of maximum capacity, assessment of response to an intervention, and dentification of specific physiological responses (e.g. desaturation, tachycardia). Laboratory-​based cardiopulmonary exercise testing is usually carried out on either a treadmill or cycle ergometer. The latter may be preferred in COPD as it provides a more stable platform and pa- tients can use their arms to stabilize their upper ribcage. However, for most people walking on a treadmill is more relevant to daily activities than cycling. Symptom limited exercise tests are usually stopped because of breathlessness or leg fatigue. The test used may alter the locus of limiting symptoms; a higher proportion of COPD patients will stop cycling because of leg fatigue than report this as a factor limiting them when they walk. Exercise tests may be incremental to assess maximum capacity, or endurance to evaluate performance at a percentage of maximum capacity. Because of the power-​time relationship, endurance tests may be more responsive to interventions than incremental ones. In laboratory tests, a metabolic cart with a mask or mouthpiece used to measure ventilation and analyse expired gas allows calcu- lation of oxygen consumption and CO2 production. Although con- sidered the ‘gold standard’, this form of testing requires expensive equipment and a high level of training to ensure accurate results. For many purposes, simpler field tests are as useful and therefore represent better value. The six-​minute walking test requires the subject to walk as far as they can for 6 minutes. It requires a course of at least 30 m and is the most widely used field walking test. Outcomes include distance walked, limiting symptoms and heart rate, and oxygen saturation can also be measured. The ATS has produced guidance on its correct implementation. The Incremental Shuttle Walking Test (ISWT) involves walking between two cones 10 m apart before a beep sounds. As the interval between beeps shortens, the person has to walk more quickly. The test stops when they are unable to keep up with the pace. A prac- tice walk is done first and the better of the two results taken. An endurance shuttle walk test is performed in the same course but at a fixed speed (interval between beeps) set to correspond to 85% of the peak walking speed on an ISWT. The main outcome of this is the endurance time. Walking tests are reproducible and responsive to change, but need to be performed correctly, in particular the use of practice walks. Values are associated with breathlessness, health status, and survival and are included in some prognostic indices such as the BODE score. α-​1-​antitrypsin α-1-​Antitrypsin is a polymorphic glycoprotein that is a potent in- hibitor of serine proteases, with greatest affinity for the enzyme neutrophil elastase. It is synthesized in the liver and increases from its usual plasma concentration of about 2 g/​litre as part of the acute phase response. Reduced A1AT activity increases lung damage occurring in response to cigarette smoke and is associated with ac- celerated lung function decline. α-​1-​antitrypsin levels and phenotype should be measured in all patients who present with COPD at a young age (<50 years), and in those with a family history of COPD at an early age. A serum concentration of 15–​20% of the normal value is highly suggestive of homozygous α1-​antitrypsin deficiency. Some guidelines rec- ommend α1-​antitrypsin assessment for all patients with COPD to improve case finding in relatives. See Chapter 12.13 for further dis- cussion of α1-​antitrypsin deficiency. 7.0 [H+] nmol/litre pH kPa 7.1 7.2 7.3 7.4 7.5 7.6 Arterial PCO2 5 25 HCO3 – isopleths mmols/litre Metabolic acidosis Metabolic alkalosis Respiratory alkalosis Acute respiratory acidosis Chronic respiratory acidosis 10 15 35 30 0 0 15 30 45 60 75 90 mmHg 2 4 6 8 10 12 60 100 90 80 50 70 40 30 20 0 10 20 Normal range Significant bands of single disturbances in human whole blood in vivo Fig. 18.8.25  A nonlogarithmic acid–​base diagram derived from the measured acid–​base status of patients within the five abnormal bands illustrated and of normal subjects (hatched box). This plot of CO2 tension against hydrogen ion concentration (pH) allows the likely acid–​base disturbance and calculated bicarbonate value (obtained from the relevant isopleth) to be rapidly determined, while changes during treatment can be plotted serially for each patient. Reprinted from The Lancet, 297(7706), Flenley DC, Another nonlogarithmic
acid–​base diagram?, 961–​5, Copyright © 1971, with permission from Elsevier.

18.8  Chronic obstructive pulmonary disease 4119 Other routine tests Routine electrocardiography can be useful in the assessment of patients with COPD though it is an insensitive technique in the diagnosis of cor pulmonale. However, an argument can be made in its favour given that comorbidities are common, including rhythm disturbances, and some medications can prolong the QT interval. A full blood count may reveal anaemia of chronic disease, which commonly occurs in COPD. Polycythaemia may be present in pa- tients with severe COPD and predisposes to vascular events. It should be suspected when the haematocrit is greater than 47% in women and 52% in men, and/​or the haemoglobin is greater than 16 g/​dl in women and 18 g/​dl in men, provided other causes of spurious polycythaemia, due to decreased plasma volume, such as caused by dehydration or diuretics, can be excluded. Imaging Chest radiography The most basic imaging modality is chest radiography. It is usually normal in early disease and may be so in individuals with signifi- cant impairment. As COPD progresses the lung fields may become hyperinflated, with flattening of the diaphragms such that the border of the diaphragm in the midclavicular line is at or below the anterior end of the sixth rib (Fig. 18.8.26). The accuracy of chest X-​ray in COPD is low, but it may be useful for excluding alternative diag- noses and identifying co-​occurring conditions such as fibrosis, bronchiectasis, and cardiac failure. Routine repeat chest X-​rays are not indicated in the follow-​up of patients with COPD. Chest radiology appearances of lung hyperinflation include: • a low flattened diaphragm; • increased retrosternal air space occurs when the horizontal dis- tance from the anterior surface of the aorta to the sternum exceeds 4.5 cm on the lateral film at a point 3 cm below the manubrium; • an obtuse costophrenic angle on the posterior–​anterior or lateral chest radiograph; • inferior margin of the retrosternal air space is 3 cm or less from the anterior aspect of the diaphragm. The vascular changes associated with emphysema result from loss of alveolar walls and appear as: • a reduction in size and number of pulmonary vessels, particularly at the periphery of the lung; • vessel distortion, producing increased branching angles, excess straightening, or bowing of vessels; • areas of increased lucency; • hilar vessels may be prominent. A general increased transradiancy may be due to the chest radio- graph being overexposed. Focal areas of transradiancy surrounded by hairline walls represent bullae (Fig. 18.8.27). These may be mul- tiple, as part of a generalized emphysematous process, or local- ized. An ‘increase in lung markings’ rather than areas of increased transradiancy has often been described in patients with COPD: the cause of these changes is unknown, but may at least be contributed to by nonvascular linear opacities due to scarring. Fig. 18.8.26  Chest radiograph shows hyperinflated lung fields with flattening of the diaphragm. Fig. 18.8.27  Chest radiograph shows bullous changes, particularly marked in the upper zones.  

section 18  Respiratory disorders 4120 Thoracic CT scanning CT scanning is increasingly used for the evaluation of COPD (Fig. 18.8.28 and 18.8.29). It can provide information about • the extent of emphysema; • the type of emphysema (centrilobular vs. panacinar); • the pattern of emphysema—​especially homogenous vs. heterogeneous; • integrity and position of interlobar fissures; • airway disease—​airway wall thickening, bronchiectasis; • vascular abnormalities—​increase in pulmonary artery/​aorta ratio; • presence of other lung conditions—​pulmonary fibrosis, pleural plaques, lung nodules, and masses. CT scans are usually interpreted based on visual appearances, but quantitative techniques have been developed. At present these are mostly in use for research purposes only. Microscopic emphy- sema can be quantified by measuring CT lung density, which is expressed on a linear scale in Hounsfield units (water = 0; air = –​ 1000). Density masking techniques quantify the area of lung with a density below a certain threshold of Hounsfield units (e.g. –​950 or –910 HU) which is taken to represent emphysema. Emphysema scored in this way is associated with lung function, symptoms, and mortality risk. One limitation is that lung density depends on lung volume so there are technical concerns evaluating change over time as TLC increases with worsening disease. A related approach is to calculate the fifteenth percentile mean lung density, the PD15. This measure has been shown to be responsive to change in clin- ical trials. Emphysema occurs in three main histological patterns; centrilobular/​ centriacinar, paraseptal, and panacinar. In centrilobular emphysema CT shows low attenuation areas with ill-​defined margins producing a ‘moth-​eaten’ appearance. It tends to occur more in the upper zone, particularly in early disease. Panacinar emphysema produces a more uniform appearance of low attenuation lung and occurs more fre- quently in the lower parts of the lung. These two patterns frequently occur in the same individual. Paraseptal emphysema occurs adja- cent to connective tissue structures with appearances that highlight interlobular septa so that emphysematous areas, which are usually peripheral, are highly demarcated. The typical pattern of disease in α1-​antitrypsin deficiency is lower lobe predominant, pan-​acinar emphysema with airway wall thinking, but any COPD phenotype can occur. CT scanning is crucial for identifying patients with the appro- priate pattern of emphysema for lung volume reduction procedures and should be considered in patients with an FEV1 below 50% and if there is concern about pulmonary fibrosis or bronchiectasis. CT can be helpful in distinguishing airways predominant phenotypes from emphysematous pattern. Airways abnormalities include bronchial wall thickening, areas of focal air trapping (mosaicism) and mucus plugging. CT scans in patients with COPD frequently reveal nodules, 95% of which are not malignant but they may require follow-​up (the British Thoracic Society has recently produced guidance). The use of CT to screen high risk populations for lung cancer is relevant to patients with COPD, the presence of which is itself a risk factor for lung ma- lignancy, independent of smoking. CT screening may identify em- physema in individuals without a prior diagnosis of COPD. Other infiltrative processes including respiratory bronchiolitis interstitial lung disease (RB-​ILD), Langerhans cell histiocytosis and interstitial fibrosis may also be identified. Pulmonary vascular changes can also occur in COPD. In health, the aorta has a greater diameter than the pulmonary artery. Increase in pulmonary artery dimensions and thus in the PA/​A ratio may indicate the presence of pulmonary hypertension. Data from the COPDGene and ECLIPSE cohorts has shown that a PA/​A ratio more than 1 is associated with greater exacerbation risk. The presence of coronary artery calcification is a frequent inci- dental finding which may have prognostic implications and be an indication for further investigation. Evidence of osteoporosis is also common. Fig. 18.8.28  Well-​demarcated peripheral emphysema on thoracic CT scan. Fig. 18.8.29  ‘Moth-​eaten appearance’ of centrilobular emphysema on thoracic CT scan.

18.8  Chronic obstructive pulmonary disease 4121 Contrast-​enhanced CT is usually not indicated unless there is specific concern about the possibility of thromboembolic disease. Echocardiography This can be useful in COPD, though lung hyperinflation may make it more technically challenging because aerated lung reduces the acoustic window. It allows assessment of pulmonary arterial pres- sure as well as identification of right heart strain including right-​ sided chamber dilatation. As cardiac comorbidities are common, incidental left-​sided and valvular disease may also be identified in patients with COPD. Combined COPD scoring systems Although FEV1 provides a simple measure of airflow limitation, this only captures one element of the impact of COPD on lung function, and it is well recognized that lung function is only one element of this complex disease. For these reasons, a range of scoring systems have been proposed, which capture other features including meas- ures of breathlessness, exercise capacity, exacerbation frequency, body mass index, and health-​related quality of life, as well as age (Table 18.8.9). These can be used to stratify patients for treatment and to estimate prognosis. BODE index For prognosis, the most widely used score is the BODE index which includes body mass index, airflow obstruction (FEV1), dyspnoea (mMRC score), and exercise capacity (Table 18.8.10). The hazard ratio for death from any cause increases by 1.34 and for respiratory death by 1.62 for every point increase on the BODE scale. It should be noted, however, that although the es- timates are useful at a population level they are of limited ac- curacy for individual patients. A modified version of this, the i-​BODE, uses a different walking test, substituting the ISWT for the 6MWT. GOLD classification The 2007 Global Initiative for Chronic Obstructive Lung Disease (GOLD—​https://​www.goldcopd.org) COPD classification system incorporated only FEV1 and hypoxia: Stage I: Mild FEV1 ≥80% predicted Stage II: Moderate 50% ≤FEV1 <80% predicted Stage III: Severe 30% ≤FEV1 <50% predicted Stage IV: Very severe FEV1 <30% predicted or FEV1 <50%

predicted plus chronic respiratory failure This has developed such that the 2017 GOLD classification now combines the extent of airflow obstruction (stage I to IV) with a category based on symptom burden and exacerbation history (A-​ D) (Fig. 18.8.30). To use this classification assessment first iden- tify the extent of airflow obstruction, then assess symptoms with the mMRC dyspnoea score or the CAT score—​less symptomatic (left boxes mMRC 0–​1, CAT <10) or more symptomatic (right boxes mMRC≥ 2 or CAT ≥10). Next, assess the risk of exacerba- tions using the GOLD spirometric grade (GOLD 1–​2 low risk lower boxes, GOLD 3–​4 high risk upper boxes), or assess the number of exacerbations the patient has had in the last 12 months (0–​1 low risk, lower boxes, 2 or more high risk upper boxes). If the latter case the method giving the highest risk should be chosen. This form of assessment categorizes patients into four symptom groups and four airflow categories: Patient group A—​Low risk, less symptoms Patient group B—​Low risk, more symptoms Table 18.8.9  Composite prognostic indexes in chronic obstructive pulmonary disease Composite Index Components BODE BMI, FEV1, mMRC, 6MWD i-​BODE BMI, FEV1, mMRC, ISWT mBODE BMI, FEV1, mMRC, peak V.o2 eBODE BMI, FEV1, mMRC, 6MWD, exacerbation rate BODEx BMI, FEV1, mMRC, exacerbation rate Inflammatory BODE BODE, inflammatory biomarkers, age, and hospitalization history ADO Age, mMRC, FEV1 DOSE mMRC, FEV1, smoking status, exacerbation rate CODEx Comorbidity, obstruction, dyspnoea, and previous severe exacerbations Definition of abbreviations: 6MWD, 6-​minute-​walk distance; ADO, age, dyspnoea, and airflow obstruction index; BMI, body mass index (kg/​m2); BODE, body mass index, airflow obstruction, dyspnoea, and exercise capacity index; BODEx, exacerbations replace 6MWD in the original BODE; CODEx, comorbidities, airflow obstruction, dyspnoea, and exacerbations index; DOSE, dyspnoea, airflow obstruction, smoking status, and exacerbations index; eBODE, exacerbations added to original BODE; FEV1, forced expiratory volume in 1 second (severity of airflow obstruction); inflammatory BODE, inflammatory markers added to original BODE; mBODE, modified BODE in which 6MWD is replaced by peak oxygen consumption; mMRC, level of dyspnoea according to the Modified Medical Research Council questionnaire. Reproduced with permission of the © ERS 2018: European Respiratory Journal Apr 2015, 45(4), 879–​905; DOI: 10.1183/​09031936.00009015. Table 18.8.10  The body mass index, airflow obstruction, dyspnoea, and exercise capacity (BODE) index in COPD Variable Points on BODE index 0 1 2 3 FEV1 (% predicted) ≥65 50–​64 36–​49 ≤35 Distance (m) walked in 6 min ≥350 250–​349 150–​249 ≤149 MRC dyspnoea scale 0–​1 2 3 4 Body mass index ≥21 ≤21

section 18  Respiratory disorders 4122 Patient group C—​High risk, less symptoms Patient group D—​High risk, more symptoms This classification should have the advantage of encouraging a holistic approach to COPD evaluation, incorporating informa- tion systematically that can be used to guide treatment. A disad- vantage is that the boundaries between categories are arbitrary and may change over time, adding complexity. The ‘holistic’ na- ture of the score may even be a problem, as more symptomatic individuals (Grade B) may be symptomatic for reasons other than COPD (e.g. obesity or comorbidities such as cardiac disease or anxiety). Differential diagnosis COPD needs to be distinguished from other causes of breathless- ness (Table 18.8.11). The features noted in Table 18.8.11 tend to be characteristic of the respective diseases, but do not occur in every case. Furthermore, there could be overlap between two or more categories, and diseases might coexist. Although the differences between asthma and COPD have his- torically been emphasized, both diagnostic categories encompass a range of phenotypes and both are common conditions. The diag- nosis of asthma itself predicts COPD in later life, and it can be impossible to make a precise distinction between the two clin- ically, particularly where there is a significant smoking history. Bronchiectasis can occur in the absence of airflow obstruction, but the pathological features of airway wall thickening and airway dilatation are frequently present in patients with COPD, meaning that it also occurs as a COPD phenotype rather than a distinct condition. TB is strongly associated with smoking and there is an association between TB and increased risk of COPD. Congestive cardiac failure is a common comorbidity of COPD. Connective tissue disease should be considered as well as conditions that sometimes mimic COPD (e.g. lymphangioleiomyomatoisis and histiocytosis X). Management of stable COPD Although the underlying pathophysiology of COPD is largely irre- versible, optimum management of COPD can improve symptoms and exercise capacity, reduce exacerbations, and in some instances FEV1 (% predicted) GOLD I

80 GOLD II ≥2 exacerbations (or ≥1 requiring hospital admission) Assessment of symptoms/risk of exacerbations 0 or 1 exacerbations (not leading to hospital admission) Symptoms mMRC 0–1 CAT <10 mMRC ≥2 CAT ≥10 GOLD III 30–49 50–79 C D A B GOLD IV <30 Fig. 18.8.30  GOLD 2017 COPD classification—​association between symptoms, spirometric classification, and risk of exacerbations in COPD—​see text for discussion. Table 18.8.11  Differential diagnosis of COPD Diagnosis Suggestive features COPD Onset in midlife Slowly progressive symptoms Smoking history Asthma Symptoms since childhood Variable symptoms—​day to day and at night History of atopy Nasal symptoms Congestive heart failure Basal crepitations on chest auscultation Cardiomegaly on chest radiograph ECG abnormalities Restrictive spirometry History of hypertension or ischaemic heart disease Bronchiectasis Large volumes of purulent sputum Episode of severe chest disease in childhood Radiograph shows bronchial dilatation or wall thickening Interstitial lung disease Fine end-​inspiratory crepitations Restrictive spirometry Desaturation on exercise Connective tissue disease Medications (e.g. amiodarone, nitrofurantoin) Tuberculosis Classic radiographic findings Fever, night sweats High local prevalence Microbiological confirmation Obliterative bronchiolitis Onset in young age and nonsmokers History of fume exposure or rheumatoid arthritis CT scan shows hypodense areas on expiration Diffuse panbronchiolitis Patients typically male nonsmokers History of chronic sinusitis CT scan shows diffuse centrilobular nodular opacities and hyperinflation

18.8  Chronic obstructive pulmonary disease 4123 improve survival. The goals of COPD management are shown in Table 18.8.12 and Fig. 18.8.31. There are many national guidelines for COPD. In the United Kingdom a National Institute for Clinical Excellence (NICE) guideline is available, together with a Quality Standard Document for service delivery published in 2011, as well as a range of subsequent updates on therapies (see http://​www.nice.org.uk/​guidance/​conditions-​and-​ diseases/​respiratory-​conditions/​chronic-​obstructive-​pulmonary-​ disease). Joint guidelines on COPD, from the ATS, ERS, ACP, and ACCP were published in 2011. Subsequent joint statements on integrated care for COPD patients, on pulmonary rehabilitation, on the use of field walking tests, and identifying outstanding re- search questions have also been published (see http://​www.thor- acic.org/​statements/​copd.php). The GOLD project also produces international guidelines for COPD management (see http://​www. goldcopd.com/​). Management priorities in COPD should be those interventions which are the best value. The London Respiratory Network, working with the London School of Economics, has produced a ‘Pyramid of Value’ graphic to focus attention on these (Fig. 18.8.32). Vaccination Annual influenza vaccination is recommended as it has been shown to reduce exacerbations and mortality from influenza in patients with COPD. The vaccine is adjusted each year to improve effective- ness against circulating strains. Pneumoccocal vaccination is intended to reduce the risk and severity of streptococcal pneumonia, the commonest cause of community-​acquired pneumonia. It is recommended for patients with COPD aged 65 years and older, as well as those under 65 years of age with FEV1 less than 40% predicted, in whom it has been shown to reduce the incidence of community-​acquired pneumonia. Smoking cessation Smoking cessation is crucial to prevent COPD and also a crucial part of the management of the condition. Smoking cessation improves survival in COPD patients (Fig. 18.8.33) and also reduces symp- toms, in particular cough and sputum production. A Making Every Contact Count approach should be adopted so that every health professional is trained and motivated to give very brief smoking cessation advice on each occasion that they encounter the patient (Table 18.8.13). Online training is available in the United Kingdom from The National Centre for Smoking Cessation and Training. Acute exacerbations are opportunities to intervene and times when patients may be especially motivated to quit. Because smoking cessation produces such dramatic health bene- fits, the value of interventions rises the more intensive and effective they are (Table 18.8.14). Around 80% of smokers start before they are 20, so smokers with COPD will have a long history of smoking and may well have Table 18.8.12  Goals of COPD management Reduce decline in lung function Improve day to day symptoms Minimize side effects of treatment Prevent exacerbations Improve survival Address physical and mental health/​comorbidities Manage resources—​value, sustainability, and distributive justice Promote patient autonomy and appropriate self-​management Provide good quality end-​of-​life care Quality care across the COPD pathway Fig. 18.8.31  Quality care across the COPD pathway. CDM, chronic disease management; QA, quality assured; EOL, end of life. From ‘An Outcomes Strategy for COPD and Asthma in England’, Department of Health, © Crown copyright 2011. https://​www.gov.uk/​government/​uploads/​system/​uploads/​attachment_​data/​file/​216139/​dh_​128428.pdf

section 18  Respiratory disorders 4124 made quit attempts previously. Advice to quit smoking should be objective and nonjudgemental. Many smokers with COPD express guilt at continuing to smoke and may avoid discussion of the subject. It may be helpful to highlight that their addiction often started in childhood. In addition, considerable scientific effort by the tobacco industry has gone into making tobacco products as addictive as possible. This includes manipulating the pH to increase the solu- bility of nicotine and masking this with flavourings such as menthol to produce a ‘smooth’ taste. Counselling should include an assessment of the level of addiction (the Fagerstrom index) and motivational interviewing to promote desire to quit. Reasons why quitting would be of benefit to them should be outlined, but also the factors that motivate them to con- tinue smoking should be explored. Counselling can be effective in both individual and group sessions, depending on personal prefer- ence and resources. Increasing exercise levels is often recommended, though the evi- dence that it actually promotes smoking cessation itself is weak. Smoking cessation is associated with withdrawal symptoms including mood disturbance, anxiety, increased appetite, vivid dreams, and gastrointestinal disturbance. Anxiety and stress are often given as reasons to delay or defer quit attempts, and as reasons for relapse. Smokers should be reassured that nonsmokers and ex-​smokers actu- ally experience less anxiety symptoms than smokers. Smoking cessa- tion in COPD patients has been associated with weight gain, but this includes an increase in lean body mass and therefore may be beneficial. Nicotine replacement therapy Nicotine replacement therapy (NRT) can be delivered in sev- eral ways, including patches, gum, inhalators, nasal spray, and lozenges. The optimum approach includes a slow release background Fig. 18.8.32  Pyramid of value for COPD interventions. Relative value expressed as cost per quality-​adjusted life year (QALY) if different COPD interventions. Developed by the London Respiratory Network and the London School of Economics.  0 1 0.95 0.9 Proportion of patients with no event Time since LHS Baseline, y 0.85 0.08 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Special intervention group Usual care group Fig. 18.8.33  Smoking cessation improves survival in COPD. Reproduced from Anthonisen NR, et al. (2005). The effects of a smoking cessation intervention on 14.5-​year mortality: a randomized clinical trial. Ann Intern Med, 142(4), 233–​9, Copyright © 2005, The American College of Physicians. Table 18.8.13  Very brief smoking cessation advice ASK Assess current and past smoking behaviour ADVISE Provide information on consequences of smoking and smoking cessation. Advise person quit smoking ASSIST Provide options for later/​additional support Advise on stop smoking medications Table 18.8.14  Value of smoking cessation interventions in COPD 1 year abstinence rate Cost per QALY Usual care 1.4% Minimal counselling 2.6% £14 735 Intensive counselling 6% £7149 Intensive counselling + pharmacotherapy 12.3% £2092 Data from Hoogendoorn M, et al. (2010). Long-​term effectiveness and cost-​effectiveness of smoking cessation interventions in patients with COPD. Thorax, 65, 711–​8.

18.8  Chronic obstructive pulmonary disease 4125 delivery mechanism such as a patch, combined with a more rapid onset system such as gum or spray which can be used acutely when cravings occur. Some patches work for 24 hours and some 16 hours, the latter being intended to cover waking hours only. Nicotine delivered in this way has few harmful effects and can always be considered less harmful than smoking, but NRT should be avoided during acute coronary syndromes because of vasoconstricting effects. There have also been concerns that nico- tine should also be avoided in pregnancy because it was thought to be associated with low birth weight, but NRT is much less harmful than smoking to mother and fetus, and the SNAP trial in pregnant smokers has demonstrated that NRT was associated with better long-​term child outcomes. E Cigarettes Many smokers find that they are able to satisfy their nicotine addic- tion by using e-cigarettes. These devices heat a liquid carrying agent (propylene glycol or vegetable glycerin) which contains varying con- centrations of nicotine as well as a range of flavours. Inhaling vapour is substantially safer than smoking, so as long as smokers switch completely to vaping they are likely to substantially reduce their risk of harm, and doing so has been reported to produce improvements in COPD exacerbation rates, COPD assessment tool scores, and 6-minute walking distance over a 3-year period. Some toxicty has been identified, so people with COPD who have quit smoking this way should be advised to try to quit vaping too if they can, though not at the expense of going back to smoking. Varenicline This medication is a partial agonist of the nicotine receptor, reducing cravings but also blocking the acute effect of smoking and thus breaking the cycle of reinforcement. It is the most effective pharmacological ap- proach, and usually used for 12 weeks, with a 2 week run in period before the quit date, while the dose is uptitrated. Gastrointestinal side effects are common. Mood disturbances can occur, which improve when the medication is stopped. Large population studies have shown that early concerns that it may be associated with increased suicide risk are not justified, and the EAGLES trial showed that it can be given safely in people with mental health problems. Bupropion This tricyclic antidepressant is also licenced for smoking cessation. It is contraindicated in patients with a history of epilepsy. Repeat quit attempts The best time to attempt to quit smoking is when a person has just relapsed, before they have fully re-​established their smoking habit. Strategies that ration supported quit attempts may therefore be counter- productive. Similarly, time limits to the duration of treatment support should not be too strict. More prolonged treatment may be appropriate in heavily addicted individuals who are at an increased risk of relapse. Pulmonary rehabilitation Pulmonary rehabilitation is a supervised programme of exercise training combined with education to help patients to understand their condition and self-​manage. The 2015 Cochrane Review of Pulmonary Rehabilitation confirmed the strong evidence base for the therapy, which is one of the highest value interventions in COPD. It improves exercise capacity (Fig. 18.8.34), breathless- ness, and health status as well as anxiety. It is also associated with reduced hospital admissions. These improvements exceed the min- imum clinically important difference and generally exceed the bene- fits seen with pharmacotherapy. It is important that clinicians are aware of this, so they can confidently explain the concept to patients who may be wary of exercise after a long period of avoiding exertion because of the symptoms it provokes. In addition, observational Study or subgroup Deering 2011 Faulkner 2010 Griffiths 2000 Gurgun 2013 Hernandez 2000 McNamara 2013 Xie 2003 Casey 2013 Pulmonary rehab N Mean (SD) Mean (SD) 29 (152) 41.82 (50.56) –5 (172) 71 (118) 56.3 (64.9) 9.5 (138.6) 31 (50.7407) 70 (138) 27 (162) –1.43 (51.12) 12 (125) –2 (99) 8.13 (49.2) –22.9 (167.6) –1 (1.81) 3 (167) 11 6 93 30 20 30 25 –100 –50 0 50 100 Favours pulmonary rehab Favours usual care 148 14 8 91 16 17 15 25 145 15.2% 2.00 [–33.99, 37.99] 43.25 [3.13, 83.37] –17.00 [–179.62, 145.62] 73.00 [41.55, 104.45] 48.17 [14.70, 81.64] 32.40 [–67.79, 132.59] 32.00 [13.82, 50.18] 67.00 [–17.92, 151.92] 39.77 [22.38, 57.15] 13.1% 1.1% 17.9% 16.6% 2.8% 29.4% 3.8% 100.0% 331 363 Total (95% CI) Heterogeneity: Tau2 = 181.56; Chi2 = 10.34, df = 7(p = 0.17); I2 = 32% Test for overall effect: Z = 4.48 (p < 0.00001) Test for subgroup difference: Not applicable N Usual care Mean Difference IV, Random, 95% CI IV, Random, 95% CI Mean Difference Weight Fig. 18.8.34  This Cochrane review highlights the effectiveness of pulmonary rehabilitation in COPD. From McCarthy B, et al. (2015). Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 2015, Issue 2, CD003793.

section 18  Respiratory disorders 4126 data suggest that pulmonary rehabilitation works ‘in the real world’. The benefits seen in patients who complete clinical programmes are of a similar magnitude to those seen in randomized clinical trials. Although the evidence base for pulmonary rehabilitation is ex- tremely strong, there are many outstanding questions regarding the optimum duration of programmes, location, and training mo- dalities, as well as whether and how often programmes should be repeated. A typical programme includes a mixture of aerobic and strength training. The former may involve free walking, treadmills, or exercise bikes, and other specialized equipment. Fixed gym equipment, free weights, or elastic resistance bands are often used for strength training. Exercise prescription is based on an initial as- sessment, usually a walking test, although some programmes use more complicated cardiopulmonary exercise testing. Programmes typically last a minimum of six weeks and usually con- sist of twice weekly sessions with additional home exercise. As the pro- gramme progresses the level of exercise should be increased. It is crucial that patients are encouraged to develop a home exercise regime during the course so that they can continue to exercise once the programme is finished. Behaviour change is an important goal, but this may require longer than is necessary to achieve initial benefits in walking distance and other measures. Continuation exercise programmes, sometimes organized by groups of patients and in some situations available on prescription, can be helpful, but must not be considered a substitute for a properly constituted pulmonary rehabilitation programme itself. It is clear that a true training effect, with lower lactate production for a given workload, can be achieved in COPD. In addition to this effect, there is also a psychological effect, with pulmonary rehabili- tation operating as a graded exposure therapy, in effect addressing ‘phobia’ about exercise and breathlessness. A minimum outcome set, both to assess individuals and to evaluate the effectiveness of the programme itself, should include a walking test (e.g. ISWT, 6MWD), and a health status measure (e.g. CAT score or CRDQ or CCQ). The HAD score, which generally im- proves following pulmonary rehabilitation, is used as a screening tool to identify patients who may benefit from additional psych- ology input or referral. The Lung Information Needs Questionnaire (LINQ) can be used to assess the impact of education programmes. All patients with significant breathlessness (MRC dyspnoea score

  1. should be considered for pulmonary rehabilitation, as should those who consider themselves to be limited. The cut off for treat- ment is arbitrary and based partly on resources: patients with less breathlessness do benefit from pulmonary rehabilitation and should also be encouraged to exercise, but they may well be able to do this in a more conventional environment. The educational programme for pulmonary rehabilitation should cover a range of topics, and programmes should be staffed by a range of health professionals including physiotherapists, occupational therapists, health psychologists, nurses, pharmacists, and smoking cessation advisors (Table 18.8.15). Pulmonary rehabilitation is a group activity and may also serve to reduce the social isolation experienced by many older people with severe lung disease that limits their mobility. It is also a holistic therapy with potential benefits to comorbidities that COPD patients have as well as COPD itself. Inspiratory muscle training is sometimes incorporated into pulmonary rehabilitation programmes. Although it is possible to improve performance on tests of inspiratory pressures with prac- tice, it is not clear that these improvements actually translate into clinical benefit. The National Emphysema Therapy Trial (NETT) study demonstrated that maximum inspiratory pressures improve after pulmonary rehabilitation in the absence of specific inspiratory muscle training, and routine use cannot be recommended. Post-​exacerbation pulmonary rehabilitation Several trials have addressed the specific issue of post-​exacerbation pulmonary rehabilitation, with patients enrolled in a program within 2 weeks of discharge from hospital. It is a highly effective intervention in this context. A 2011 Cochrane review found that it significantly reduced hospital admissions (pooled odds ratio 0.22 [95% CI 0.08–​0.58], number needed to treat (NNT) 4 [95% CI 3–​8], over 25 weeks), and mortality (OR 0.28; 95% CI 0.10–​0.84), NNT 6 [95% CI 5–​30] over 107 weeks). Pharmacotherapy Inhaled therapies form the basis of pharmacological treatment for COPD. They have two broad functions: bronchodilatation and sup- pression of the inflammatory response. There are two classes of bronchodilator:  anticholinergic drugs and β2-​agonists. These are available in short-​acting as required forms, and long-​acting (once or twice daily treatment) forms. Inhaled corticosteroids are beneficial in some patient groups, but inflammation in COPD typically dis- plays only limited corticosteroid sensitivity. Inhalers which include a combination of long-​acting bronchodilators and corticosteroids are frequently used. Other medications include theophyllines and mucolytics. Long-​ term antibiotic therapy may have a role. With the advent of non-​ invasive ventilation, respiratory stimulants are rarely used. Clinical trials in COPD have generally studied the effects of medi- cations in largely undifferentiated COPD populations. This means that modest overall effects may disguise greater (or lesser) effects in specific patient phenotypes. Studies have also in general excluded patients with significant comorbidity, which has implications for the general applicability of findings in clinical practice. Inhaler technique Existing inhaler devices are relatively inefficient, with only a small proportion of drug delivered to the target region. This depends on factors including means of activation, particle size, and patient com- pliance with the required inhalation technique. Numerous studies have shown that patients’ inhaler technique is often poor, and this aspect of care is frequently neglected when a new drug is prescribed. Inhaler technique should be taught carefully when a new inhaler is introduced. Different devices require different techniques and both patients and healthcare professionals require training. Written or online materials are helpful to reinforce this, and reassessment and reinforcement of inhaler technique must be part of routine care. Table 18.8.15  Topics to cover in pulmonary rehabilitation Breathing strategies Early treatment Proper use of medications When and how to contact healthcare providers Smoking cessation Eating properly Exercise Travel/​sex/​leisure Dealing with anxiety/​panic attacks Lung function Move from teaching to self-​management

18.8  Chronic obstructive pulmonary disease 4127 The metered dose inhalers (MDI) combine drug with a hydro- fluorocarbon propellant to produce an aerosol. Dry powder inhalers (DPI) are either pure drug or drug combined with a bulking agent to produce particles of the appropriate size. Worldwide, MDIs are the most commonly prescribed, and also tend to be easier to manufac- ture and cheaper. Some key elements of inhaler technique are out- lined in Table 18.8.16. A key difference is that with MDIs a slow steady inspiration is required, whereas for DPIs a rapid inhalation is needed. In general, DPIs are easier to use and patient technique is more often correct with them than with MDIs. Of note, HFC propel- lants in MDIs are powerful greenhouse gases and are responsible for 4% of the United Kingdom NHS’s entire carbon footprint. MDI aerosols emerge at high speed, so even with the best inhaler technique the bulk of the material is actually swallowed rather than inhaled. To improve coordination, some MDIs are breath-​actuated. Manual dexterity as well as coordinating breathing may be difficult for some patients. The use of a spacer device (Fig. 18.8.35) may as much as double lung deposition from MDIs as it allows the particles to slow down, hence their use is recommended for all long-​acting MDIs and inhaled corticosteroids. Bronchodilators Although COPD is characterized by ‘fixed’ airflow obstruction, bronchodilator medications—​β2-​agonists and anticholinergic drugs—​can act to relax airway smooth muscle and so reduce airway resistance (Fig. 18.8.36). In general the effect of these is smaller than is seem in bronchial asthma, but is clinically meaningful. In add- ition to usually modest improvements in FEV1, bronchodilators also improve lung emptying, reducing lung volumes and dynamic hyperinflation. This can translate into improved symptoms and ex- ercise capacity, even in patients whose FEV1 does not improve with therapy, hence bronchodilator responsiveness testing by spirometry is not recommended to guide therapy. Bronchodilator use has not been shown to modify decline in lung function in COPD. β2-​Agonists The main action of β2-​agonists is to relax airway smooth muscle by stimulating β2-​adrenergic receptors, which increase cAMP. Inhaled β2-​agonists are preferred to oral preparations because they are as efficacious in much smaller doses and have fewer side effects. They have a relatively rapid onset of action and are therefore used for symptomatic relief, and they can also increase exercise tolerance in patients with COPD. The effects of short-​acting β2-​agonists (e.g. salbutamol and terbutaline) last for 4–​6 h. There is no evidence that the response to a β2-​agonist diminishes with time, and patients with COPD should be told to take them as required, although those with severe disease may prefer to take regular doses three to four times daily to obtain symptomatic relief. Long-​acting β2-​agonists (LABAs) can be given twice daily (such as salmeterol and formoterol) or once a day (indacaterol) due to their prolonged receptor occupancy. Formoterol and indacaterol have a more rapid onset of action than salmeterol. In randomized placebo-​controlled studies LABAs have been shown to improve Table 18.8.16  Inhaler technique: metered dose (MDI) vs. dry powder (DPI) devices Metered dose inhalers Dry powder inhalers Shake inhaler Prime device Remove cap Breathe out fully Breathe out fully Place in mouth Place device in mouth Rapid maximum inhalation Start to breathe in steadily Hold breath for a few seconds Activate device Continue to breathe in steadily to maximum Hold breath for a few seconds Fig. 18.8.35  Spacer devices to improve drug deposition from metered dose inhalers. M1 ACh Relaxation Contraction Smooth muscle cell Anticholinergic Theophylline β-agonist cAMP 5'-AMP M2 M3 Fig. 18.8.36  Mechanisms of action of bronchodilators. Anticholinergics block muscarinic receptors so that acetylcholine is unable to act upon them; β-​agonists increase levels of cAMP; theophylline blocks conversion of cAMP to 5′-​AMP. M1, M2, and M3 are three distinct types of muscarinic cholinergic receptors. ACh, acetylcholine.

section 18  Respiratory disorders 4128 symptoms, FEV1, quality of life, and to reduce exacerbation rates. They have no effect on rate of decline in FEV1 or mortality. Newer LABAs include olodaterol and vilanterol. Side effects of treatment with β2-​agonists include tachycardia and tremor, as well as the potential to precipitate cardiac rhythm disturb- ances in susceptible patients, although this is uncommon with inhaled therapy except when high does are used via a nebulizer. In this con- text, particularly in older patients, hypokalaemia can occur. These ef- fects show tachyphylaxis, unlike the bronchodilator actions. There is little evidence to support the use of sustained-​release oral β2-​agonists (bambuterol) in patients with COPD and they are not recommended. Anticholinergics Anticholinergic drugs block the effect of acetylcholine on mus- carinic receptors. Like β2-​agonists, short-​acting anticholinergics (e.g. ipratropium and oxitropium) affect both central and peripheral airways, and also reduce functional residual capacity. They take 30 to 60 min to reach peak effect in most patients with COPD, which is slower than β2-​agonists, but their duration of action is longer (6–​10 h). Tiotropium bromide is an anticholinergic agent that has greater se- lectivity for M 1 and M 3 muscarinic receptors, and has a longer time course of action so can be given once daily. Tiotropium and similar long-​acting antimuscarinic agents (LAMAs) improves symptoms, health status, decrease lung overinflation, improve the effectiveness of pulmonary rehabilitation, and decrease exacerbation rates in patients with COPD (Fig. 18.8.37). As with LABAs, LAMAs have not been convincingly shown to alter the progression of lung function decline. Anticholinergics are poorly absorbed, which limits systemic side effects with inhaled preparations. The main side effect is dry mouth. Data from trials does not suggest that tiotropium increases cardiac risk, but caution is suggested in people with unstable cardiac disease as this population were excluded from trials. Several newer long-​acting antimuscarinic agents (LAMAs)—​ aclidinium bromide, glycopyrronium, and umeclidinium—​have be- come available. Within the classes of both LABAs and LAMAs, there are few comparative data to guide selection between molecules. Licensing studies confirm that these drugs improve lung function and symp- toms as well as reducing exacerbations, but have generally com- pared them to placebo rather than existing members of the same class (Table 18.8.17). The two classes of bronchodilator have dif- ferent mechanisms of action, so their effects are complementary. Dual use is associated with reduced exacerbation risk, reduced breathlessness and increased quality of life and is therefore pre- ferred first line therapy in the absence of features suggesting steroid responsiveness. Inhaled corticosteroids Inflammation in COPD is relatively nonresponsive to corticoster- oids, particularly when compared to asthma. There is, however, evidence that inhaled corticosteroids (ICS) can improve lung func- tion and reduce exacerbation frequency, both alone and in combin- ation with a LABA in trials such as ISOLDE and TORCH, and with a LAMA. Mean effects were modest and it is likely that there are distinct steroid responsive and nonresponsive phenotypes within COPD. Although these cannot be precisely delineated features sug- gesting steroid repressiveness include any previous, secure diagnosis of asthma or of atopy, a higher blood eosinophil count, substantial variation in FEV1 over time (at least 400 ml) or substantial diurnal variation in peak expiratory flow (at least 20%). Early clinical trials of ICS used high doses in order not to miss an effect through underdosing. A consequence of this is that the li- cenced doses tend to be high. In COPD, moderate dose ICS (800 µg beclomethasone dipropionate (BDP) equivalent) has a similar clin- ical efficacy to very high dose ICS (2000 µg BDP equivalent). ICS in combination with long-​acting bronchodilators are recommended for patients with frequent (>2/​yr) exacerbations and in those with more severe disease (FEV1<50% predicted; see Fig. 18.8.38). The ef- fects of inhaled corticosteroids are attenuated by smoking. Side effects include oral thrush and bruising. Patients should be advised to gargle and spit out after using ICS to reduce absorp- tion. Although ICS reduce exacerbations they are associated with an increased risk of pneumonia, which is dose related and there- fore more of an issue with high potency molecules like fluticasone. (Fig. 18.8.39). High doses of ICS are also associated with adrenal suppression (Fig. 18.8.40). 80 60 40 20 0 0 6 12 18 24 Month Tiotropium Hazard ratio, 0.86 (95% CI, 0.81 –0.91) p<0.001 No. at risk Tiotropium 2986 1996 1496 1223 983 838 709 610 26 776 634 545 460 21 1284 1010 1815 3006 Placebo Placebo COPD exacerbation Probability of exacerbation (%) 30 36 42 48 Fig. 18.8.37  Tiotropium reduced exacerbations of COPD in the UPLIFT trial. There were also fewer deaths in the treatment arm (p = 0.09.) Reproduced from Tashkin DP, et al. (2008). A 4-​year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med, 359, 1543–​54, Copyright © 2008, Massachusetts Medical Society. Table 18.8.17  Considerations around new long-​acting inhaled therapies The effects of LAMAs and LABAs are likely to be class effects with few important differences between drugs New combinations have become available in single devices (e.g. LAMA/​LABA combinations) Switching between drugs in a class is unlikely to be of general benefit, although may sometimes help an individual who is intolerant of a particular drug Newer inhalers tend to be introduced at lower prices than existing ones to capture market share Consideration of costs to the healthcare system must include time taken to teach and maintain inhaler technique Molecules in longer use (formoterol, salmeterol, tiotropium) have a longer safety record Newer delivery devices may or may not be preferred by individual patients, who may or may not find them easier to use correctly

18.8  Chronic obstructive pulmonary disease 4129 Strategy for use of inhaled therapies A strategy for use of inhaled therapies for stable COPD is shown in Fig. 18.8.41. Oral corticosteroids Oral corticosteroids are used for the treatment of acute exacer- bations in COPD. Long-​term oral steroid use is associated with systemic side effects including osteoporosis, weight gain, myop- athy, and diabetes as well as increased mortality. The term ‘main- tenance steroids’ should be avoided as there is little evidence that steroids ‘maintain’ COPD patients and it tends to encourage their use. Oral steroid trials (e.g. prednisone 30 mg/​day for 14 days) are sometimes used for diagnostic purposes:  a large response may suggest a diagnosis of asthma, but should not be used to guide treatment decisions as the ISOLDE study showed clearly that the response to a 2 week prednisone trial did not predict subsequent response to ICS. Other drugs Theophyllines Theophyllines, or methylxanthine derivatives, produce a modest bronchodilator effect in patients with COPD. There is still controversy over their exact mode of action: they may act as nonselective phos­ phodiesterase inhibitors, producing bronchodilatation by increasing cAMP, but anti-​inflammatory effects have also been proposed. Many patients are unable to tolerate them because of nausea which unfortu- nately cannot be predicted in advance of a therapeutic trial. Theophyllines are usually administered orally in chronic disease, or intravenously during acute exacerbations. They have a relatively narrow therapeutic index and monitoring of blood levels should be considered (therapeutic range for bronchodilator effects 10–​20 mg/​l). Slow release oral preparations are preferred, and prescription should be by specific preparation. Toxic effects include tremor, convulsions, and arrhythmias. Other anti-​inflammatory theophylline effects may occur at lower doses. It had been proposed that low-​dose theophylline will improve corticosteroid sensitivity via histone deacetylase (HDAC). However a large trial (TWICS) found no benefit from this. Theophylline levels are reduced by smoking and doses may there- fore need to be reduced when patients quit. Antibiotics, in particular ciprofloxacin, increase levels and oral doses should be halved if this antibiotic is used. The possible beneficial effects of theophyllines have to be balanced against their potential side effects and toxicity. This means that they are usually reserved for patients with more severe disease in whom other treatments have failed to control symptoms adequately. Phosphodiesterase 4 inhibitors Phosphodiesterase 4 (PDE4) inhibitors, like theophyllines, also in- hibit the breakdown of cyclic AMP and should therefore reduce in- flammation. Roflumilast is an oral PDE4 inhibitor given once daily which has been shown to improve FEV1 in patients already receiving treatment with a long-​acting bronchodilator. Roflumilast also re- duced the frequency of moderate to severe exacerbations in patients with severe to very severe COPD who were chronic sputum produ- cers (chronic bronchitis) and who had a history of exacerbations. It may therefore have a role as an add on therapy to patients with these characteristics to reduce exacerbations. Trials to date have not, how- ever, added it to patients with this phenotype already established on ‘triple therapy’ with a LAMA, LABA, and ICS. Use of PDE4 inhibitors is limited by side effects. The most im- portant of these are nausea, reduced appetite, abdominal pain, diar- rhoea, sleep disturbance, and headache. Significant weight loss is common and hence Roflumilast should not be given to patients who are underweight, and it should be given with caution in patients with depression. It should not be used with theophyllines. Long-​term antibiotics Recent studies have renewed interest in the use of antibiotics to pre- vent exacerbations, although concerns remain around value, possible side effects, and the development of drug resistance. The best data are for macrolide antibiotics, with studies of both erythromycin and azithromycin. A study by the US COPD Clinical Research Network randomized 1142 high risk COPD patients to receive azithromycin, at a dose of 250 mg daily (570 participants), or placebo (572 par- ticipants) for 1 year in addition to their usual care. The median time to the first exacerbation was 266 days (95% CI, 227–​313) for 104 102 100 Mean FEV1 % of baseline 98 96 94 92 90 88 86 84 82 80 0 1 2 3 4 5 6 Month since randomization Placebo Budesonide Formoterol Formoterol/Budesonide Formoterol/Prednisolone 7 8 9 10 11 12 Fig. 18.8.38  Combinations of ICS and LABA had a bigger impact on FEV1 than either component alone. Reproduced with permission of the © ERS 2018: European Respiratory Journal Dec 2003, 22(6), 912–​19; DOI: 10.1183/​09031936.03.00027003. 2.0 1.9 1.8 1.7 1.6 1.5 1.4 Rate ratio 1.3 1.2 1.1 1.0 0.9 0 200 400 600 800 1000 Daily dose in μg (Fluticasone equivalents) 1200 1400 1600 1800 2000 Fig. 18.8.39  Effect of fluticasone dose on pneumonia in patients with COPD. From Suissa S, et al. (2013). Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax, 68, 1029–​36.

section 18  Respiratory disorders 4130 azithromycin, vs. 174 days (95% CI, 143–​215) for placebo (p <0.001). There were 1.48 exacerbations per patient year in the azithromycin group, as compared with 1.83 per patient year in the controls. Of note, little evidence of treatment effect was observed in current smokers. Azithromycin can be effective taken less frequently (250  mg three times per week rather than daily) and has fewer drug interactions than erythromycin, but it is significantly more expen- sive. Caution is required in patients with a prolonged QTc, and liver function tests should be measured before it is started. The possibility of hearing impairment, which occurs less frequently at lower doses, should be mentioned to patients and they should stop medication and seek medical attention if they notice this or Fig. 18.8.40  When should COPD patients receive a corticosteroid warning card? Produced by The London Respiratory Network, 2015. 

18.8  Chronic obstructive pulmonary disease 4131 develop tinnitus. Caution is needed in the presence of atypical mycobacterial infections. Pulsed therapy with moxifloxacin for 5 days every 8 weeks has also been shown to reduce exacerbations, but the use of quinolones in this way raises concerns as they are the only oral agents that can be used in pseudomonal infections. Trials so far have followed patients up for 1 year only, so the longer term use of antibiotic remains a matter for clinical judgement. It should be remembered that COPD exacerbations cluster in time. Treatment may need to be indefinite, but depending on the individual patient response pauses in treatment in the summer or after a long period without exacerbations can be considered (Table 18.8.18). Fig. 18.8.41  Use of inhaled therapies for stable COPD. NICE guidance on COPD, © Crown copyright 2019. Table 18.8.18  An approach to long-​term oral antibiotics in COPD Initiation Should a trial of oral antibiotics be considered? Frequent exacerbations (>4/​yr) Life-​threatening exacerbations Daily productive sputum Inhaled therapy optimized Other causes addressed (smoking cessation, chest physiotherapy, GORD, Vitamin D deficiency) Are there cautions or contraindications? Drug intolerance Prolonged QT interval on ECG Abnormal liver function tests Hearing impairment Atypical mycobacterial infection Continuation Good response—​exacerbations dramatically reduced in frequency. No longer significant daily sputum production, Continue for one year, then consider pause over the course of the next summer and resume in winter Moderate response—exacerbations modestly improved
(e.g. still occurring but seem less severe) Continue for one year, then consider pause over the course of the next summer No response Stop after 3 months

section 18  Respiratory disorders 4132 Mucolytics Mucolytic agents are intended to reduce sputum viscosity and facili- tate expectoration. Carbocisteine may reduce exacerbations in pa- tients with milder disease, but overall effect size is small. In COPD patients with a chronic productive cough a trial of carbocisteine can be considered, but it should be stopped after 4 weeks if ineffective. α1-​antitrypsin α1-​antitrypsin replacement is feasible and in some countries offered as standard care. Evidence of benefit from trials is limited, although a re- cent study has shown that IV supplementation reduced decline in CT lung density, a measure of emphysema. However, it is not clear how this translates into clinical benefit, making estimations of the value of replacement (which is extremely expensive) difficult. Replacement therapy is not currently recommended in the United Kingdom. Choice of medications Medication for COPD should, as with other conditions, be chosen on the basis of evidence for efficacy, safety, and value. The London Respiratory Network key messages for Responsible Respiratory Prescribing are useful (Table 18.8.19). Chest physiotherapy Chest physiotherapy interventions can be useful in COPD to assist breathing control and improve sputum clearance. Techniques to assist breathing control include advice to slow expiration down and avoid breath stacking. Adopting postures which support the shoulders such as tripod sitting and wall leaning can be helpful to speed recovery from breathlessness (Fig. 18.8.42). Pursed lip breathing slows expir- ation and generates a positive pressure to reduce airway closure. It is not clear that teaching patients who do not do this spontaneously is helpful as it may simply focus attention on breathlessness. Small ran- domized controlled trials as well as larger cohort studies suggest that group singing training may be of benefit in COPD and this approach is becoming increasingly popular with patient groups. Dynamic airway collapse can make it more difficult to clear sputum. Coughing harder, which generates increasing intrathoracic pressure, may simply worsen this and is tiring. Techniques are often taught in the context of pulmonary rehabilitation and need to be tailored to the individual. In general, increased physical activity and the accompanying increase in respiration helps with sputum clearance, hence exercise is encouraged. Patients should under- stand that active and purposeful sputum clearance (e.g. morning and evening) will reduce the reservoir for infection to develop and should also reduce expectoration at other times. All patients with chronic cough, irrespective of continence status, should be taught to contract the pelvic floor muscles before forced expirations and coughing. A key technique is ‘huffing’, which moves sputum from the small airways to the larger. This, combined with relaxed breathing control breaths and slow deep breaths, forms The Active Cycle of Breathing approach to mobilize sputum into larger airways making them easier to clear with less effort. This is par- ticularly important in the management of patients with bronchiec- tasis: see Chapter 18.9 for further discussion. Small, portable adjunct devices are sometimes used to facilitate sputum clearance. Oscillating positive expiratory pressure devices create positive expiratory pressure and oscillation during forced exhalation. This reduces premature airway closure and can help to mobilize secretions and reduce sputum viscosity. The Flutter® is a pipe-​shaped device with a ball-​bearing and the Acapella Choice® uses a counterweighted plug and magnet to create oscillation and positive pressure on expiration. The Cornet® is a flexible tube which deforms during exhalation causing vibration. Hypertonic (7%) saline may be helpful in patients with viscous sputum. It occasionally causes bronchospasm, so when first adminis- tered patients should be supervised and spirometry should be meas- ured before and after. Use of a predose bronchodilator may be helpful. Table 18.8.19  Responsible respiratory prescribing—​key messages 1 Respiratory medications are expensive Doing the right things: 2. When prescribing any new respiratory inhaler, ensure that the patient has undergone NICE-​recommended support to stop smoking 3. Pulmonary rehabilitation is a cost-​effective alternative to stepping up to triple therapy and should be the preferred option if available and the patient is suitable. Doing the right things right: 4. When prescribing any inhaled medication, ensure that the patient has undergone patient-​centred education about the disease and inhaler technique training by a competent trainer 5. When prescribing an MDI (except salbutamol), ensure that a spacer is also prescribed and will be used 6. When prescribing high dose inhaled corticosteroids (>1000 ug BDP/​day equivalent), ensure that the patient is issued with an inhaled steroid safety card BDP, beclomethasone dipropionate; MDI, metered dose inhaler; NICE, UK National Institute for Clinical Excellence. Fig. 18.8.42  Breathing posture for COPD. Forward leaning breathing postures may be more comfortable for people with COPD.

18.8  Chronic obstructive pulmonary disease 4133 Self-​management Relating to the interventions and treatments considered above, pa- tients with COPD should be encouraged and taught how to manage their condition (Table 18.8.20). There is evidence from systematic reviews that interventions including an action plan for worsening COPD symptoms improves health-related quality of life compared with usual care. Lung volume reduction Lung volume reduction surgery Lung volume reduction surgery (LVRS; originally ‘reduction pneumoplasty’) involves resection of the most emphysematous part of the lung. These areas are the most compliant and therefore expand the most on inspiration, restricting the ventilation of healthier areas. The remaining lung, post-​operation, is more elastic, improving ven- tilation and reducing V/​Q mismatch. Reduced gas trapping also reduces operating volumes and thus improves the efficiency of re- spiratory muscles. There are hazards associated with LVRS, including a risk of death and prolonged hospital stay due to complications such as air leak and pneumonia. A 1% mortality risk, with a 20% risk that the sur- gery will not lead to improvements, is typically quoted. Selection for LVRS requires a multidisciplinary approach including input from a physician, surgeon, and radiologist (Table 18.8.21). The largest study of LVRS was the NETT in which 608 patients underwent bilateral LVRS and 610 continued with medical therapy alone. The trial identified a high risk phenotype in whom LVRS is unsafe; patients with FEV1 less than 20% and either homogenous emphysema or TLco less than 20% predicted. LVRS was associ- ated with a survival benefit in patients with low exercise capacity and upper lobe predominant emphysema (Fig. 18.8.43). Guidelines therefore recommend LVRS for patients with that phenotype. Despite the established survival benefit very few procedures are done. In the United Kingdom an estimated 15 000 COPD patients might be eligible, but only about 100 operations per year are carried out. A BTS survey suggests that this is due to an exaggerated concern about procedural morbidity and the absence of structures to system- atically evaluate possible patients for procedures. Case series suggest that modern practice is safer than at the time of NETT, with a uni- lateral approach and VATS being preferred, but in the United States only bilateral procedures are currently reimbursed by Medicare. Bronchoscopic lung volume reduction approaches Endobronchial valves, placed to occlude the airways leading to the worst affected lobe, allow air to leave but not enter, causing the target lobe to collapse. Response in early trials was highly variable, but where effective it appeared to be associated with a survival ad- vantage. This was because valve placement is only beneficial if the interlobar fissures are intact. If the emphysematous process has damaged the fissures, collateral ventilation allows continued entry of air to the target lobe from the adjacent lobe and there is no effect. The BeLieVeR-​HIFi study demonstrated that it is possible to iden- tify responders prospectively, leading to improvements of a similar order of magnitude to LVRS. The eligibility criteria are similar to those for LVRS—​heterogeneous emphysema with an appropriate target lobe, together with hyperinflation. It is possible to measure collateral ventilation directly with the ChartisTM balloon catheter pressure and flow system. Computer scoring systems can characterize heterogeneity and also perform semi-​automated assessment of fissure integrity. These approaches improve the success rate of the procedure. The main complication is pneumothorax, which occurs in about 10% of patients. This can be delayed, but most occur within the Table 18.8.20  Aspects of self-​management in COPD Having the ability to make changes to management without needing to consult a health professional Understanding their symptoms Explaining their condition to others Smoking cessation Maintaining and increasing physical activity Ability to use physiotherapy techniques Correct use of inhalers Knowing when to contact health professionals Table 18.8.21  General criteria when considering a lung volume reduction procedure General criteria • significantly reduced exercise capacity • lung function impairment (FEV1 usually <50%) with significant hyperinflation (typically a plethysmographic RV >170% predicted) • sufficiently well to cope with surgery • prepared to accept some procedural risk (requires clinicians to be able to communicate this accurately) • there is a ‘window of opportunity’ for intervention: in ‘end-​stage’ patients it may be too late to intervene safely because lung function is too severely impaired, or because of frailty Are they too well to consider intervention? Lung function, exercise capacity, prognosis, MRC dyspnoea score <3. Are they too unwell for intervention to be safe? Lung function, frailty, exercise capacity <100 m, oxygen dependence. Has treatment been optimized? Smoking cessation, pulmonary rehabilitation, flu vaccination, inhaled and oral medication. Is their lung function likely to rule out a procedure on safety grounds? All three of FEV1, TLco and Kco <20% predicted. Do they have comorbidities that limit likely benefit or increase risk? Pulmonary hypertension, unstable cardiac disease, malignancy, cerebrovascular disease. Ongoing smoking (possibility of intervention may help to promote quit attempts). Have they ever had a CT thorax and, if so, has it been reported in terms of emphysema pattern? Review existing CTs or obtain a CT if a potential candidate as above. Review CT and lung function in MDT including respiratory physician, radiologist, and thoracic surgeon. Further investigations including echocardiogram, lung perfusion scan and a formal field exercise test (shuttle walk or 6 minute walk test) may be indicated.

section 18  Respiratory disorders 4134 first 3 days and hence a period of in-​patient observation is neces- sary. Pneumothorax usually improves with conventional intercostal tube drainage, but can be fatal. Because of the risk of complications, valve treatment is not recommended for people who are ‘too frail’ for LVRS to be considered. Other techniques for inducing lung volume reduction include endobronchial coils, which restore the elastic recoil of the lung. Bilateral treatment is required, and clinical studies thus far suggest that this treatment approach may benefit a wider group of patients with emphysema (upper lobe predominant emphysema and more homogenous emphysema), but is not suitable for patients with se- vere bullous disease. Bronchoscopic thermal vapour ablation (using steam to cause scarring) and bronchoscopic targeted vagal nerve ab- lation are also under clinical investigation. Oxygen supplementation Supplemental oxygen in COPD is a treatment for hypoxia, not breathlessness, and is prescribed to improve survival and in some individuals to increase exercise capacity. Domiciliary supplemental oxygen therapy is usually considered in three categories: • long-​term controlled oxygen therapy for at least 15 h/​day in pa- tients with chronic respiratory failure; • ambulatory oxygen therapy for exercise-​related hypoxaemia; • short-​burst oxygen therapy—​a palliative treatment for the tem- porary relief of breathlessness. Continued cigarette smoking is a contraindication to long-​term oxygen therapy because of the significant risk of fires, endangering both the patient and others. E-​cigarettes are also a potential cause of combustion and should not be used with supplemental oxygen. Long-​term oxygen therapy Long-​term oxygen therapy (LTOT; administered for at least 15 hours/​day) is indicated in patients with hypoxia defined as a PaO2 less than 7.3 kPa on two occasions while stable at least three weeks apart, or between 7.3 and 8.0 kPa in the context of pulmonary hyper- tension or polycythaemia. These recommendations are based on two multicentre trials, the MRC trial in the United Kingdom and the Nocturnal Oxygen Therapy Trial (NOTT) in the United States of America. The MRC trial of oxygen for 15 h/​day showed an increase in 5-​year survival from 25 to 41% (compared with no oxygen). The NOTT trial demonstrated the continuous use of oxygen therapy, with a mean use of 17.5 h/​day, was beneficial in terms of survival, whereas use for only 12 h/​day conferred no benefit (Fig. 18.8.44). Importantly, an absence of benefit has been demonstrated in trials of LTOT patients with less severe hypoxia, including those who desat- urated at night but had daytime PaO2 7.4–​9.2 kPa, and those with a PaO2 between 7.4 and 8.7 kPa. Fig. 18.8.43  Thoracic CT image showing upper lobe predominant emphysema in a pattern suitable for lung volume reduction surgery. 100 Cumulative % survival 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 Time (months) 02 24 h/day 02 15 h/day 02 12 h/day Controls (no added 02) Fig. 18.8.44  Combined survival data from the NOTT and MRC studies of long-​term oxygen therapy showing benefit in selected individuals. After The Lancet, 1981, 317(8222), 681–​6 and Annals of Internal Medicine, 1980, 93(3), 391–​8.

18.8  Chronic obstructive pulmonary disease 4135 Benefit from LTOT is likely to be due in part to effects on pul- monary haemodynamics. Control subjects in the MRC trial ex- perienced a 3 mm Hg/​year increase in pulmonary arterial pressure, whereas this remained stable in the treated group. A reduction in polycythemia may also be beneficial. The NOTT trial also found an improvement in cognitive function in the treated arm. Oxygen can be delivered by mask, but nasal cannulae are usually preferred. Patients on LTOT should also receive a supply of port- able oxygen to allow the patient to leave their home and to exer- cise without significant desaturation. Oxygen flow rates may have to be increased during exercise to maintain adequate oxygenation. Oxygen conserver systems, which are triggered by inspiration, de- liver pulsed oxygen, and thus reduce total oxygen consumption. An important practical point is that flow rates from oxygen delivery de- vices may not match those from wall oxygen systems, so assessment of oxygen requirement should where possible be done using the same equipment as will be used at home. Ambulatory oxygen Ambulatory oxygen may improve exercise capacity in patients with COPD who desaturate during exercise. This should be evaluated formally for two reasons. Firstly, to avoid giving oxygen therapy to individuals who will not benefit, which is a significant source of waste. Secondly, a major issue with ambulatory oxygen is that many patients who receive it do not use it because of the weight, incon- venience, or stigma. A formal demonstration of improved exercise capacity can help to ensure compliance and should be considered in the context of more general advice to maintain or increase physical activity levels. There is no evidence that oxygen provision in this context improves survival, although there may be a range of indirect benefits if individuals are able to remain more active and socially engaged. Short-​burst oxygen therapy to reduce breathlessness Many patients on maximum drug therapy for COPD remain breath- less on exercise, which has led to the use of oxygen to minimize the sensation of breathless. Studies of oxygen used in this way have failed to show any consistent effect on either breathlessness or the rate of recovery from breathlessness, and this may be a placebo ef- fect. The use of short-​burst oxygen therapy cannot be generally re- commended in COPD. Oxygen during air travel Travel in commercial aircraft involves exposure to air pressur- ized to the equivalent of breathing 15% oxygen at sea level. This will worsen hypoxaemia and may lead to symptoms and increase the risk of vascular events. Although many patients travel safely without oxygen, the BTS guidelines on managing passengers with stable respiratory disease planning air travel recommend that a hypoxic challenge test be considered in COPD patients with severe disease (FEV1 <30%) or where resting oxygen saturations are less than 95% breathing air. A hypoxic challenge test should also be considered in individuals who need ambulatory oxygen. The hypoxic challenge test involves breathing 15% O2 for 20 min- utes. Supplemental oxygen will be required if PaO2 falls below 6.6 kPa or O2 saturation below 85%. Patients already receiving LTOT should receive double their usual flow rate while at altitude. Oxygen prescribing Guidelines for responsible prescribing of oxygen in patients with COPD are shown in Table 18.8.22. Noninvasive ventilation Noninvasive ventilation (NIV) has a well-​defined place in the man- agement of decompensated hypercapnic (Type II) respiratory failure. Its role in stable COPD is less clear. Trials have been small and often evaluated ineffective NIV strategies that have not appreciably re- duced CO2 levels. It is appropriate to consider domiciliary NIV in patients with symptomatic hypercapnia—​morning headaches and drowsiness. Domiciliary NIV may also be beneficial, reducing ex- acerbations and healthcare costs, in those who have required NIV on multiple hospital admissions. However, a strategy of starting all patients admitted to hospital who required acute NIV on long-​term NIV did not improve outcomes, presumably because in many the hypercapnia does not persist. A German study recruiting COPD patients with a PaCO2 above 7 kPa evaluated NIV adjusted to target at least a 20% reduction in PaCO2 or a value below 6.5 kPa and found that this did improve survival. This needs to be balanced against the impact on quality of life which NIV may have. Tolerance of NIV varies between individ- uals and any NIV service requires significant expertise and technical support to ensure optimization of ventilator settings and that issues Table 18.8.22  Responsible oxygen prescribing for COPD

  1. Oxygen is a treatment for hypoxia not breathlessness.
  2. Oxygen is a medicine that should always be planned, prescribed, and reviewed by staff trained in oxygen prescription and use.
  3. Acute oxygen prescription must include the target oxygen saturation range and state the appropriate interface and range of flow rates to achieve this. Oxygen saturations must be monitored according to an agreed management plan.
  4. Long-​term oxygen treatment (15–​24 hours per day) should only be prescribed after specialist review and risk assessment.
  5. Those who administer oxygen should have regular and ongoing training so that they are able to monitor and respond to a patient’s oxygen saturations within an agreed management plan.
  6. Patients who may benefit from ambulatory oxygen should have a specialist assessment with access to the full range of relevant equipment to meet their individual needs and maximize their independence.
  7. Patients who smoke should not be prescribed long-​term oxygen therapy. They should be offered clear communication of the reasons oxygen therapy cannot safely be offered to them while they smoke, individualized information about the benefits of smoking cessation for them, treatment for tobacco dependence, and planned follow-​up.
  8. Specialist oxygen assessment and follow-​up should include individualized patient and carer education about oxygen treatment, comprehensive risk assessment, and carbon monoxide monitoring. Patients should be informed of their responsibility to use oxygen safely, including abstinence from smoking and of the reasons for this. Time should be allowed to check patients’ understanding of this information.
  9. Patients on long-​term oxygen therapy at risk of harm from excessive oxygen should be identified and their care plan shared with their GP and local hospitals as well as ambulance and out of hours services.
  10. Home Oxygen Service Assessment and Review services are vital to ensure evidence-​based patient-​centred care and optimal value for money, and these should be integrated with local respiratory services to be effective. From the London Respiratory Network.

section 18  Respiratory disorders 4136 such as mask fit and patient education are addressed. The HOT-​ HMV trial found that NIV was of benefit in patients whose type II respiratory failure persisted after hospital discharge. Bi-​level ventilation is also sometimes required in COPD patients who also have obstructive sleep apnoea. Lung transplantation Lung transplantation, which is discussed in Chapter 18.16, should be considered in selected patients with very advanced COPD and a life expectancy of less than 2 to 3 years, where it has been shown to improve quality of life and functional capacity. Outcomes are poor in people over 60, both because they are less able to cope with the stress of surgery and because they have increasing rates of multimorbidity which are aggravated by the antirejection therapies needed post-​transplant. Palliation and end-​of-​life care Many patents with COPD remain very symptomatic despite therapy, with health status equivalent to or worse than many common ma- lignancies. Common issues are breathlessness, anxiety, and exacer- bations (Table 18.8.23). Attention to optimizing care with smoking cessation support, pulmonary rehabilitation, and inhaled and other therapies is important. Social isolation and poverty are also frequent issues, and historically COPD patients have missed out on palliative care services. There is evidence that patients who use a hand-​held battery-​ powered fan to blow air onto their face experience significant symp- tomatic relief. Low dose oral morphine (e.g. 2.5–​5 mg twice per day) can be effective in patients with severe breathlessness: dependence and respiratory depression are not issues, although a laxative should be prescribed to prevent constipation. Anxiety attacks which are not controlled with nonpharmacological interventions may respond to sublingual lorazepam. Prognostication is difficult in COPD. The pattern of background decline mixed with acute exacerbations and recovery makes disease trajectory less easy to track than in malignancy. In addition, the pic- ture is complicated by comorbidities. Only about a third of COPD patients die from COPD, with cardiovascular causes and malig- nancy common. There are many prognostic scores which are useful for stratifying populations but of limited use for individual patients. The question ‘would you be surprised if this patient died in the next 12  months’ can be a useful trigger for considering end-​of-​ life care discussions, which need to be handled sensitively. Family members are often unaware of how severe a patient’s condition is. Discussion of ceiling of care may be appropriate (e.g. NIV but not intubation). Multimorbidity and COPD The presence of multiple long-​term conditions has become the norm rather than the exception as people age. A cross-​sectional study from a database of 1 751 841 people registered with 314 med- ical practices in Scotland found that fewer than one in five people with COPD only had COPD. COPD, being a disease of ageing as- sociated with smoking, reduced physical activity, an adverse early life environment and lower socioeconomic status, shares many risk factors with other chronic conditions which frequently co-​occur, including cardiovascular disease, osteoporosis, cognitive impair- ment, and psychological problems. Comorbidities may represent a common susceptibility to risk factors or a systemic ‘overspill’ of lung inflammation impacting directly on remote disease processes, such as the development of atherosclerosis. Importantly, the patterns of comorbidities is associated with deprivation. The most deprived pa- tients with COPD commonly display a cluster of coronary artery disease, depression, and chronic painful conditions (Fig. 18.8.45). Cardiovascular disease Data from UK primary care found that a diagnosis of COPD was associated with a 10.1-​fold increase in risk of myocardial infarc- tion and a 3.4-​fold risk of stroke. Acute exacerbations of COPD are a high risk. Raised troponin, an indicator of cardiac damage, is frequently observed during hospital admission and is associated with increased mortality. Management of vascular disease should be along conventional lines. Historically there has been reluctance to use β-​blockers in people with airway disease because of the risk of acute bronchospasm in asthma. However, β blockade appears to be generally safe in COPD patients with cardiac disease, and associated with a survival benefit. A cardioselective agent should be used, at a low dose initially and then titrated up, as necessary. Atrial arrhythmias occur commonly as a complication of COPD. They may be triggered by exacerbations and may be transient. Management is conventional. As with all patients, bronchodilator therapy should be optimized, avoiding excessive doses which con- tribute to tachycardia without additional symptomatic benefit. Nebulized bronchodilators and corticosteroids may contribute to electrolyte abnormalities, which should be corrected. Osteoporosis Osteoporosis is a common COPD comorbidity. Loss of bone density is accelerated by smoking and physical inactivity as well as being aggravated by corticosteroid treatment. Poor nutrition is common in COPD and reduced time spent outdoors mean that vitamin D deficiency is also common. Treating frank vitamin D deficiency has been shown to reduce exacerbation frequency. Osteoporotic ver- tebral collapse is particularly problematic in COPD as it can lead to restriction of the chest wall. Osteoporotic rib fractures due to coughing or other trauma can also impede respiration. Table 18.8.23  Palliative care and end-​of-​life interventions in COPD Palliative interventions Breathlessness Pulmonary rehabilitation Optimize inhaled medication—​prescription and use Specific breathing control advice Hand-​held battery-​powered fans Low dose morphine Anxiety Pulmonary rehabilitation Specific breathing control advice Talking therapies/​Cognitive behavioural therapy Low-​dose lorazepam Discuss anxieties about End-​of-​life issues Advanced directives Consider ceilings of care (e.g. NIV but not intubation) End-​of-​life tasks—​wills, and so on.

18.8  Chronic obstructive pulmonary disease 4137 Cognitive, psychological, and nervous system problems Many patients with COPD are anxious or depressed. This may be reactive in response to the symptoms and limitations of the disease and without any specific features. Screening by systematic use of a tool such as the Hospital Anxiety and Depression Score as part of an annual ‘comprehensive clinical and psychosocial assessment’ may be recommended. Beyond being a determinant of the content of depres- sive thoughts, COPD itself makes little difference to the management of depression. Exercise, talking therapies, and pharmacotherapies are used as appropriate. An overlap between anxiety and breathlessness can be addressed through pulmonary rehabilitation and learning techniques for breathing control such as pursed lip breathing. PR in part functions as a form of graded exposure to breathlessness. There is evidence from fMRI that pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations. Mild cognitive impairment related to hypoxia, which may par- ticularly affect information processing and verbal memory, has been described in COPD. This can impact on the understanding and use of self-​management plans, and should be considered if new inhaler devices are being introduced during acute exacerbations. Peripheral neuropathy (including increased phrenic nerve con- duction time) is frequently observed in COPD and increased ex- citability of the diaphragm motor cortex has been reported. COPD patients frequently describe muscle cramps, which are often attrib- uted to the use of bronchodilators, though the aetiology is not clear. Management of acute exacerbations of COPD Acute exacerbations of COPD are responsible for impaired quality of life and patient distress, as well as much of the healthcare re- source utilization. Management focuses on prevention, in particular smoking cessation, prompt treatment, avoiding unnecessary hospi- talization, and enhancing recovery. There are several definitions, but exacerbations are usually defined as episodes where there is a deterioration in symptoms that exceeds normal day to day variation and which prompt a change in treat- ment. This is an event-​based definition dependent on behaviour. Studies using symptom diaries suggest that patients under-​report exacerbations and also that nonreported exacerbations are associ- ated with worse health status. The Anthonisen criteria are used to classify exacerbations based on symptoms (Table 18.8.24). Frequent exacerbations are associated with worse health status and more rapid lung function decline. They also tend to cluster in time. Data from the ECLIPSE study suggests that the ‘frequent exacerbator’ is a relatively stable phenotype which can occur at any level of airflow obstruction, although exacerbations do become more common as lung disease progresses. This may be because of a reduc- tion in functional reserve meaning that the threshold for exacerba- tion is reached more easily. This mechanism probably explains why bronchodilator treatments, despite having no direct effect on lung inflammation, reduce exacerbation rate. Acute exacerbations of COPD are usually caused by infections, bacterial and viral, and are more common in individuals who are Patients with this condition Coronary heart disease (most affluent) Diabetes (most affluent) COPD (most affluent) Cancer (most affluent) Coronary heart disease (most deprived) Diabetes (most deprived) COPD (most deprived) Cancer (most deprived) Patients who also have this condition (%) Coronary heart disease Diabetes COPD Heart failure Stroke/TIA Atrial fibrillation Painful condition Depression Anxiety Dementia 19 7 14 13 12 16 13 9 4 23 19 16 14 10 32 21 13 3 21 4 6 9 6 14 13 7 2 24 11 6 10 5 28 21 10 2 9 6 8 6 15 14 10 3 15 13 6 9 5 31 23 15 2 24 8 5 3 6 5 12 10 7 2 12 12 17 13 4 7 5 29 19 12 3 Fig. 18.8.45  Patterns of multimorbidity in COPD and association with deprivation. From Barnett K, et al. (2012) Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-​sectional study. The Lancet, 380(9836), 37–​43. Table 18.8.24  Anthonisen criteria for COPD exacerbations Type I Type II Type III All three symptoms: Increased sputum volume Increased sputum purulence Increased dyspnoea Any two symptoms One symptom together with one minor symptom/​feature • Recent upper respiratory tract infection • Increased wheeze • Increased cough • Fever

section 18  Respiratory disorders 4138 chronically colonized. They can also be triggered by air pollution and cold temperatures, and approaches using Meteorological Office data to warn patients of increased risk have been proposed. Inflammation in airway walls, together with increased mucus pro- duction, causes an increase in airflow obstruction and ventilation per- fusion mismatch. This leads to dynamic hyperinflation, an increased work of breathing, and increased symptoms. Respiratory muscles may be unable to cope with the increased load, leading to respiratory failure. Increased circulating inflammatory mediators, catecholamines, and hypoxia have systemic effects. Right-​sided cardiac pressures in- crease and cardiac function is further restricted by hyperinflation. Atrial arrhythmias are common. These factors, together with immo- bility and corticosteroid treatment, contribute to acute loss of skel- etal muscle bulk which delays recovery and also drives bone loss. The initial approach to management should be to establish the diagnosis of acute exacerbation of COPD and to evaluate the se- verity of the exacerbation to decide on the best location for treatment (Table 18.8.25). The differential diagnosis includes cardiac failure, pulmonary embolism, and pneumothorax and pleural effusion. It may be the case that specific exacerbation phenotypes can be identified which will guide stratified approach to therapy. For ex- ample, sputum eosinophilia is associated with steroid responsiveness. In the community setting it is not necessary to obtain a chest X-​ ray or sputum if the diagnosis is clear. Many patients are able to self-​ diagnose acute exacerbations and self-​manage with a rescue pack of antibiotics and steroids. This can reduce delays to the onset of treat- ment, although they should be encouraged to inform their medical team when they do this. Some individuals may delay treatment un- necessarily and some will make excessive use of rescue medication, so this needs to be kept under review. The use of three or more rescue packs should prompt a review to establish if treatment is appropriate and whether there is a reversible cause. Having established a diagnosis of an acute exacerbation of COPD the key question is whether to manage the patient at home or in hos- pital. Roughly 20% of patients who would conventionally be admitted to hospital can be managed at home with an early supported dis- charge or admission avoidance scheme. These involve appropriately qualified health professionals reviewing and supporting patients at home daily for a limited period, with the provision of equipment such as nebulizers or short-​term home oxygen, as necessary. Criteria to guide clinical judgement are described in Table 18.8.26. Any decision to manage the patient at home should include a plan for the patient’s review. The recently developed DECAF (dyspnoea, eosinopenia, consolidation, acidosis, and atrial fibrillation) score may be a useful guide for identifying individuals who can be dis- charged safely. Outpatient management of AECOPD Bronchodilator therapy is increased. In some case this will require the use of nebulized bronchodilators. Haemophilus influenza, streptococcus pneumonias, and moraxella catarrhalis are the most common bacterial pathogens, so empirical antibiotic treatment should cover these. Amoxicillin is first line in the United Kingdom, with doxycycline recommended for those who are allergic. In patients with multiple exacerbations and in those who fail to respond, sputum culture is advised to identify antibiotic resistance and detect the presence of pseudomonas aeruginosa which will not respond to usual broad spectrum antibiotics. Oral corticosteroids (e.g. 30 mg or 0.5 mg/​kg prednisone/​day) have been shown to accelerate recovery from acute exacerbations of COPD. Long courses are unnecessary: the minimum effective dur- ation of treatment has not yet been defined, but 5 days’ treatment is likely to be sufficient. Management of patients admitted to hospital with AECOPD Hospital admission with an acute exacerbation of COPD carries a significant adverse prognosis. The 2014 Royal College of Physicians/​ British Thoracic Society COPD audit found a 4.3% mortality rate during the index admission. Patients’ usual level of breathlessness predicted in-​hospital mortality: 8% for an MRC dyspnoea score of 5; 2.9% in MRC 4; 1.7% in MRC 3. Other factors associated with an increased risk of a poor outcome are previous hospitalization, age, Table 18.8.25  Features of acute exacerbation of COPD History Cough Sputum volume and purulence Haemoptysis Sleep disturbance Wheeze Physical signs Increased respiratory rate Use of accessory muscles Tachycardia Cyanosis Confusion Peripheral oedema Investigations Pulse oximetry Chest X-​ray ECG Sputum for culture Table 18.8.26  Where to manage the patient with an acute exacerbation of COPD Treat at home? Treat in hospital? Able to cope at home Yes No Breathlessness Mild Severe General condition Good Poor/​deteriorating Level of activity Good Poor/​confined to bed Cyanosis No Yes Worsening peripheral oedema No Yes Level of consciousness Normal Impaired Already receiving LTOT No Yes Social circumstances Good Lives alone/​not coping Acute confusion No Yes Rapid rate of onset No Yes Significant comorbidity (particularly cardiac disease and insulin-​dependent diabetes) No Yes SaO2 <90% No Yes Changes on chest X-​ray No Present Arterial pH level ≥ 7.35 < 7.35 Arterial PaO2 ≥ 7 kPa < 7 kPa Based on NICE 2010 guidance on COPD management.

18.8  Chronic obstructive pulmonary disease 4139 smoking status, comorbidities, hyponatraemia, hyperglycaemia, and a low eosinophil count. Oxygen Excessive oxygen therapy is harmful in acute exacerbations of COPD. This is a hazard that must be addressed by emergency de- partments and ambulance services. Patients with respiratory failure should be given controlled oxygen therapy (24–​28%) through a ven- turi mask, or 1–​2 litres by nasal prongs adjusted to achieve an O2 saturation between 88 and 92%. In patients hospitalized with acute exacerbations of COPD arterial blood gases should be measured if saturations are below 95% on air. Pharmacotherapy Bronchodilator therapy should be increased and nebulized therapy may be required. Nebulizers should be air driven with supplemental oxygen by nasal cannula, as necessary. Corticosteroids should be given orally as in outpatient management, with intravenous ad- ministration only where patients are nil by mouth. Initial antibiotic therapy should also be as for community treatment. Noninvasive ventilation Clinical trials have demonstrated a dramatic impact on survival with bi-​level NIV in patients with a decompensated respiratory acidosis (PaCO2 >6 kPa, pH <7.35). Response should be assessed with repeat ABGs within one hour. The location of NIV treatment will vary ac- cording to the health system. With appropriate trained staff NIV can be delivered on a respiratory ward, but a high dependency environ- ment may have advantages, allowing arterial line placement, the ini- tiation (if indicated) of other supportive therapies such as inotropes, and safer use of sedation, which may be required in some individuals who find it hard to tolerate NIV. When patients are commenced on NIV is important to ensure that there is a clear treatment plan if the NIV fails as to whether intubation is appropriate. It is not ne- cessary to place a nasogastric tube routinely in patients undergoing NIV. NIV has rendered the use of respiratory stimulants (doxapram) obsolete. Invasive mechanical ventilation Acute mortality rates in patients with acute exacerbations of COPD who are intubated are no worse than for those with other medical conditions, although this represents a selected group of all those with respiratory failure. Complications include ventilator acquired pneumonia and acute lung injury as well as pneumothorax, and a tracheostomy may be necessary. Poor outcomes are common in patients who are housebound who may be forced to endure pro- longed and ultimately unsuccessful attempts to wean. Intubation in this population can be considered to be futile. Patients in whom invasive mechanical ventilation is being considered are often semi-​ conscious, so it is helpful in this situation for the issues to have been discussed in advance such that a clear expression of the individual’s wishes is available. Acute exacerbations of COPD are associated with immobility and an inflammatory response, hence venous thromboembolism prophylaxis should be administered. Corticosteroids and β2-​ agonists may cause hypokalaemia and this and other electrolyte disturbances should be monitored for and corrected. Physiotherapy input to assist early mobilization may be beneficial, but evidence does not support routine chest physiotherapy in acute exacerbations of COPD to assist sputum clearance. A care bundle approach to discharge (Fig. 18.8.46) has been suggested to systematize care, with some evidence that Inform the COPD CNS of all COPD patients within 24 hours of arrival including patients discharged. Extension CARE BUNDLE STEPS

  1. If patient is a smoker offer smoking cessation assistance
  2. Pulmonary rehabilitation -assessed for suitability
  3. Written COPD patient information given including:
  4. Satisfactory use of inhalers demonstrated and understood
  5. Outpatient follow up appointment made and given to patient All required documents are included in package For community referral Fax For clinic referral Fax First point of contact, either by the CNS Nurses of Physiotherapist, who will assess and refer patient. Nurse to contact if not done prior to discharge (fax referral form) • British Lung Foundation Self Management Book • Oxygen alert WALLET card • Information about the Breathe Easy Group Please assess during medication rounds. Observe the patients using the device(s) and document on electronic prescribing record adequate technique demonstrated. (Refer to pharmacist or CNS if extra support is needed). Patient should see respiratory medical specialist and COPD respiratory nursing specialist within 1 month of discharge. (Appointment should be scheduled and patient made aware of location, time and date). Completed Not done Completed Not done Completed PRIOR TO DISCHARGE DAY OF DISCHARGE Patient Sticker GO TO Patient COPD Safe Discharge Checklist To be completed by nurse with the patient. Note: Ensure phone Call scheduled for 48–72 hours post discharge. (6) Nurse (initials) Checklist Completed Completed Declined N/A Not done Not done Completed Declined N/A Not done Date: Fig. 18.8.46  COPD discharge care bundle. This care bundle is a group of evidence-​based items that should be delivered to all patients being discharged from hospital following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). The care bundle aims to improve quality of care, patient experience, and minimize the risk of re-​hospitalization. Adapted from Hopkinson NS, et al. (2012). Designing and implementing a COPD discharge care bundle. Thorax, 67, 90–​2.

section 18  Respiratory disorders 4140 implementation is associated with a reduced rate of readmis- sions. Items included are smoking cessation, assessment for post-​ exacerbation pulmonary rehabilitation, inhaler technique, the provision of written information and arranging follow-​up. Close liaison between hospital and community teams is important for continuity. Although there is variation in readmission rates, the extent to which hospitalization in frail patients with multiple comorbidities can actually be reduced is often exaggerated in dis- cussions in this area. A safe discharge checklist (Fig. 18.8.47) can also be used, signed by both the discharge nurse and the patient, to ensure that these im- portant steps have been carried out and to reinforce their implemen- tation within the system. FURTHER READING Action on Smoking and Health (2015). Smoking still kills: protecting children, reducing inequalities. http://​ash.org.uk/​information-​and-​ resources/​reports-​submissions/​reports/​smoking-​still-​kills/​ Albert RK, et al. (2011). Azithromycin for prevention of exacerbations of COPD. New Engl J Med, 365, 689–​98. Barnett K, et al. (2012). Epidemiology of multimorbidity and impli- cations for health care, research, and medical education: a cross-​ sectional study. Lancet, 380, 37–​43. Bolton CE, et al. (2013). British Thoracic Society guideline on pul- monary rehabilitation in adults: accredited by NICE. Thorax, 68, ii1–​ii30. Fig. 18.8.47  COPD safe discharge checklist. Adapted from Hopkinson NS, et al. (2012). Designing and implementing a COPD discharge care bundle. Thorax, 67, 90–​2.

18.8  Chronic obstructive pulmonary disease 4141 Bott J, et al. (2009). Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient. Thorax, 64, i1–​52. Boutou AK, et al. (2013). Lung function indices for predicting mor- tality in COPD. Eur Respir J, 42, 616–​25. Burney PG, et al. (2015). Global and regional trends in COPD mor- tality, 1990–​2010. Eur Respir J, 45, 1239–​47. Campbell JD, et al. (2012). A gene expression signature of emphysema-​ related lung destruction and its reversal by the tripeptide GHK. Genome Med, 4, 67. Celli BR, et al. (2004). Standards for the diagnosis and treatment of pa- tients with COPD: a summary of the ATS/​ERS position paper. Eur Respir J, 23, 932–​46. Celli BR, et al. (2015). An Official American Thoracic Society/​European Respiratory Society Statement:  research questions in chronic ob- structive pulmonary disease. Am J Respir Crit Care Med, 191, e4–​e27. Criner GJ, et  al. (2011). The National Emphysema Treatment Trial (NETT): Part II: lessons learned about lung volume reduction sur- gery. Am J Respir Crit Care Med, 184, 881–​93. Davey C, et  al. (2015). Bronchoscopic lung volume reduction with endobronchial valves for patients with heterogeneous emphysema and intact interlobar fissures (the BeLieVeR-​HIFi study): a random- ised controlled trial. Lancet, 386, 1066–​73. Fotheringham I, et al. (2015). Comparison of laboratory-​ and field-​ based exercise tests for COPD:  a systematic review. Int J Chron Obstruct Pulmon Dis, 10, 625–​43. Gimeno-Santos E, et al. (2015). The PROactive instruments to measure physical activity in patients with COPD. Eur Resp J, 46, 988–1000. Hancock DB, et al. (2010). Meta-​analyses of genome-​wide association studies identify multiple loci associated with pulmonary function. Nat Genet, 42, 45–​52. Hogg JC, et  al. (2004). The nature of small-​airway obstruction in chronic obstructive pulmonary disease. N Engl J Med, 350, 2645–​53. Holloway RA, Donnelly LE (2013). Immunopathogenesis of chronic obstructive pulmonary disease. Curr Opin Pulm Med, 19, 95–​102. Hopkinson NS, et  al. (2004). Corticospinal control of respiratory muscles in chronic obstructive pulmonary disease. Respir Physiol Neurobiol, 141, 1–​12. Hopkinson NS, Polkey MI (2010). Does physical inactivity cause chronic obstructive pulmonary disease? Clin Sci (Lond), 118, 565–​72. Hopkinson NS, Baxter N on behalf of the London Respiratory Network (2017). Breathing SPACE – a practical approach to the breathless patient. NPJ Prim Care Respir Med, 27(1):5. doi: 10.1038/s41533-016-0006-6. Kohansal R, et al. (2009). The natural history of chronic airflow ob- struction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med, 180, 3–​10. Langer D, et al. (2014). Lung hyperinflation in chronic obstructive pul- monary disease: mechanisms, clinical implications and treatment. Expert Rev Respir Med, 8, 731–​49. Lewis A, et al. (2016). Singing for Lung Health – a systematic review of the literature and consensus statement. Nature Prim Care Resp J, 26, 16080. Lim SS, et al. (2012). A comparative risk assessment of burden of dis- ease and injury attributable to 67 risk factors and risk factor clus- ters in 21 regions, 1990–​2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet, 380, 2224–​60. Mathur A, Dempsey OJ (2019). Electronic cigarettes: a brief update. J R Coll Physicians Edinb, 48, 346–51. Mercado N, Ito K, Barnes PJ (2015). Accelerated ageing of the lung in COPD: new concepts. Thorax, 70, 482–​9. Miller MR, et al. (2005). Standardisation of spirometry. Eur Respir J, 26, 319–​38. Nacul L, et al. (2011). COPD in England: a comparison of expected, model-​based prevalence and observed prevalence from general practice data. J Public Health (Oxf), 33, 108–​16. Oba Y, Keeney E, Ghatehorde N, Dias S (2018). Dual combination therapy versus long-acting bronchodilators alone for chronic obstructive pul- monary disease (COPD): a systematic review and network meta-analysis. Cochrane Database of Systematic Reviews, DOI: 10.1002/14651858. CD012620.pub2. Polosa R, et al. (2018). Health effects in COPD smokers who switch to electronic cigarettes: a retrospective-prospective 3-year follow-up. Int J Chron Obstruct Pulmon Dis, 13, 2533–42. Puhan M, et al. (2009). Pulmonary rehabilitation following exacerba- tions of chronic obstructive pulmonary disease. Cochrane Database Syst Rev, 1, CD005305. Royal College of Physicians (2016). Non tobacco nicotine products – Nicotine without the Smoke: Tobacco Harm Reduction. https:// www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-
tobacco-harm-reduction-0 Royal College of Physicians (2018). Hiding in plain sight: treating tobacco dependency in the NHS. https://www.rcplondon.ac.uk/projects/ outputs/hiding-plain-sight-treating-tobacco-dependency-nhs Salvi S, Barnes PJ (2010). Is exposure to biomass smoke the biggest risk factor for COPD globally? Chest, 138, 3–​6. Schols AM, et  al. (2014). Nutritional assessment and therapy in COPD: a European Respiratory Society statement. Eur Respir J, 44, 1504–​20. Shrikrishna D, Coker RK (2011). Managing passengers with stable re- spiratory disease planning air travel: British Thoracic Society recom- mendations. Thorax, 66, 831–​3. Svanes C, et al. (2010). Early life origins of chronic obstructive pul- monary disease. Thorax, 65, 14–​20. van Gemert F, et al. (2015). Prevalence of chronic obstructive pul- monary disease and associated risk factors in Uganda (FRESH AIR Uganda): a prospective cross-​sectional observational study. Lancet Glob Health, 3, e44–​e51. Wiegman CH, et  al. (2015). Oxidative stress–​induced mitochon- drial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol, 136, 769–​80. Zoumot Z, Jordan S, Hopkinson NS (2014). Emphysema: time to say farewell to therapeutic nihilism. Thorax, 69, 973–​5.

18.9 Bronchiectasis 4142 R. Wilson and D. Bilton

18.9 Bronchiectasis 4142 R. Wilson and D. Bilton

ESSENTIALS A bronchiectatic lung contains permanently dilated subsegmental airways that are inflamed, tortuous, and often partially or totally ob- structed with secretions. Pathogenesis involves airway inflamma- tion which can cause further bacteria-​driven host-​mediated lung damage. Causes include developmental defects, damage caused by previous infection, immune deficiency, mucociliary clearance de- fects, and mechanical obstruction, but in many cases (40–​60%) the cause is unknown. Clinical features—​bronchiectasis should be suspected when there is a history of persistent cough productive of sputum throughout the year, with chest infections leading to increased symptoms. About 80% of patients have upper respiratory tract symptoms. Clinical examination is often normal, although ‘classical’ severe cases show finger clubbing and widespread coarse crackles. Investigation—​the ‘gold standard’ for diagnosis is high-​resolution CT of the chest, which reveals dilated bronchi that may be inflamed, causing wall thickening and mucus plugging. The chest radiograph is normal in at least 50% of cases, but abnormal thickened and di- lated bronchi may produce tramline opacities and ring shadows. Investigations to determine the underlying cause will be determined by clinical suspicion but should include tests for treatable condi- tions (e.g. immunoglobulin deficiency, allergic bronchopulmonary aspergillosis, and nontuberculous mycobacteria). Disease status is assessed by high-​resolution CT, lung function tests, sputum culture, and measurement of inflammatory markers. Management—​involves the treatment of the specific underlying cause (when possible) and treatment of the bronchiectasis itself, with the most important elements being sputum clearance by physio- therapy and antimicrobials, which need to be given in high dose. Patients with more severe disease, who have frequent exacerbations and are often chronically infected with Pseudomonas aeruginosa, may be treated with continuous nebulized antibiotics or oral macrolide antibiotics. Surgery can be a curative for patients with single lobe, focal bronchiectasis, and lobar resection may also be indicated for otherwise uncontrollable bleeding, or if it is felt that a particular lobe is acting as a ‘sump’ of infection which prevents good control of symptoms with medical therapy. Lung transplantation may be ap- propriate in carefully selected cases. Introduction The definition of bronchiectasis is based on morbid anatomy de- scribed first by Laennec as abnormal chronic dilatation of the bronchi. The word itself is from the Greek bronchion (windpipe or tube) and ektasis (stretched out or extension). In 1819 Laennec de- scribed the condition in an infant who died following whooping cough, but by 1891 it was recognized in a textbook of medicine that bronchiectasis was ‘not a separate disease’ but ‘a result of various affectations of the bronchi’. Thus bronchiectasis is not a precise diag- nosis but the final pathology of a number of causes which may re- quire their own specific treatment. The ‘gold standard’ for diagnosis today is the presence of abnormal dilated bronchi on high-​resolution CT in a patient with a persistent cough productive of sputum. Epidemiology Estimates in the United Kingdom up to 1953 varied from 0.77 to 1.3 per 1000 population, but it seems that following the introduction of antibiotic therapy for pulmonary infection, the control of tuber- culosis, and effective vaccination for whooping cough and measles, that the prevalence of bronchiectasis in the United Kingdom—​at least of the more severe type—​had fallen, as judged by a reduction in hospital admissions and deaths. However, recent studies have suggested that the prevalence is increasing in the last decade in Europe and the United States. For example, a recent study based on healthcare claims in the United States of America suggested an esti- mated prevalence ranging from 4.2 per 100 000 persons aged 18–​34, to 271.8 per 100 000 among those aged 75 years and older. Prevalence was higher in women than men at all ages. The ageing population, use of therapeutic agents that reduce host defence e.g. in rheum- atological conditions, CT scans in chronic obstructive pulmonary disease (COPD) showing coexistent bronchiectasis, and an in- crease in the prevalence of nontuberculous mycobacterial infections may all have led to this increase. However, since the diagnosis of bronchiectasis depends on the cardinal feature of abnormal chronic dilation of one or more bronchi, it is likely that people with chronic sputum production previously not investigated by bronchography or CT may have been mislabelled as ‘bronchitic’, leading to historical 18.9 Bronchiectasis R. Wilson and D. Bilton

18.9  Bronchiectasis 4143 underestimation of the true prevalence. Only the development of noninvasive imaging applied to large community surveys will tell us the true prevalence of bronchiectasis in the population. In less developed countries, where antibiotics are less readily available, socioeconomic conditions are poor, and the prevalence of both tuberculosis and HIV infection are high, bronchiectasis is re- garded as a common problem. Pathology Macroscopic inspection of bronchiectatic lung reveals permanent dilatation of subsegmental airways, which are inflamed, tortuous, and often partially or totally obstructed with secretions. The process also includes bronchioles, and at end stage there may be marked fi- brosis of small airways. In allergic bronchopulmonary aspergillosis (ABPA) the changes are predominantly in proximal airways, and bronchiectasis caused by cystic fibrosis, post-​tuberculosis, and ABPA is likely to be more marked in the upper lobes. There is a spectrum of disease ranging from cylindrical, where there is uniform dilatation, to saccular, where there may be gross terminal dilatation of the end bronchi (sac- cules or cysts). An intermediate form is termed varicose bronchiec- tasis, when dilatation along the length of the bronchus is uneven. Microscopic features The overall appearance is of chronic inflammation in the bronchial wall, with inflammatory cells and mucus in the lumen. Neutrophils are the dominant cell population in the bronchial lumen, with mainly mononuclear cells in the bronchial wall. There is character- istic destruction of the elastin layer of the bronchial wall with a vari- able amount of fibrosis. The label follicular is applied when, as part of extensive mural inflammation, there is lymphoid follicle forma- tion, which may in subepithelial sites cause finger-​like projections blocking the bronchial lumen. Aetiology and pathogenesis There is a broad spectrum of causes and underlying conditions as- sociated with bronchiectasis: these are summarized in Table 18.9.1. The pathogenesis of bronchiectasis requires the combination of an infectious insult with associated impaired clearance mechanisms that may result from structural abnormalities of the airway, impaired mucociliary clearance, or defective immune defences. Experimental animal models support the theory that local obstruction and infec- tion distal to the obstruction are both required in order to produce bronchiectasis. Furthermore the infection is required to be active, with damage to the airway wall then occurring as a result of direct microbial insult and the secondary effects of the host inflammatory response which is driven by the bacterial infection. It has been pro- posed that a ‘vicious cycle’ explains the development of bronchiec- tasis in a predisposed individual given a trigger insult (Fig. 18.9.1). Neutrophil elastase is thought to play a key role. Neutrophils are recruited as part of the natural defences, but the inflammation is not self-​limiting and in patients with bronchiectasis neutrophils traffic into the airway lumen, attracted by persistent bacterial infec- tion, with free neutrophil elastase activity usually present. Elastase, a neutrophil-​derived serine proteinase, is known to digest elastin, which is an important structural protein of the bronchial wall, in- hibit ciliary beating, damage epithelia, act as a mucus secretagogue, and inhibit opsonophagocytosis via cleavage of immunoglobulins. All these actions contribute to persistence of bacteria in the respira- tory tract and to long-​term tissue damage. Fig. 18.9.1 clearly demonstrates that however a patient enters the pathway (e.g. following damage to the airway by an infectious insult such as tuberculosis, or primary ciliary dyskinesia which inhibits mucociliary clearance, or with immunoglobulin deficiency which favours persistence of microbes in the bronchial tree), the vicious cycle becomes self-​perpetuating with the final outcome of airway damage, which might spread into the normal bystander lung. Developmental defects The congenital forms of bronchiectasis frequently show defi- ciency of the elements of bronchial wall which are necessary to Table 18.9.1  Causes of bronchiectasis and associated conditions Type of cause Examples Developmental defects Structural Deficiency of bronchial wall (e.g. Williams–​Campbell syndrome and Ehlers-​Danlos syndrome) Pulmonary sequestration Tracheobronchomegaly (Mounier–​Kuhn syndrome) Immune deficiency Primary:   Panhypogammaglobulinaemia   Selective immunoglobulin deficiency Secondary:   HIV infection   Malignancy (chronic lymphocytic leukaemia) Excessive immune response Allergic bronchopulmonary aspergillosis Post lung transplantation α-1 antitrypsin deficiency Mucociliary clearance defects Primary ciliary dyskinesia Cystic fibrosis Young’s syndrome Toxic insult Aspiration of gastric contents Inhalation of toxic gases or chemicals (e.g. ammonia) Mechanical obstruction Intrinsic (e.g. tumour or foreign body) Extrinsic (e.g. tubercular lymph node) Post-​infective Bordetella pertussis Measles Tuberculosis Nontuberculous mycobacteria Associated conditions Chronic rhinosinusitis Rheumatoid arthritis Inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Coeliac disease Yellow nail syndrome Connective tissue disorders and vasculitides Idiopathic

section 18  Respiratory disorders 4144 maintain normal anatomy and prevent collapse, and hence ‘ob- struction’ of the airway. They may occur due to premature degen- eration as well as congenital absence/​abnormality. Mounier–​Kuhn syndrome describes tracheobronchomegaly, which as the name suggests describes severe proximal dilatation, while Williams–​ Campbell syndrome occurs due to deficiency of bronchial car- tilage. Pulmonary sequestration predisposes to bronchiectasis because of repeated infections in the affected segment caused by poor clearance. Immune deficiency Childhood bronchiectasis should trigger an extensive assessment of phagocytic and cellular immune defences. X-​linked hypogamma­ globulinaemia, a rare disorder, presents early in life, with bronchi- ectasis a frequent complication if untreated. Adult-​onset common variable immunodeficiency or panhypogammaglobulinaemia fre- quently presents with recurrent respiratory infection and is com- plicated by bronchiectasis if untreated. Selective immunoglobulin deficiencies of a particular class and functional antibody deficiencies (e.g. failure to respond in the normal way to polysaccharide antigen), also occur. The importance of functional antibody deficiencies in the presence of normal immunoglobulin levels has been recognized as a risk factor for recurrent respiratory tract infections and develop- ment of bronchiectasis. In subjects with low levels of specific anti- bodies to polysaccharide antigen (e.g. Streptococcus pneumoniae or Haemophilus influenzae type b), the patient should be vaccinated and the levels measured again after 6 weeks. Failure to mount and maintain adequate responses to the vaccination is a milder form of common variable immunodeficiency. Patients with functional anti- body deficiency and normal immunoglobulin levels can be managed with prompt antibiotic therapy but may require immunoglobulin therapy if there is evidence of disease progression despite optimal antibiotic treatment. Immune defects may be secondary to malignancy or be related to treatment with immunosuppressive agents. In addition, bronchiec- tasis is now a recognized complication of HIV disease. Excessive immune response Fig. 18.9.1 illustrates the damage that may occur as a result of the host response to chronic airway infection. ABPA is a condition in which excessive eosinophilic inflammation caused by the bodies reaction to inhaled fungal spores characteristically causes prox- imal upper-​lobe bronchiectasis. The appearance of obliterative bronchiolitis and subsequent bronchiectasis in lung transplant re- jection further highlights the role of a damaging immune response in the development of the condition. α-1 antitrypsin deficiency more commonly causes emphysema due to unopposed neutrophil elastase, particularly in patients who smoke, but in some patients bronchiectasis is the predominant disease for reasons which are not understood. Disorders of mucociliary clearance Cystic fibrosis provides the archetypal model of a genetic predispos- ition for the development of bronchiectasis. In this disorder there is dysfunction of the cystic fibrosis transmembrane regulator (CFTR), a transmembrane chloride channel and ion transport regulatory protein. The resulting abnormal salt and water transport across re- spiratory epithelia predisposes to respiratory infection and the ef- fects of the vicious cycle are clearly demonstrated as a structurally normal lung suffers progressive airway damage and the develop- ment of bronchiectasis. In primary ciliary dyskinesia ineffective ciliary beating impairs mucociliary clearance, leading to mucus retention and recurrent infections in the paranasal sinuses, middle ear, and lungs, with progression to bronchiectasis. It is an inherited disorder, mostly in an autosomal recessive pattern, with an estimated incidence of 1 in 15 000 to 1 in 30 000 births. The diagnosis is made by light mi- croscopy to examine ciliary beat pattern and electron microscopy to examine ultrastructure. Nasal nitric oxide concentrations are extremely low in primary ciliary dyskinesia and provide a useful screening test to identify patients for further investigation with brush biopsy of the nasal epithelium. In the largest subgroup of this syndrome, in which electron microscopic appearances were originally described, the cilia were found to lack dynein arms, the structure responsible for movement of cilia or spermatozoa. Subsequently it has been appreciated that a range of compo- nents of the cilia are affected. Much progress has been made in recent years identifying the genetic defects responsible for the ultrastructural abnormalities, and in explaining primary ciliary dyskinesia with normal ultrastructure. The gene that encodes the Trigger insult e.g. microbial or toxic Lung damage/ Decreased mucociliary clearance Persistence of microbes in bronchial tree Microbial exotoxins Chronic microbial infection Inflammatory mediators released Persistent host response, i.e. inflammation Neutrophil elastase Toxic oxygen species Tissue damage Neutrophil elastase is ciliotoxic and a mucus secretagogue Elastase cleaves immunoglobulins inhibiting opsonophagocytosis Inhibit cilial beating Damage epithelium Fig. 18.9.1  The vicious cycle of infection and inflammation leading to progressive tissue damage in bronchiectasis.

18.9  Bronchiectasis 4145 human intermediate dynein, DNAI1, has been shown to exhibit recessively inherited mutations in some primary ciliary dyskinesia families. Furthermore, mutations in DNAH5, the gene encoding a heavy chain of the outer dynein arm, have been shown in almost one-​half of primary ciliary dyskinesia subjects that have defects of this dynein arm. The intriguing observation that about 50% of all subjects with immotile cilia syndrome have situs inversus is true for most sub- groups, apart from those who have absent cilia or those whose main characteristic is lack of the two central microtubules. When ciliary dyskinesia is associated with abnormal situs the condition is called Kartagener’s syndrome after the paediatrician who described four patients with the association of dextrocardia, sinusitis, and bronchi- ectasis in 1933. Young’s syndrome seems to represent an acquired defect of mucociliary clearance in which obstructive azoospermia is associ- ated with sinusitis and bronchiectasis. The condition may occur after successful parentage and may be associated with mercury poisoning from ‘tooth powders’ used in infancy (Pink’s disease). Secondary cil- iary dyskinesia refers to the situation in which cilia are intrinsically normal but ciliary beating is reduced because of toxic damage from neutrophil or bacterial products. Tobacco smoke and other envir- onmental pollutants have also been implicated in reducing ciliary beat frequency. Toxic insult In some patients (e.g. fire victims) there is a clear history of an in- halation accident or exposure to hot gases. Aspiration of gastric con- tents is another important cause of bronchiectasis, in that treatment to prevent aspiration will prevent further airway damage. Mechanical obstruction Bronchiectasis confined to a single lobe may be the result of a local mechanical obstruction either in the lumen (intrinsic), for ex- ample, tumour or foreign body, or originating outside the lumen (extrinsic), for example, from lymph node enlargement from tu- berculosis or tumour (Fig. 18.9.2). In patients with localized bron- chiectasis, a bronchoscopy should be considered to exclude an obstructing lesion. Post-​infective bronchiectasis The true incidence of post-​infective bronchiectasis is difficult to confirm, as studies are retrospective, relying on memory or his- tories obtained ‘second hand’ from parents. The microorganisms known to cause infection likely to progress to bronchiectasis are Bordetella pertussis, measles virus, adenoviruses, Trypanosoma cruzi, Mycobacterium tuberculosis, and nontuberculous myco- bacterial infections, which have become more prevalent in recent years. These can cause primary infections that lead to bronchiec- tasis, or can infect patients with bronchiectasis from another cause. Mycobacterium avium complex and M. abscessus are the two species most often implicated. Some patients who present with symptoms of bronchiectasis in adult life may report a childhood episode of whooping cough or measles, but it is uncertain how relevant this history is to their pres- entation if there has been a prolonged period without symptoms, and patients should only be labelled as post-​infective if symptoms have been persistent, without remission since childhood. Associated conditions The association of rheumatoid arthritis with bronchiectasis is well recognized. Patients often have marked small airways disease. Treatment needs to achieve the right balance of immunosuppres- sion, which helps the underlying inflammatory disease process, but may impair antimicrobial defences. The association between in- flammatory bowel disease, most commonly ulcerative colitis, and bronchiectasis highlights the usefulness of immunosuppression, as some patients with both conditions report an improvement in chest symptoms when they take systemic corticosteroids. The classic pres- entation is that a patient without any respiratory history presents several months after pan-​colectomy for ulcerative colitis with a pro- ductive cough. Patients will often produce large volumes of purulent sputum which is sterile, and the CT scan shows diffuse inflamma- tory changes which can progress to bronchiectasis. Idiopathic Even in specialist bronchiectasis clinics, the underlying cause of bronchiectasis remains unknown in 40–​60% of patients, who are currently labelled as having ‘idiopathic’ disease. The most common presentation is with onset of productive cough in adult life, sym- metrical predominantly lower lobe cylindrical bronchiectasis, and chronic rhinosinusitis. Clinical features History Bronchiectasis should be suspected when there is a history of per- sistent productive cough throughout the year. Patients have often been treated for recurrent chest infections and labelled as ‘bron- chitic’, sometimes despite the absence of a smoking history. Fig. 18.9.2  Carcinoid tumour in the intermediate bronchus (see arrow). The patient presented with localized bronchiectasis in the
right lower lobe.

section 18  Respiratory disorders 4146 Early in the disease patients may produce mucoid sputum until they suffer an exacerbation associated with viral upper respiratory tract infection, when the sputum becomes purulent due to sec- ondary bacterial infection. Exacerbations involve increased sputum volume and purulence, breathlessness, and may be associated with pleuritic chest pain, haemoptysis, and fever, and patients may also become wheezy. About 80% of patients with bronchiectasis have upper respira- tory tract symptoms, with postnasal drip being the most common. About 30% have chronic sinus infection, with fewer having re- current ear infections, although the latter are often present in pri- mary ciliary dyskinesia. Patients with bronchiectasis also suffer from undue tiredness, which many find just as troublesome as the productive cough. Examination ‘Classical’ severe cases of bronchiectasis seen in the preantibiotic era or in less developed countries are associated with obvious clin- ical signs including finger clubbing and widespread coarse crackles. Nowadays it is much more likely for clinical examination to be normal: the absence of clubbing or lung crackles does not exclude bronchiectasis. Pulmonary function tests usually show airflow obstruction, but mild restriction is also recognized, particularly in patients with loss of volume in the affected lobes. Investigation and diagnosis Radiological imaging The gold standard for the diagnosis of bronchiectasis is thin-​section high-​resolution CT of the chest, which has replaced the more in- vasive investigation of bronchography. Dilatation is present if the internal diameter of the bronchus is greater than the diameter of its accompanying pulmonary artery. The classic appearance of a cross-​section of a thick-​walled dilated bronchus next to the accom- panying pulmonary artery is the ‘signet ring’, as shown in Fig. 18.9.3. Bronchial dilatation is also recognized when airways are seen in lon- gitudinal section on CT and there is a failure of tapering as the bron- chus courses towards the periphery. There is a morphological spectrum of bronchiectasis, with cylin- drical bronchiectasis forming one group, cystic or saccular bronchi- ectasis at the other end of the spectrum, and an intermediate group termed varicose bronchiectasis also recognized. The CT appearances are well described: in cylindrical bronchiectasis there is uniform dilatation of the bronchi as they extend towards the periphery; cystic bronchiectasis is recognized by rings representing the markedly di- lated bronchi, which may be clustered together and may contain air fluid levels; varicose bronchiectasis produces a beaded appearance, best shown when bronchi are imaged in the plane of the scan. Active inflammation is illustrated by airway wall thickening, mucus plug- ging of small (‘tree-​in-​bud’ appearance of exudative bronchiolitis) and large airways, and patches of consolidation. The chest radiograph is normal in at least 50% of patients with CT or bronchographic evidence of bronchiectasis. If the chest radio- graph is abnormal, the findings relate to abnormal thickened and dilated bronchi which produce tramline opacities and ring shadows. Retained mucus may be manifest as tubular opacities, and there may be associated volume loss of the affected lobe. Determining the state of disease Once high-​resolution CT has proven the presence of bronchiec- tasis, investigations are directed at defining the current status of the disease and then at attempting to define an underlying cause. Table 18.9.2 highlights the minimum required to assess the cur- rent disease status. Examination of a sputum specimen is crucial, it being important to document the character of the sputum (i.e. mucoid or purulent) and to determine the infecting organism. The common bacteria are nontypeable Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Pseudomonas aeruginosa. H. influ- enzae is the most common (40–​60%). P. aeruginosa is usually as- sociated with worsening symptoms and more severe lung disease. As patient’s sputum microbiology may alter over time it is helpful to obtain repeated samples to ensure that an appropriate antibiotic management plan is in place. Measurement of inflammatory markers allows an assessment of the patient’s current ‘inflammatory burden’. Patients may come Fig. 18.9.3  A CT scan of a patient with bronchiectasis showing many characteristic ‘signet ring’ signs. Table 18.9.2  Investigations to assess current disease status Investigation Purpose High-​resolution CT Assess extent of bronchiectasis Lung function tests To assess airflow obstruction, lung volumes, and gas trapping Include assessment of reversibility to β2 agonists and anticholinergic agents Sputum culture To assess infecting microorganisms, including culture for acid-​fast bacilli and fungi Haematology Differential white count, ESR, and CRP CRP, C-​reactive protein; ESR, erythrocyte sedimentation rate.

18.9  Bronchiectasis 4147 to accept persistent purulent sputum over a period of time and not complain of being particularly unwell, in which case a raised erythrocyte sedimentation rate and/​or C-​reactive protein would weigh the argument in favour of early antibiotic intervention. Determining the cause of disease Table 18.9.3 outlines the investigations required to investigate a cause of bronchiectasis, and it is important to emphasize that know- ledge of the aetiology of bronchiectasis does alter management and thus prognosis. Panhypogammaglobulinaemic patients are trans- formed by immunoglobulin replacement; ABPA is a treatable cause of bronchiectasis, with corticosteroid treatment and/​or antifungal antibiotics producing major improvements in symptoms and well-​ being, restoring lung function, and preventing the development of further bronchiectasis; untreated M. avium complex infection may progress inexorably; rheumatoid arthritis, inflammatory bowel dis- ease, primary ciliary dyskinesia, and cystic fibrosis (CF) all have different treatments specifc to their diagnosis. Similarly, the appreci- ation that chronic aspiration is the precipitant of lung damage leads to appropriate therapeutic manoeuvres aimed at prevention of fur- ther damage. Cystic fibrosis/​bronchiectasis overlap The diagnosis of CF should be considered in any patient with un- explained bronchiectasis (particularly of the upper lobes) begin- ning in childhood. Mixed infection with Staphylococcus aureus and P. aeruginosa should also raise the possibility. Male infertility and a family history are useful pointers when present, but a normal sweat test does not exclude the diagnosis, in particular in mutations which produce mild disease. The diagnostic label of atypical cystic fibrosis has been coined to describe patients with mild nonclassic cystic fibrosis: where there is diagnostic doubt, the patient should be re- ferred to a specialist cystic fibrosis centre for further investigations. Management The principles of management of bronchiectasis are outlined in Box 18.9.1. The medical approach is two-​pronged, with close attention given to treating any underlying cause while also treating the established bronchiectasis. Sputum clearance As mucociliary clearance is reduced in bronchiectasis, and excess secretions that build up contain bacteria and inflammatory me- diators, it seems sensible to assist sputum clearance. This can be achieved in several ways including physical exercise; physiotherapy breathing techniques which may incorporate percussion and pos- tural drainage (Table 18.9.4); and various assist devices that can be used to assist expectoration. This does not simply prevent mucus retention but also allows a patient to expectorate sputum at a chosen convenient time, rather than coughing throughout the day or night. There are insufficient controlled trials to prove or disprove their use- fulness in terms of disease modification or survival. The use of mucolytics in bronchiectasis is controversial. The success of DNase in CF has not been repeated in bronchiectasis with another cause. There is limited evidence to support the use of nebulized hypertonic saline, but patients with sticky secretions report this helpful. A study of inhalation of an osmotic agent, dry powdered mannitol, failed its primary end point of reducing ex- acerbations but did improve patients’ sense of well-​being. Some Table 18.9.3  Investigations to assess underlying causes of bronchiectasis Investigation Purpose Bronchoscopy If CT suggests bronchial obstruction—​to establish whether tumour or foreign
body is present Nasal brushing/​biopsy To establish ciliary beat frequency, beat pattern, and obtain tissue for EM of cilia Nasal nitric oxide Screening test for primary ciliary dyskinesia Semen analysis If primary ciliary dyskinesia, Young’s syndrome, or CF is suspected CF genetics and sweat test To exclude CF Immunoglobulins and vaccine responses to Pneumovax, Hib, and tetanus To identify immunodeficiency Barium swallow, videofluoroscopy ± oesophageal manometry If aspiration is suspected α1-​Antitrypsin measurement To identify α1-​antitrypsin deficiency Autoantibody screen To identify associated connective tissue disorders or vasculitis Aspergillus skin testing and IgE and RAST to aspergillus To identify ABPA ABPA, allergic bronchopulmonary aspergillosis; CF, cystic fibrosis; EM, electron microscopy, Hib, Haemophilus influenzae B; RAST, radioallergosorbent test. Box 18.9.1  Principles of management of bronchiectasis • Medical treatment specific to the determined cause of bronchiectasis (if present) • Medical treatment for bronchiectasis: − Sputum clearance − Physiotherapy − Mucolytic therapy − Antimicrobial therapy for acute exacerbation − Continuous antibiotic prophylactic therapy − Anti-​inflammatory therapy − Bronchodilator therapy • Surgical treatment: − Resection of localized bronchiectasis; resection of severe disease acting as a ‘sump’ leaving milder disease elsewhere − Lung transplantation for end-​stage disease

section 18  Respiratory disorders 4148 patients also report sputum easier to expectorate when taking an oral mucolytic (e.g. carbocisteine). Antimicrobial therapy The modern approach to antimicrobial treatment in bronchiec- tasis has been derived from regimens used in CF that have yielded impressive results in survival. There are three approaches to the use of antimicrobial therapy in bronchiectasis. The first involves the treatment of acute exacerbations. The second is based on the ‘vicious cycle’ hypothesis, suggesting that continuous (inhaled or oral) targeted antimicrobial therapy reduces bacterial numbers, thereby reducing the level of inflammation and hence improving patient well-​being and reducing the potential for further lung damage. Recent clinical trials have shown that inhaled antibiotics cause a marked reduction in bacterial numbers in sputum, which may decrease symptoms. There is limited evidence that this is translated into decreased exacerbations, but this has been shown in two studies, one with gentamicin and the other colomycin, and several other trials are ongoing. The third approach is long-​term oral macrolide therapy, which has been shown in several studies to reduce exacerbation frequency and might benefit patients by a combination of the antibacterial and anti-​inflammatory properties of this class of antibiotic. Developing an antibiotic regime for treatment of bronchiectasis depends on knowledge of a patient’s infecting organism, but sev- eral principles apply regardless of the bacterial species. First, high doses are often required to penetrate scarred, thickened bronchial walls, and the tenacious secretions act as a physical barrier to re- duce antibiotic penetration to the microbes while harbouring drug-​ inactivating enzymes such as β-​lactamases. Secondly, to avoid a high oral dose of an antibiotic, which may result in unacceptable side effects, the nebulized or parenteral route is often employed to achieve high levels of drug in the bronchial lumen. Thirdly, a longer course of antibiotic is often required (e.g. 14 days). Finally, to determine the best treatment regimen for a patient, it is worth assessing their initial response to an agent appropriate for the infecting organism, in particular the rapidity of return of purulent sputum. If purulent sputum becomes mucoid after a 14-​day course of oral antibiotics and remains mucoid until the next viral trigger, then one is likely to recommend ‘exacerbation only’ treatment. By contrast, if sputum returns to being purulent within a few days of treatment finishing, it is likely that continuous suppressive therapy will be required. Patients with chronic Pseudomonas aeruginosa infection usually have more severe disease and worse airflow obstruction, and because of this they suffer increased morbidity and mortality. Although they may respond to oral ciprofloxacin initially, resistance often develops with repeated courses, and it is much more likely that an acute ex- acerbation will require intravenous antibiotic therapy with appro- priate anti-​pseudomonal antibiotics. Furthermore, these patients will often require maintenance therapy with nebulized antibiotic and/​or an oral macrolide antibiotic to control symptoms and pre- vent exacerbations. Fig. 18.9.4 suggests a plan for developing a regimen for a patient depending on the characteristics of their sputum and the infecting organism. Inhaled antibiotics This mode of treatment has the advantage of achieving high con- centrations of antibiotic in the airway lumen, which improves bacterial killing and makes resistance development less likely. There are several antibiotics in development for inhaled therapy, but at the moment the choice lies between colomycin and genta- micin, since tobramycin and aztreonam have a licence in CF only. A recent meta-​analysis included eight trials with 590 patients in which nebulized aminoglycosides, ciprofloxacin, aztreonam, or colomycin were given for 4 weeks to 12 months compared to pla- cebo. These were more effective than placebo in reducing sputum bacterial load, eradicating bacteria from sputum, and most im- portantly reducing the risk of exacerbations. Ten per cent (10%) of patients experienced bronchospasm after taking the inhaled anti- biotic, so a supervised trial with spirometry before and after should be conducted. Bronchodilator therapy Patients with bronchiectasis may have a restrictive or an obstructive picture. Some patients will have significant reversibility, hence it is worth assessing each individual for their response to β2-​agonists and anticholinergic agents. Anti-​inflammatory therapy The ‘vicious cycle’ hypothesis suggests that the addition of anti-​ inflammatory therapy to antibiotics should be of benefit. Trials of oral corticosteroids have shown significant benefit in terms of lung function in cystic fibrosis. Short-​term trials of inhaled corticoster- oids have been carried out in bronchiectasis, but the evidence for their use is limited and further trials are required. A trial of inhaled steroids is justified if the patient has significant airflow obstruction, particularly if they have benefited from oral steroids, but objective measures should be taken and the inhaled steroids stopped if no improvement is demonstrated. However, benefits may be seen in symptoms other than airflow obstruction, such as cough frequency, sputum volume, and ease of expectoration, so the assessment may not be straightforward. Therapy with macrolides Macrolide antibiotics were first shown in Japan to benefit patients with diffuse panbronchiolitis, an inflammatory airway condition Table 18.9.4  The active cycle of breathing technique to help expectorate sputum

  1. 3 or 4 quiet breaths to relax ‘breathing control’
  2. 3 or 4 slow deep breaths in and out ‘deep breaths’ Huffing
  3. Take a medium sized breath in
  4. Squeeze the breath out by contracting the abdominal muscles keeping mouth and throat open. The breath should be prolonged, but not continued until the lungs are empty
  5. Take a large breath in
  6. Squeeze the air out as before
  7. Cough and expectorate any sputum. If you don’t produce any sputum with 1 or 2 coughs, try to stop coughing by using your breathing control
  8. Allow your breathing to settle with breathing control and then repeat the cycle until your chest feels clear

18.9  Bronchiectasis 4149 which can progress to bronchiectasis. Three double-​blind placebo controlled trials have shown their benefit in bronchiectasis in terms of reducing exacerbation frequency, improving lung function, redu- cing sputum volume, and improving quality of life. Several meta-​ analyses of published trials have confirmed these benefits. The mechanism of action is thought to be immunomodulation, but macrolides build up to very high concentrations within phagocytes and a direct effect on bacteria may occur, which might be bacterial killing, suppression of bacterial growth, or inhibition of production of bacterial virulence factors. Azithromycin is the macrolide most often chosen. Different treatment regimens have been used in the trials, but 250 mg or 500 mg (chosen depending on severity of dis- ease and patient size) three times weekly (Monday, Wednesday, and Friday) is commonly adopted. This is well tolerated and makes use of the pharmacokinetics of the antibiotic which concentrates and persists in tissues. Gastrointestinal disturbance and hearing impairment are the most common side effects of long-​term macrolide treatment. Patients must be warned before starting treatment that if tinnitus or impaired hearing occurs, they must stop the antibiotic and seek ad- vice. Full blood count, renal and liver function should be monitored about every 3 months. Macrolides are an important part of the treatment of non-​ tuberculous mycobacteria, and patients should have a negative sputum for acid-​fast bacilli before starting treatment to avoid the de- velopment of macrolide resistance. Concern has also been expressed from a societal viewpoint about increase in macrolide resistance with widespread long-​term use. Monitoring response to treatment Each patient should have a tailored management plan, which should include instructions about physiotherapy, antibiotic prophylaxis if used, and antibiotic management during an infection. It is critical that both the patient and physician agree defined criteria for assessing response. Lung function produces an objective measure of response, but the introduction of antibiotics may not alter lung function to a great degree, although it should improve sputum colour, volume, and consistency, and reduce exacerbation frequency. This leads to an improvement in general well-​being. Diary cards documenting these parameters have proved helpful, and studies have confirmed the validity of grading sputum colour as a marker of the microbial and inflammatory load in these patients. A number of disease-​specific health status questionnaires have been developed and these may be used in the future. This approach also facilitates patient education and self-​management plans. Surgery Surgery is the only ‘curative’ treatment for a select group of patients and should be carefully considered. In particular, for single-​lobe, focal bronchiectasis, surgery removes the need for lifelong medical therapy. However, it is important that patients undergo careful as- sessment regarding the distribution of bronchiectasis and the pos- sibility of underlying causes which would predispose to disease recurrence. Surgery is unlikely to produce a cure if bronchiectasis is present in several lobes, and lobar resection is then indicated only if there is uncontrolled bleeding unresponsive to bronchial artery em- bolization, or if it is felt—​after a failure of aggressive antimicrobial Patient unwell – increased sputum, breathlessness Antibiotic sensitive species, e.g. Haemophilus influenzae (sputum culture, history) Antibiotic resistant species, e.g. Pseudomonas aeruginosa (sputum culture, history) Sputum culture High dose oral antibiotics (guided by sensitivity) – longer course Patient well Fall in sputum volume Sputum M to MP = Treatment success Patient unwell No change in sputum volume Sputum remains MP or P = Treatment failure Treat with IV antibiotics appropriate to sputum culture until sputum volume falls and sputum M to MP Follow until relapse Early relapse –within 6–8 weeks Treat with successful agent, then think about maintenance therapy choice of oral or nebulized antibiotic Prolonged period well Treat with successful agent for exacerbations only Oral ciprofloxacin – longer course Patient unwell Sputum remains P = Treatment failure Treat with IV anti- pseudomonal antibiotics Patient well Sputum M to MP = Treatment success Follow until relapse Prolonged period well Early relapse –within 6–8 weeks Treat with successful agent, then establish maintenance therapy with nebulized antibiotic /oral macrolide Treat with successful agent M = mucoid MP = mucopurulent P = purulent Fig. 18.9.4  Guide to therapy for patients with bronchiectasis.

section 18  Respiratory disorders 4150 therapy—​that a particular lobe is acting as a ‘sump’ of infection which prevents good control of symptoms with medical therapy. Lung transplantation Lung transplantation provides an effective treatment for end-​stage bronchiectasis, providing that an underlying cause has been care- fully assessed and treated and is unlikely to jeopardize the trans- planted organs (e.g. patients with immunoglobulin deficiencies are not discounted from transplant assessment provided they are re- ceiving adequate immunoglobulin replacement therapy). Complications The most common complication to precipitate hospital admission in patients with bronchiectasis is infective exacerbation, which may be associated with pleuritic chest pain and minor haemoptysis. Massive haemoptysis is rare nowadays, but is managed by bronchial artery embolization. Metastatic spread of infection rarely occurs in the developed world with good control of pulmonary infection with antibiotics, and for similar reasons empyema is now very rare. Amyloidosis is described as a ‘classic’ complication of bronchiec- tasis, but is now extremely rare in the United Kingdom. Arthropathy is a complication of bronchiectasis which seems to flare in associ- ation with the chest disease, and antimicrobial treatment will often result in remission of joint pain. Some patients may suffer vasculitic skin lesions in association with flares of bronchiectasis. Prognosis It was reported in 1940 that 70% of 400 patients with bronchiec- tasis were dead before the age of 40. The situation is clearly different now, as in the developed world we do not often see the florid post-​ infective saccular type of bronchiectasis, but more commonly see patients presenting in their fourth and fifth decade of life with CT findings of cylindrical bronchiectasis. However, bronchiectasis does shorten life as well as impacting on patient well-​being. One study of 116 patients identified a 14-​year survival of 81%, while another of 372 patients an 8.8 year survival of 75%, and another of 91 pa- tients followed prospectively for 13 years showed 70.3% survival. On multivariate analysis, poor exercise capacity, Pseudomonas infec- tion, and lung function impairment (obstruction with restriction) were identified as independent factors associated with mortality. In a subsequent CT scan analysis of the same patients, pulmonary hyper- tension was identified as the most important radiological feature as- sociated with mortality. A Finnish study published in 1997 used the national hospital dis- charge register to identify patients with newly diagnosed bronchiec- tasis from 1982 to 1986, comparing them with age-​ and sex-​matched patients with COPD and asthma discharged at the same time. Over a 10-​year follow-​up the prognosis for those with bronchiectasis was better than that for patients with COPD, but poorer than that of those with asthma. Bronchiectasis was the main cause of death in 13% of patients with the condition. It is clear in the published studies that chronic Pseudomonas aeruginosa infection is associated with increased mortality. Generally, bronchiectasis progresses slowly, but some patient groups have a worse prognosis. Two prognostic scoring systems have recently been published (the BSI and FACED scores) from studies of patients over a relatively short time period (5 years or less). They have identified similar prognostic factors: age, body mass index, FEV1, previous hospital admissions, severity of breathless- ness, chronic Pseudomonas infection, chronic infection by other bacteria, and radiological severity are weighted when calculating the BSI score, whereas the FACED score is simpler and only involves five of these factors. Future developments It is likely that a careful search for genetic factors which affect lung defences will yield new causes of bronchiectasis and allow the cur- rent so called ‘idiopathic’ group to be assigned a cause. The role of inhaled and macrolide antibiotics in bronchiectasis patients with frequent exacerbations needs to be studied further in terms of patient selection for these treatments, the choice of antibiotic and optimal regimen, and their benefits and side ef- fects. Exacerbation frequency or time to first exacerbation after the introduction of the treatment may be blunt tools to assess the benefit of new treatments and will need to be refined. Diary cards to assess number of days with symptoms above a certain level have been used successfully in COPD, and new disease specific quality of life questionnaires may help. However, new biomarkers will be important, and lung clearance index is one such measure recently reported. The principle of enhancing sputum clearance to break the vi- cious cycle of infection and inflammation will be investigated further, as will new anti-​inflammatory treatments. An approach which reduces exacerbations without recourse to chronic anti- biotic therapy will be welcomed. Finally, given clear evidence of increased mortality associated with chronic Pseudomonas infection, the benefits of preventative strat- egies together with microbiological surveillance and early eradica- tion treatment with antibiotics will need to be explored. Application of molecular techniques that are much more sensitive than sputum culture to identify bacteria soon after they colonize will likely help in this regard. FURTHER READING Brodt AM, et al. (2014). Inhaled antibiotics for stable non-​cystic fibrosis bronchiectasis:  a systematic review. Eur Respir J, 44, 382–​93. Hill AT, et al. (2019). British Thoracic Society Guideline for bronchi- ectasis in adults. Thorax, 74(S1), 1–69. Loebinger ML, et al. (2009). Mortality in bronchiectasis, a long term study in bronchiectasis assessing the factors influencing survival. Eur Respir J, 34, 843–​9. Polverino E, et al. (2017). European Respiratory Society guidelines for the management of adult bronchiectasis. Eur Respir J, 50, 1700629. Wu Q, et  al. (2014). Long-​term macrolides for non-​cystic fibrosis bronchiectasis: a systematic review and meta-​analysis. Respirology, 19, 321–​9.

M.A. Kokosi and A.U. Wells 18.11.5 The lung in vas

M.A. Kokosi and A.U. Wells 18.11.5 The lung in vasculitis 4200 G.A. Margaritopoulos and A.U. Wells

section 18  Respiratory disorders 4200 Some patients with interstitial lung disease associated with con- nective tissue disorders are refractory to conventional immunosup- pression. Rituximab, a chimeric anti-​CD20 monoclonal antibody, results in rapid depletion of B lymphocytes from the peripheral cir- culation and has shown significant clinical and functional benefit in severe, progressive CTD-​ILD. Its efficacy is most impressive in patients with polymyositis/​dermatomyositis, but it probably has no significant effect on progression of lung fibrosis in systemic scler- osis, and its effect in rheumatoid arthritis-​associated interstitial lung disease is uncertain. FURTHER READING Alunno A, et al. (2017). Clinical, Epidemiological, and Histopathological Features of Respiratory Involvement in Rheumatoid Arthritis. Biomed Res Int, 2017, 7915340. doi: 10.1155/2017/7915340. Barnes H, et al. (2018). Cyclophosphamide for connective tissue disease-associated interstitial lung disease. Cochrane Database Syst Rev, 1:CD010908. doi: 10.1002/14651858.CD010908.pub2. Bouros D, et al. (2002). Histopathological subsets of fibrosing alveol- itis in patients with systemic sclerosis and their relationship to out- come. Am J Respir Crit Care Med, 165, 1581–​6. Corte TJ, Du Bois RM, Wells AU. (2015). Infiltrative and interstitial lung diseases: connective tissue diseases. In: Broaddus VC, et al. (eds). Murray and Nadel’s Textbook of Respiratory Medicine, 6th edn, pp. 1165–87. Elsevier Saunders, Philadelphia. DeMarco PJ, et al. (2002). Predictors and outcomes of scleroderma renal crisis: the high-​dose versus low-​dose D-​penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum, 46, 2983–​9. El Hadidi KT, et al. (2018). Characteristics of systemic lupus erythematosus in a sample of the Egyptian population: a retro- spective cohort of 1109 patients from a single center. Lupus, 27, 1030–8. Elhai M, et al. (2019). Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective co- hort study. Ann Rheum Dis, 78, 979–87. Friedman AW, Targoff IN, Arnett FC (1996). Interstitial lung disease with autoantibodies against aminoacyl-​tRNA synthetases in the absence of clinically apparent myositis. Semin Arthritis Rheum, 26, 459–​67. Haupt HM, Moore GW, Hutchins G (1981). The lung in systemic lupus erythematosus. Analysis of the pathologic changes in 120 patients. Am J Med, 71, 791–​8. Hoyles RK, Wells AU (2007). Pulmonary fibrosis in collagen vascular diseases. In: Costabel U, du Bois RM, Egan JJ (eds). Diffuse paren- chymal lung disease. Basel, Karger, pp. 185–​96. Hoyles RK, et  al. (2006). A multicenter, prospective, randomized, double-​blind, placebo-​controlled trial of corticosteroids and intra- venous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum, 54, 3962–​70. Hyland RH, et  al. (1983). A systematic controlled study of pul- monary abnormalities in rheumatoid arthritis. J Rheumatol, 10, 395–​405. King TE, Kim EJ, Kinder BW (2011). Connective tissue disease. In: Schwarz MI, King TE (eds) Interstitial lung disease, 5th edn, pp. 689–764. People’s Medical Publishing House, USA. Marie I, et  al. (1998). Pulmonary involvement in polymyositis and dermatomyositis. J Rheumatol, 25, 1336–​43. Papiris SA, et al. (1999). Lung involvement in primary Sjögren’s syn- drome is mainly related to the small airways disease. Ann Rheum Dis, 58, 61–​4. Roofeh D, et al. (2019). Management of systemic sclerosis-associated interstitial lung disease. Curr Opin Rheumatol, 31, 241–9. Tashkin DP, et al. (2006). Cyclophosphamide versus placebo in sclero- derma lung disease. N Engl J Med, 354, 2655–​66. 18.11.5  The lung in vasculitis G.A. Margaritopoulos and A.U. Wells ESSENTIALS Lung involvement in vasculitic disease can manifest as diffuse al- veolar haemorrhage or as other pulmonary vasculopathy. Presenting features of diffuse alveolar haemorrhage include fever, weight loss, and other systemic symptoms in association with cough, breathless- ness, and clinical signs suggestive of pneumonia. Haemoptysis may be present but is not invariable. A fall in haemoglobin over a day or longer suggests the diagnosis, and bronchoalveolar lavage is usually diagnostic. Other pulmonary vasculopathies present with breath- lessness on exertion. Investigation reveals isolated reduction in gas transfer (carbon monoxide diffusing capacity), with or without pul- monary hypertension. Many vasculitic disorders can affect the lung, most notably including (1)  eosinophilic granulomatosis with polyangiitis (previ- ously known as Churg–​Strauss syndrome)—​ typified by rhinitis with nasal polyps and treatment-​resistant late-​onset asthma followed, with chest radiography shows patchy lung infiltration in up to 80% of patients. (2) Granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis)—​chronic rhinitis, sinusitis, or mastoid- itis is typically followed by progression to generalized disease over months to years. The main lung manifestations are with pulmonary nodules (which can cavitate), localized or diffuse infiltrates, alveolar haemorrhage that may be part of a pulmonary–​renal syndrome, and large and small airway disease. Management—​limited disease is generally treated with oral cor- ticosteroid, given as monotherapy or in combination with a second-​ line immunosuppressive agent. Oral corticosteroid with either cyclophosphamide or rituximab are typically used to induce remis- sion of generalized disease. Azathioprine or methotrexate with low dose oral prednisolone are used to maintain remission. Introduction It is useful to subdivide pulmonary vasculitides into primary sys- temic or secondary, and to differentiate them from nonvasculitic disorders that can affect the pulmonary circulation, listed in Table 18.11.5.1. The secondary and nonvasculitic diseases are dis- cussed in other chapters: Table 18.11.5.2 summarizes the primary

18.11.5  The lung in vasculitis 4201 vasculitides, indicating those in which the lung is involved. According to Chapel Hill International’s nomenclature (2012 re- vision), Churg–​Strauss syndrome and Wegener’s granulomatosis have been renamed as eosinophilic granulomatosis with polyangiitis (EGPA) and granulomatosis with polyangiitis (GPA), respectively. Clinical manifestations of pulmonary vasculitis Lung involvement in vasculitic disease can manifest as: • diffuse alveolar haemorrhage; • an isolated reduction in gas transfer (carbon monoxide diffusing capacity, DLco), with or without pulmonary hypertension. Investigations listed in Box 18.11.5.1 should be performed if pul- monary vasculitis is suspected. Diffuse alveolar haemorrhage The presenting features of diffuse alveolar haemorrhage include fever, weight loss, and other systemic symptoms in association with cough, breathlessness, and clinical signs suggestive of pneumonia. A history of previous haemoptysis is sometimes helpful, but in other cases diffuse alveolar haemorrhage presents acutely. Chest radiog- raphy shows consolidation, typically resolving within a matter of days, unlike the usual time-​course in infective pneumonia. High-​ resolution CT may reveal an extensive ground-​glass appearance, denoting partial alveolar filling. A fall in haemoglobin over a day or longer is diagnostically useful, and chronic iron-​deficiency anaemia can arise from low-​grade haemorrhage over a lengthy period. Bronchoalveolar lavage is usually diagnostic in the absence of haemoptysis, revealing overt blood staining in sequential lavage in the acute presentation, or the presence of numerous macrophages containing iron, identified by Perl’s stain, in chronic disease. The gas transfer corrected for alveolar volume (Kco) is elevated in acute haemorrhage, but only if measured within 36 h, seriously limiting the diagnostic yield. Diffuse pulmonary haemorrhage occurring without identifiable cause or association is known as idiopathic pul- monary haemosiderosis (see Chapter 18.14.1). Isolated gas transfer deficit, with or without
pulmonary hypertension Pulmonary vasculopathies other than alveolar haemorrhage present with breathlessness on exertion. Clinical examination of the respira- tory system and routine lung imaging are normal. Lung function tests show preservation of lung volumes with an isolated reduction of DLco. In severe pulmonary vascular disease pulmonary hyper- tension may be clinically overt, and in other cases it is detected by echocardiography, especially if tricuspid regurgitation allows Doppler Table 18.11.5.1  Pulmonary vascular disease Vasculitic Nonvasculitic Primary systemic Thromboembolic Secondary Primary pulmonary hypertension • Rheumatological Secondary pulmonary hypertension • Pulmonary–​renal Systemic sclerosis • Behçet’s syndrome Idiopathic pulmonary haemosiderosis • Chronic infection Arteriovenous malformations • Lymphoma • Drugs   Penicillamine   Hydralazine   Propylthiouracil   Nitrofurantoin Table 18.11.5.2  2012 revised International Chapel Hill consensus nomenclature of systemic vasculitis Systemic vasculitis Lung disease • Large vessel Giant cell arteritis Rare Takayasu’s arteritis Frequent • Medium-​size vessel Polyarteritis nodosa Rare Kawasaki disease No • Small vessel (medium-​size vessel involvement may
be present) Granulomatosis with polyangiitis Frequent Eosinophilic granulomatosis with polyangiitis Frequent Microscopic polyangiitis Frequent Henoch–​Schönlein purpura No Essential cryoglobulinaemia No Box 18.11.5.1  Investigations to be considered if lung vasculitis is suspected Imaging • Chest radiography and high-​resolution CT Lung function tests • DLco/​Kco Blood gases Renal function • Urine dipstick testing and microscopy for proteinuria, haematuria, and cellular casts; measurement of serum creatinine; consider renal biopsy (if evidence of nephritis) Immunology • Antineutrophil cytoplasmic antibodies (ANCA), antiglomerular base- ment membrane (anti-​GBM) antibodies, immune complexes, rheuma- toid factor, antinuclear antibodies, antiphospholipid antibodies Bronchoscopy/​Bronchoalveolar lavage • Iron-​laden macrophages • Exclusion of low tract respiratory infections • Assessment of the large airways (stenosis-​endobronchial lesion) Biopsy • Renal • Skin • Lung (surgical)

section 18  Respiratory disorders 4202 estimation of pulmonary artery pressures. Vasculopathies other than vasculitis should be considered in this clinical context, including ab- lative vasculopathies (as in systemic sclerosis and primary pulmonary hypertension) and coagulopathies leading to thromboembolism or intrapulmonary microvascular thrombosis (see Chapter 16.15.2). The following sections discuss lung involvement in specific vascu- litic disorders, followed by discussion of key clinical problems, prog- nosis, and treatment. Eosinophilic granulomatosis with polyangiitis First described by Churg and Strauss in 1951, this rare condition has an estimated annual incidence of approximately 3 per million and mostly affects adults aged 30 to 50 (although the reported age range is 7–​74  years). There is no strong gender predilection. Typically, asthma and eosinophilia are associated with the characteristic histo- logical findings (Fig. 18.11.5.1), consisting of profuse eosinophilic infiltration, extravascular granulomatous inflammation, and necro- tizing arteritis affecting small to medium-​sized vessels. There is little information about geographical variation. Aetiology and pathogenesis The underlying pathogenetic mechanism is generally considered to be an eosinophilic granulomatous response to a foreign antigen, akin to the eosinophilic granulomatosis seen in schistosomiasis. In support of this hypothesis, immunological stimuli (vaccination or immunotherapy) have been reported to trigger the disease, al- though the pauci-​immune nature of the histopathology has yet to be explained. The introduction of antileukotriene therapy for asthma has been associated with an increased incidence of EGPA, but it remains unclear whether the drug triggers the onset of dis- ease. It is also possible that reduction or withdrawal of corticoster- oids with better control of asthma unmasks the condition in some cases, although some individuals who have never received cortico- steroids have developed the syndrome with the introduction of an antileukotriene agent. The HLA-​DRB1*04 and *05 alleles and the related HLADRB4 gene are associated with increased risk of developing EGPA. There is evidence suggesting that the disease is mediated by a Th-​2 response through the release of cytokines such as IL-​4,-​13,-​5. Th1 and Th17 cells are involved in advanced stages, whereas T regulatory cells are reduced in active disease. It has recently been proposed that B-​cells can contribute to the development of the disease. Antineutrophil cytoplasmic antibodies (ANCA), first described in 1982, are frequently present in systemic vasculitides involving small and medium-​sized vessels, including EGPA, GPA, and microscopic polyangiitis. ANCA are directed against cytoplasmic antigens in polymorphonuclear leucocytes and monocytes and are subcategorized according to their immunofluorescent staining pattern as C (cytoplasmic), P (perinuclear), or A (atypical). The pathogenetic significance of ANCA is unclear, but ANCA recep- tors on the surface of neutrophils are upregulated at disease sites, and ANCA can also interact with endothelial cells to cause injury and coagulation. All ANCA patterns have been reported in EGPA, but P-​ANCA occur most frequently, usually directed against myeloperoxidase (MPO) and only very infrequently against pro- teinase 3 (PR3). Pulmonary presentation and diagnostic criteria Two sets of diagnostic criteria have been used: Lanham’s criteria and the criteria of the American College of Rheumatology. In addition to systemic features such as fever and weight loss, Lanham defined the disease as requiring: • asthma • eosinophilia greater than 1.5 × 109/​litre in the peripheral blood • evidence of systemic vasculitis in two or more organs other than the lung The American College of Rheumatology definition requires the satisfaction of at least four of the following six criteria: • the presence of asthma • eosinophilia greater than 10% in the peripheral blood • evidence of a neuropathy in a vasculitic pattern (e.g. mononeuritis multiplex) • transient pulmonary infiltrates • a history of sinus disease • evidence of extravascular eosinophilia on biopsy In most patients asthma precedes vasculitic manifestations, often by years, although these features develop simultaneously in up to 20% of cases. Typically the prodromal phase consists of rhinitis with nasal polyps, which often lasts for years before the eventual devel- opment of late-​onset asthma that is generally resistant to treatment. The second phase is characterized by eosinophilia in the peripheral blood and tissues and often follows a relapsing and remitting course. The final phase, systemic vasculitis, often follows the onset of the Fig. 18.11.5.1  A case of eosinophilic granulomatosis with polyangiitis showing a pulmonary artery surrounded by granulomatous inflammation and a florid mixed inflammatory cell infiltrate that includes abundant eosinophils.

18.11.5  The lung in vasculitis 4203 second phase by several years and is immediately preceded by im- provement in asthma. This pattern of evolution of disease is more than 95% specific and sensitive for EGPA. Respiratory failure and status asthmaticus account for 10% of deaths. Other organ involvement Skin lesions These are seen in about 60% of patients, generally manifesting as palpable purpura or subcutaneous nodules. Skin infarcts also occur. Cardiac involvement The heart may be involved diffusely, producing congestive cardiac failure or restrictive cardiomyopathy. Eosinophilic myocarditis is present in up to 50% of cases, with coronary artery vasculitis and pericardial effusions much less frequent. Cardiac disease is the most common cause of death. Renal disease This is much less common than in GPA or microscopic polyangiitis, but the histopathology is very similar, consisting of a focal segmental necrotizing glomerulonephritis. Renal disease is generally mild, but end stage renal failure is reported. See Chapter 21.10.2 for further discussion. Nervous system involvement Mononeuritis multiplex such as drop wrist or drop foot, confirmed by nerve conduction studies or sural nerve biopsy, is the most common manifestation, occurring in up to 75% of patients. Cranial nerve involvement is less common, but cerebrovascular disease may occur. Gastrointestinal involvement Vasculitis of the mesenteric vessels may produce bowel abnormal- ities, including perforation, and less commonly eosinophilic infiltra- tion may cause obstruction. Musculoskeletal system Arthritis is relatively common, as are myalgias. Investigation Chest radiography shows patchy lung infiltration in up to 80% of patients and pleural disease is present in up to 50%. High-​resolution CT is much more sensitive than chest radiography, although the full spectrum of abnormalities has yet to be defined. The most frequent findings are patchy ground-​glass infiltration and patchy consolida- tion. An extensive ground-​glass appearance is usual in patients in whom alveolar haemorrhage is due to capillaritis, whereas consoli- dation is more suggestive of granuloma formation in association with involvement of medium-​sized vessels. Pulmonary infiltrates are much more common than pulmonary nodules and, in contrast to GPA, cavitation of nodules is extremely rare. Bronchial wall thick- ening and bronchiectasis have also been described. Table 18.11.5.3 lists the major pulmonary manifestations. There is a peripheral blood eosinophilia, matched by a marked eo- sinophilia on bronchoalveolar lavage. The diagnostic role of ANCA continues to be debated. ANCA, usually P-​ANCA-​MPO, are present in up to two-​thirds of patients, but in some series their prevalence is much lower and P-​ANCA also occur in many other nonvasculitic autoimmune and infectious conditions. Thus, the presence of P-​ANCA is no more than a useful ancillary finding, increasing the diagnostic likelihood, and the absence of P-​ANCA should not ma- terially influence the diagnostic algorithm. ANCA-​positive patients more frequently have peripheral neuropathy, glomerulonephritis, and purpura compared to ANCA negative patients, who have more frequent lung, myocardial, and gastrointestinal symptoms. Eotaxin-​3, an eosinophil attracting chemokine, could be an at- tractive biomarker for the future, as at a cut-​off level of 80 pg/​ml it has a sensitivity and specificity of 87.5% and 98.6%, respectively, to diagnose active EGPA. The classical triad at lung biopsy consists of necrotizing angiitis, granulomas, and tissue eosinophilia (Fig. 18.11.5.1). Giant cells and fibrinoid necrosis are present. However, it is not uncommon for histological appearances to be indeterminate, with the presence of some but not all of the characteristic features, and in some cases there is overlap with the histopathological appearances of GPA or microscopic polyangiitis. Surgical biopsies have a much higher diag- nostic yield than transbronchial biopsies, which seldom disclose vasculitis. Granulomatosis with polyangiitis The systemic features of GPA are described in Chapter 19.11.7. It is the third most prevalent systemic vasculitis (after giant cell arter- itis and vasculitis in rheumatoid arthritis), and occurs throughout the world with an annual incidence of 3–​11 per million, depending upon the geographic region. It mainly affects adults aged 30–​50 (al- though it may occur in any age group), and there is no gender pre- dilection. The histological abnormalities consist of granulomatous inflammation associated with necrotizing vasculitis, affecting small to medium-​sized vessels (Fig. 18.11.5.2). Lung involvement occurs at some stage of disease in up to 85% of cases; upper respiratory tract and renal involvement (due to necrotizing glomeruloneph- ritis) are frequent. Aetiology and pathogenesis Studies of possible genetic associations have yielded conflicting re- sults, with linkage to HLA DR1 or HLA DR2 in some but not all Table 18.11.5.3  Distinguishing thoracic features in primary vasculitis Thoracic features Eosinophilic granulomatosis with polyangiitis Granulomatosis with polyangiitis Microscopic polyangiitis Subglottic stenosis + + Multiple nodules + + Solitary nodules + Cavities + Localized infiltrates + + Transient infiltrates + + Pleural involvement + + Cardiac involvement +

section 18  Respiratory disorders 4204 populations. The importance of environmental factors is equally un- certain. Case–​control studies have suggested that exposure to silica or silicone might be pathogenetic in some cases. ANCA-​positive vasculitis mimicking GPA has been induced by propylthiouracil, hydralazine, and penicillamine, possibly by modifying MPO and thereby creating an antigenic stimulus. However, the most sug- gestive data relate to infection, especially with Staphylococcus au- reus. Chronic nasal carriage of S.  aureus is substantially more prevalent in GPA than in control populations, and it has been sug- gested that staphylococcal acid phosphatase might be antigenic in susceptible individuals. An immunostimulatory role for S. aureus B-​cell superantigens has also been proposed. The partial efficacy of prophylactic trimethoprim–​sulfamethoxazole in reducing both infection and the likelihood of relapse of GPA provides further in- direct support for an infectious pathogenesis. Pathogenetic concepts are complicated by the histological spec- trum of disease, ranging from prominent granulomatous lesions, associated with a lymphocytosis on bronchoalveolar lavage, to ful- minant necrotizing vasculitis, in which a bronchoalveolar lavage neutrophilia is the rule. The genesis of granulomata is not well understood, but there is strong indirect evidence that neutrophils play a key role in initiating vasculitis. PR3 is the main target antigen for C-​ANCA, which is found in about 90% of patients with gener- alized GPA (as compared to 50% of patients with localized disease). As in other ANCA-​positive vasculitides, there is in vitro and animal model evidence to suggest that PR3-​ANCA might interact with primed neutrophils, leading to neutrophil degranulation and thus to endothelial damage and further neutrophil recruitment. Pulmonary presentation Involvement of the upper and/​or lower respiratory tract is the presenting feature in 90% of cases. Disease usually evolves in two phases. Initially there is chronic rhinitis, sinusitis, or mastoid- itis, after which most patients progress to generalized disease over months to years, with lower respiratory tract involvement in 65 to 85% often manifesting with cough, which may be purulent, and less frequently with haemoptysis due to diffuse alveolar haemorrhage. Systemic symptoms, including fever and weight loss, are frequent in generalized disease, along with variable involvement of other organs as described in Chapter 19.11.7. Lung involvement is asymptomatic in about one-​third of cases, with the main lung manifestations being (see Table 18.11.5.3): • one or more nodules, which can cavitate (Fig. 18.11.5.3a) • localized or diffuse infiltrates (Fig. 18.11.5.3b) • alveolar haemorrhage that may be part of a pulmonary–​renal syndrome • large and small airway disease Investigations As in other vasculitides, classical features are not always present at biopsy, with many patients having only one or two of the three car- dinal histological features (granuloma, necrosis, vasculitis). If a lung Fig. 18.11.5.2  A case of granulomatosis with polyangiitis (GPA) showing an area of geographic necrosis around a partly destroyed pulmonary vessel. This focus is surrounded by chronic inflammation and fibrosis, within which there is granulomatous inflammation with the giant cells showing a somewhat pyramidal morphology. Fig. 18.11.5.3  GPA most often presents radiologically. CT scans may reveal one or more nodules, which can cavitate (a), or localized (b) or diffuse infiltrates.

18.11.5  The lung in vasculitis 4205 biopsy is required, surgical biopsy is preferred, transbronchial bi- opsies having a much lower diagnostic yield, especially when not targeted to areas with overt abnormalities on chest radiography or high-​resolution CT. In advanced pulmonary disease the haz- ards of biopsy should prompt a search for an alternative biopsy site, including the kidney, skin, and skeletal muscles. Endoscopic nasal biopsy appearances are most often nonspecific, although positive features in a few cases provide a definitive diagnosis. Irrespective of the biopsy site, suggestive appearances may be diagnostic when combined with clinical and serological information even when diag- nostic histological features are absent. The two main patterns on chest radiography and high-​resolution CT are nodules and consolidation, with pleural effusions an occa- sional finding. High-​resolution CT offers the important advantage of better definition of nodule cavitation, a key diagnostic feature, and may also disclose abnormalities of the large intrathoracic and extrathoracic airways, including subglottic stenosis, stenosis of large airways, and bronchiectasis. Subglottic stenosis is present in up to 25% of cases and can develop without concomitant systemic disease activity. Fibre-​optic bronchoscopy may show tracheobronchitis, including ulceration and ‘cobblestoning’ of the mucosa, or airway stenosis. Bronchoalveolar lavage fluid contains an excess of neutrophils and usually of eosinophils (with diffuse infiltrates) or lymphocytes (more interstitial disease), but is most useful in excluding alveolar haem- orrhage or infection, including opportunistic infection in treated patients. Haematological and biochemical investigations reflect the in- flammatory process. The diagnosis should never be based upon C-​ ANCA positivity in isolation because these are also found in other contexts, including other vasculitides, chronic bacterial infections, and cryoglobulinaemia. Microscopic polyangiitis The main description of microscopic polyangiitis occurs elsewhere (Chapter  19.11.7), but this necrotizing vasculitis affects small to medium-​sized vessels, with few or no immune complex deposits, and lung disease occurs in 35–​55% of cases. Pulmonary presentation Lung involvement is less frequent than in GPA. The major pres- entation (Table 18.11.5.3) is diffuse alveolar haemorrhage, which can have a poor prognosis. Pulmonary capillaritis may be associ- ated with evidence of disease outside the lung, particularly nec- rotizing glomerulonephritis, mononeuritis multiplex, and skin lesions. It is often difficult to distinguish microscopic polyangiitis from GPA clinically. The key histological distinction is the absence of granulomas, which are characteristically present in GPA. Renal biopsies can be identical in the two conditions. Microscopic polyangiitis also needs to be distinguished from polyarteritis nodosa that, by definition, only affects arteries, rarely arterioles, and never small vessels. Renal vasculitis with microaneurysm formation occurs in polyarteritis nodosa but not microscopic polyangiitis, and diffuse alveolar haemorrhage does not occur in polyarteritis nodosa. Other diseases Other primary systemic vasculitides occasionally present with re- spiratory features. Takayasu’s arteritis This arteritis affects predominantly the aorta and its main branches but involves the pulmonary arteries in up to 50% of patients, pre- senting with pulmonary vascular occlusion. Giant cell arteritis There is rarely objective evidence of lung involvement, but 25% of patients with giant cell arteritis have cough, hoarseness, and sore throat at presentation. The other systemic vasculitides that feature in the Chapel Hill International consensus nomenclature, but which rarely, if ever, pre- sent with lung disease, are Henoch–​Schönlein purpura and essential cryoglobulinaemia. Behçet’s disease This occurs predominantly in Mediterranean countries and can produce pulmonary vascular inflammation affecting all sizes of vessels and resulting in pulmonary arterial aneurysms, arterial and venous thrombosis, pulmonary infarcts, and pulmonary haemor- rhage. It is crucial to differentiate haemorrhage from thrombosis because of the treatment implications. Pulmonary veno-​occlusive disease This is a disorder of unknown cause that manifests with progressive occlusion of the postcapillary venules, resulting in features similar to those of pulmonary oedema. There is no known effective treatment. Differentiation from cardiogenic causes of raised pulmonary venous pressure must be made. Key clinical problems in vasculitis Diagnosis Ideally, typical histological appearances should be present, and when they are not present the requisite number of clinical criteria should be met. However, formal diagnostic criteria are merely a basis for diagnostic negotiation in many cases. Classification systems fail to capture the entire spectrum of vasculitic disease, with many patients having features overlapping between diagnostic entities. With the advent of ANCA antibodies, formes frustes of full blown vasculitic syndromes are increasingly diagnosed, with transient or no fulfil- ment of full diagnostic criteria in many instances. Even in cases sat- isfying diagnostic criteria, the clinical heterogeneity of the vasculitic syndromes is notorious, it often being stated that no two patients are alike. An appreciation of these difficulties informs the clinician of the need for a versatile diagnostic approach. When vasculitis is suspected but full clinical criteria are not satisfied, a histological diagnosis should generally be sought, targeted to involved organs. Failure to capture typical appearances at biopsy does not necessarily exclude a diagnosis of vasculitis as vasculitic processes may be patchy and nonspecific inflammatory change may be evident: this

section 18  Respiratory disorders 4206 applies especially to upper airway biopsies in patients with GPA. An empirical diagnosis of a vasculitic syndrome must sometimes be made, and in these cases—​which tend to foment a great deal of in- security in patients and clinicians alike—​it is essential to do every- thing possible to exclude the most frequent differential diagnoses, namely infection and malignancy. When formal diagnostic criteria for a vasculitic syndrome are not fulfilled and empirical treatment is required, the general approach—​ including initial treatment and monitoring—​should be as for the vasculitic syndrome most closely resembling the particular clin- ical presentation of the patient. When the diagnosis is uncertain the initial treatment should be definitive because a satisfactory re- sponse provides useful ancillary diagnostic support (‘diagnosis by therapeutic challenge’): a tentative initial therapeutic approach often merely serves to prolong diagnostic uncertainty. Prognosis The outcome of the more frequent vasculitic syndromes was poor when they were first described, but has improved strikingly, as best illustrated by the mortality of GPA: the mean survival of 5 months in early reports has now been transformed, with complete initial re- mission in 75% of cases, increasing further with the recent use of rituximab. However, despite these improvements, long-​term follow-​ up continues to be needed in GPA (relapse occurs in 50–​70% of cases) and other vasculitides. The improvement in prognosis in GPA, also seen in EGPA, in part reflects the increasing use of immunosuppressive agents in combination with corticosteroid therapy. However, the increasing detection of milder disease, including patients with limited involve- ment, has also undoubtedly improved average outcome. Localized GPA has a better outcome than disease with multiorgan involve- ment. The prognosis of EGPA is generally good for those with iso- lated intrathoracic disease (5-​year survival 88%), but worsens with two or more extrapulmonary complications (5-​year survival 54%), particularly with proteinuria more than 1 g/​day, renal insufficiency (creatinine >140 µmol/​litre), cardiomyopathy, gastrointestinal dis- ease, or central nervous system involvement. The causes of death in vasculitis can be broadly subdivided into sepsis (as a complication of treatment) and disease progression. In GPA death from progressive disease is most commonly due to renal failure or lung involvement. In EGPA the main cause of death is cardiac disease, followed by renal failure, cerebrovascular involve- ment, and gastrointestinal disease, with lung disease accounting for 10% of deaths. Treatment As a general rule, treatment of vasculitis includes two phases: induction of remission with aggressive therapy against vascu- litis; and maintenance of remission with the aim of establishing the minimum level of therapy required to prevent relapse. The choice of treatment is based on the activity and extent of disease (Table 18.11.5.4). Limited disease Treatment recommendations are based mainly on expert opinion, given the lack of clinical trials. Immunomodulation with oral cor- ticosteroid, given as monotherapy or in combination with a second-​ line immunosuppressive agent such as methotrexate, azathioprine, or mycophenolate mofetil is the most frequent regimen used in this group of patients. Early generalized disease The combination of corticosteroid and cyclophosphamide is most often used to induce remission. Methotrexate at a dose of 0.3/​mg/​kg/​week has less side effects and is better tolerated than cyclophosphamide, but is associated with a higher rate of relapse. Generalized active disease The combination of oral corticosteroids and oral cyclophospha- mide achieves remission in 55–​80% of cases. The initial dose of oral steroids is 1 mg/​kg/​day, but in more severe cases intravenous administration at the dose of 7.5–​15 mg/​kg/​day for 1–​3 consecu- tive days is preferred. A major benefit of initial pulsed therapy is that lower doses of oral corticosteroids can subsequently be used in rapid responders, thus minimizing long-​term steroid-​related side effects such as infections, diabetes, and osteoporosis. Treatment with steroids should be carried on for at least 6–​12 months after the initial presentation of the disease as earlier discontinuation is asso- ciated with an increased risk of relapse. Cyclophosphamide can be administered orally (2 mg/​kg/​day) or intravenously (600 mg/​m2 at three-​ to four-​weekly intervals), depending on disease severity. The side effects include neutropenia and infections, haemorrhagic cystitis, late bladder cancer, and infer- tility (with bladder side effects less prevalent with the use of intra- venous regimens). Intravenous cyclophosphamide is also less toxic with regard to other side effects, but is associated with a higher rate of relapse compared to oral cyclophosphamide. Rituximab, an anti-​CD20 monoclonal antibody, was initially used to treat relapsing disease (375 mg/​m2 weekly for four weeks). More recently, it has proved to be more effective than oral cyclo- phosphamide for induction of remission, used in combination with steroid therapy, and equally effective in the treatment of al- veolar haemorrhage. When rituximab is used to induce remission, it is often possible to avoid or minimize maintenance therapy, of- fering an important advantage of over cyclophosphamide-​based induction regimens. Taken together, trial data and accumulated clinical experience suggest that rituximab may be superior to cyclophosphamide as induction therapy, although not always ap- proved for use due to cost considerations. Rituximab is the agent of choice when there are contraindications to cyclophosphamide and for relapse following cyclophosphamide therapy (especially Table 18.11.5.4  EUVAS (European Vasculitis Study Group) classification EUVAS classification Clinical features Limited Isolated upper airways disease Early generalized End-​organ involvement that lacks a clear or immediate threat to organ function Generalized active End-​organ involvement with clinically significant impairment of organ function Severe Immediate threat of organ failure or death Refractory Disease that was failed to respond to conventional therapies Remission (maintenance) No evidence of ongoing vasculitic activity

18.11.5  The lung in vasculitis 4207 when there is a high cumulative oral cyclophosphamide dose), and when there are concerns about infertility with the use of cyclophosphamide. Severe disease In severe disease with diffuse alveolar haemorrhage or renal failure, plasma exchange should be considered early, together with high doses of intravenous methyl-​prednisolone and cyclophosphamide. In cases of life-​threatening disease at presentation, the use of ini- tial combination intravenous therapy with methyl-​prednisolone, cyclophosphamide, and rituximab should be considered, especially if plasma exchange is not available. Refractory disease Intravenous immunoglobulin has been used in refractory disease, particularly in the setting of recurrent infections and in pregnant woman who cannot receive immunosuppressive agents. This treatment is less toxic than the regimens described here, but is contraindicated in patients with severe renal disease (creatinine level >300 μmol/​l). Maintenance of remission For the maintenance of remission, azathioprine (2 mg/​kg/​day) has been used after 3–​6 months’ treatment with cyclophosphamide, re- ducing total exposure to cyclophosphamide without an increase in the rate of relapse. Methotrexate at a dose of 25 mg/​week is as ef- ficacious as azathioprine as maintenance therapy. Mycophenolate mofetil is associated with a higher rate of relapse than methotrexate or azathioprine and is not recommended as second-​line therapy. It is usual practice to combine azathioprine or methotrexate with low dose oral prednisolone (e.g. 5–​10 mg daily). In general, maintenance treatment should be continued for at least 18 months and must often be used for many years, but long-​term treatment decisions can only be made on a case by case basis. Prophylactic co-​trimoxazole (trimethoprim 160 mg/​ sulfa­ methoxazole 800 mg three times weekly) is often recommended when long-​term intense immunomodulation has been instituted to prevent opportunistic infection by Pneumocystis jirovecii. It has been efficacious in suppressing disease activity in GPA patients with localized upper respiratory tract or minor lower respiratory tract disease, but does not have an established ancillary role in aggressive systemic disease, although usually justifiable in this context as antipneumocystis prophylaxis. FURTHER READING Frankel SK, et al. (2012). The pulmonary vasculitides. Am J Respir Crit Care Med, 186, 216–​24. Greco A, et  al. (2015). Churg–​Strauss syndrome. Autoimmun Rev, 14, 341–​8. Guillevin L, et al. (1996). Prognostic factors in polyarteritis nodosa and Churg–​Strauss syndrome. A prospective study in 342 patients. Medicine, 75, 17–​28. Jayne D, et  al. (2003). A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoanti- bodies. New Engl J Med, 349, 36–​44. Jennette JC, et  al. (2013). 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum, 65, 1–​11. Keogh KA, et  al. (2006). Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-​label pilot trial. Am J Respir Crit Care Med, 173, 180–​7. Lanham JG, et  al. (1984). Systemic vasculitis with asthma and eo- sinophilia: the clinical approach to the Churg–​Strauss syndrome. Medicine (Baltimore), 63, 65–​81. Lhote F, Guillevin L (1998). Polyarteritis nodosa, microscopic polyangiitis and Churg–​Strauss syndrome. Semin Respir Crit Care Med, 19, 27–​46. Nguyen Y, Guillevin L. (2018). Eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Semin Respir Crit Care Med, 39, 471–81. Pagnoux C, Guillevin L (2015). Treatment of granulomatosis with polyangiitis (Wegener’s). Expert Rev Clin Immunol, 11, 339–​48. Specks U (2011). Pulmonary vasculitis. In: Schwarz MI, King TE Jr (eds). Interstitial lung disease, 5th edn, pp. 765–804. People’s Medical Publishing House, USA.

Peter D. Wagner and Pallav L. Shah 18.2 The clinic

Peter D. Wagner and Pallav L. Shah 18.2 The clinical presentation of respiratory disease 3947 Samuel Kemp and Julian Hopkin

ESSENTIALS Respiratory disease can present in many ways, with variations attrib- utable to many factors. The clinical presentation directs diagnostic hypothesis making, the choice of diagnostically discriminating in- vestigations, and the most appropriate management. If a detailed history is not taken, the patient not observed carefully and examined diligently, and the information from these sources is not analysed correctly, then inappropriate investigation and management is likely. History—​common symptoms of respiratory disease are breathless- ness, cough, haemoptysis, and pleuritic chest pain, details of which can point to particular diagnoses. An account of environmental exposures at work and home, and of family history, is critically im- portant in some cases. Clinical examination—​environmental exposures at work and home, and of family history, is critically important in some cases, which can point to particular diagnoses, as can respiratory rate, pulse rate, and temperature. Immediate pointers to respiratory disorder are repeated cough, wheeze or stridor, painful breathing, laboured or ineffective breathing, or cyanosis, but it is crucial to remember that respiratory failure can present as a torpid or drowsy state without clear respiratory distress. Observation of the chest, followed by pal- pation, percussion, and auscultation must be performed systemat- ically, and the physician who practices these skills regularly will be better at them than the one who does not. In chronic respiratory dis- ease, where breathlessness and disability are to be assessed, walking with the patient and observing exercise tolerance and distress (and pulse oximetry) can provide valuable information. Introduction The clinical presentation of respiratory disease is protean, with many diseases of different respiratory structures presenting in both common and rare ways. The presentation varies according to many factors—​heterogeneity of disease under one diagnostic banner, the natural vagaries of one disease, comorbidities, age and family and social circumstances, and personality traits such as timidity or sto- icism. The proper assessment of the clinical presentation therefore needs care and thought. The clinical presentation directs the formulation of diagnostic hypotheses, choice of discriminating investigations, and ultimately the most appropriate management. The combination of the clinical presentation and its careful assessment usually provides the cru- cial signal as to the seriousness or threat of an acute disorder, and the impact of disease on life and its quality likely to be caused by a chronic problem. A detailed and skilfully taken history will pick up and follow leads offered by the patient, often revealing the diagnosis even before the patient is examined. Indeed, the information from a carefully conducted clinical review by the patient often provides a more complete view of the condition and its impact than the sum of body scans and/​or detailed molecular and physiological inves- tigations. These diverse methodologies are of course complemen- tary in good clinical practice, where at the point of management the patient’s investigations need to be interpreted in the context of the clinical picture. General features are especially important in the clinical exam- ination of a patient who has, or might have, a respiratory disorder, and they are noticeable from the start of the clinical review in the clinic or medical admissions unit. In the latter, accurate monitoring and documentation of respiratory rate, pulse rate, and tempera- ture are essential. Serious disease may be reflected by an expression of anguish, especially when it is acute, or of dejection when it has progressed inexorably over some time, but mortal disease can also present unobtrusively. Immediate pointers to respiratory disorder, whatever its origin, are repeated cough, wheeze, or stridor, painful breathing, laboured or ineffective breathing, or evident cyanosis. Symptoms Breathlessness Breathlessness refers to an uncomfortable or distressing sensation that occurs when actual ventilation is perceived not to satisfy de- mand, defined by the American Thoracic Society as ‘a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity’. Breathlessness is a complex physiological phenomenon. Its per- ception is cerebral, with two principal components relevant to most 18.2 The clinical presentation
of respiratory disease Samuel Kemp and Julian Hopkin

Section 18  Respiratory disorders 3948 breathless patients, both of which depend on integration of infor- mation. The first allows the perception of breathlessness, and the second allows gauging of its distressfulness. In the first component, the interconnecting neural pathways allow comparison between the volume of efferent motor neurone output to drive respiration, and the volume of afferent sensory input recording the ventilatory effects achieved from juxtacapilliary and stretch receptors, carotid body chemoreceptors, and muscle spindles. Breathlessness results when a mismatch occurs between the two—​where the motor output (representing effort) exceeds the sensory input (the result achieved). In the second component, further connecting intracerebral neur- ones allow for this perception of breathlessness to be emotionally interpreted with regards to its degree of distressfulness, introducing a significant psychological component in some individuals. This model offers an understanding of how diverse disorders of the bronchi (limiting airflow) and of the lung parenchyma, pleura, and chest wall (limiting distension) cause breathlessness. It also offers an understanding of how two patients (i.e. with chronic ob- structive pulmonary disease, COPD), can have the same derange- ment of lung function and blood gas measurements, but suffer very different degrees of distress due to their breathlessness and different degrees of impact on their lives. Such variability in emotional ap- prehension of breathlessness is important to recognize. It can valu- ably influence the deployment of rehabilitation programmes, or perhaps cognitive behavioural therapy, in the patient with chronic distressing breathlessness. The character of breathlessness, as related in the history—​onset and duration (sudden, acute, subacute, or chronic—​see Table 18.2.1), severity, and any associated symptoms—​may provide clear diagnostic pointers. One should assess the intensity of the distinct sensations, the degree of distress involved, and the impact on activities of daily living. Most asthmatics clearly describe episodic breathlessness, with a feeling of chest tightness with audible wheeze, and regular early morning (c.04.00–​06.00 h) worsening. Many can relate some episodes to exposures to extrinsic triggers (e.g. cats, perfumes, cig- arette smoke, or occupational agents, such as flour in bakers). In chronic obstructive pulmonary disease, the typical picture is pro- gressive exertional breathlessness over many months or years, punctuated by exacerbations of this breathlessness during bouts of winter-​season, virus-​initiated bronchitis, with cough and purulent sputum. Progressive breathlessness, with strict limitation of exer- cise, is often a feature of pulmonary fibrosis and related disorders of the pulmonary parenchyma. Progressive breathlessness over days and weeks, where the symptoms by night and in bed are worse than the day, and where there are repeated awakenings from sleep by breathlessness, and relief from sitting up, suggest heart failure. Pneumothorax often presents as truly abrupt onset of breathlessness with or without pleural pain. The character of the breathlessness is often less decisive than in the examples given here, and it is only the complete clinical picture (with the full history and clinical examination) and the chest radio- graph that advances the diagnostic possibilities, and then further investigations that clarify the diagnosis. For example, most phys- icians are only too familiar with variable presentation of pulmonary embolism across a clinical spectrum of breathlessness syndromes, fleeting pleuritic pain, and sudden circulatory arrest. Moreover, there is always the potential for diagnostic confusion between the rare manifestation of a common disease (pulmonary oedema due to malaria in the pregnant female), the occasional respiratory manifest- ation of a multisystem disease (e.g. lupus pneumonitis, or infection in the immunosuppressed), the usual manifestation of a relatively rare respiratory disease (cryptogenic organizing pneumonia), or an idiosyncratic reaction to a medication such as pulmonary eosino- philia syndrome (see ‘Medication history’, later). It should also be noted that breathlessness is not always a prom- inent presenting symptom in cases of respiratory failure. In respira- tory failure due to progressive neuromuscular disorder, chest wall deformity and severe obesity, fatigue and morning headaches due to CO2 retention may dominate the clinical picture. Cough Cough can be productive or nonproductive, and assessment should establish the amount of sputum produced as well as its consistency and colour. The timing of the cough may be helpful in diagnosing a cause. For example, a cough in the early morning, after exercise, on exposure to allergens such as dust, pollen, animals, or cold air, may point towards an asthma diagnosis. If the patient complains of cough following a meal or when bending down, gastro-​oesophageal reflux should be considered. The cough reflex is triggered by irritant and chemical receptors, predominantly of the upper respiratory tract and large airways, and cough can be the principal manifestation of many acute and chronic lung diseases, but also of other disorders (Table 18.2.2). Viral upper respiratory tract infection is the commonest cause of acute onset cough with or without sputum. This can take some 2–​3 weeks to subside fully in the otherwise healthy person. In asthma, Table 18.2.1  The onset and duration of different causes of breathlessness Onset Causes Immediate Acute upper airway obstruction Cardiac arrhythmia Flash pulmonary oedema Pneumothorax Pulmonary embolism Acute (minutes
to hours) Asthma exacerbation Chronic obstructive pulmonary disease exacerbation Hyperventilation syndrome Metabolic acidosis Pneumonia Pulmonary embolism Pulmonary oedema Upper airway obstruction Subacute (days) Acute interstitial pneumonias Atelectasis Pleural effusion Vasculitis Chronic Anaemia Asthma Bronchiectasis Chronic obstructive pulmonary disease Cystic fibrosis Interstitial lung disease Neuromuscular disease Obesity Occupational lung disease Pregnancy Pulmonary vascular disease Thoracic cage deformities

18.2  The clinical presentation of respiratory disease 3949 chronic obstructive pulmonary disease, and bronchiectasis, such viral infections may be accompanied by significant decline in airflow function, with breathlessness and wheeze, or respiratory failure. Cough of acute onset due to inhalation of foreign body is relatively rare, but needs consideration and investigation by bronchoscopy in adults as well as children when there is stridor (see ‘Breath sounds’, later) or localized inspiratory wheeze in the chest, when dry cough persists unabated, or when the chest radiograph shows asymmetric lung field volumes. A foreign body may inflate or deflate a lung or lobe, dependent on the mechanics of the obstruction. Chronic cough is usually defined as a cough lasting more than 8 weeks, and needs thorough investigation to determine its cause. Chronic cough, with little or no sputum, can often be due to gastro-​ oesophageal reflux disease, paranasal sinus disease, or common medications. A  detailed drug history is important, as drugs can cause cough directly (e.g. angiotensin-​converting enzyme inhibi- tors) or through their effects on the lung (see later). Other features of the history should provide useful pointers to sinus disease (past history of sinus surgery, postnasal drip, nasal blockage, or periodic facial discomfort or fullness) or reflux (episodic ‘heartburn’, regur- gitation of food, or acid brash, morning sore throats, although often related to nonacid reflux). Long-​standing cough (of many years’ duration) is usually due to tobacco smokers’ chronic bronchitis or bronchiectasis. Milder forms of bronchiectasis (although often related to nonacid reflux), history of sinus surgery, postnasal drip, nasal blockage, or periodic facial discomfort or fullness should also be recognized and noted. Asthma is also a common cause of chronic or periodic cough, and in some instances this symptom overshadows wheeze. There may be epi- sodic ‘heartburn’, in others the diagnosis may require bronchoscopic biopsy to demonstrate the eosinophilic bronchitis typical of asthma. Chronic or periodic cough in some instances overshadows wheeze as a symptom. The possibility of tuberculosis must be addressed by chest radiograph, microscopy, and culture of any sputum, since clin- ical examination of the lungs is rarely useful (except in advanced cases). Likewise, the clinical features of surgically curable car- cinoma of the bronchus are not reliable, hence smokers with a new or change in cough require CT scanning of the thorax and/​or bron- choscopy. Other infections, such as lung abscess due to various bacterial infections or fungal infections with localized endemicity (e.g. coccidioidomycosis and paracoccididioidomycosis in the Americas) need the same approach as for the already-​mentioned tuberculosis, supplemented as appropriate by serology for certain mycoses, CT scanning, or bronchoscopic samplings for microscopy and culture. A prominently productive cough usually suggests bronchial dis- order, such as bronchiectasis or others as just described. In bacterial infection, sputum changes colour to yellow or green owing to the presence of granulocytes and neutrophil myeloperoxidase (green); brown or rusty-​coloured sputum is seen in pneumococcal pneu- monia; frank pus may be expectorated in cases of lung abscess or bronchiectasis. Parenchymal lung disease may also cause productive cough, as in mucinous adenocarcinoma or tuberculosis. Experienced clinicians recognize that pneumonia may occur without cough and often without sputum, and where the clinical picture is dominated by systemic disturbance (fever, chills, anorexia, or confusion in older people), and with or without other respiratory symptoms such as pleuritic pain or breathlessness. In some pneu- monias (e.g. pneumocystis in the immunosuppressed), breathless- ness is regularly the cardinal respiratory symptom. Cough, despite the predominance of airways receptors in its production, can be an important and distressing feature of paren- chymal lung disease such as idiopathic pulmonary fibrosis, when opioids may provide the most useful relief. Cough may also feature in pleural effusion or pneumothorax, perhaps because of the bron- chial distortion caused. Haemoptysis Haemoptysis is a frightening symptom, hence presentation to the physician is often rapid, albeit that the amount of blood is frequently overestimated by the patient. Careful enquiry will almost always exclude epistaxis, haematemesis, or other upper airway bleeding (gums, pharynx). There are several important causes (Table 18.2.3). In developing countries, tuberculosis and AIDS-​related diseases are the commonest causes, whereas in industrialized nations these are lung cancer, bronchiectasis, infection, and pulmonary embolism. Haemoptysis can occur in simple bouts of acute infective bronchitis, and is a well-​recognized feature of pneumonia, as may occur for in- stance with pneumococcal or klebsiella infection. Haemoptysis, often periodic and coinciding with infective exacerbation, is a common feature of bronchiectasis. Though the bleeding can be relatively pro- fuse, it almost invariably subsides spontaneously and quickly with antibiotic treatment. Haemoptysis is an important presenting feature of carcinoma of the bronchus, tuberculosis, or pulmonary embolism, when the quantity of blood per se may not be impressive. If haemoptysis occurs without clinical features of acute bron- chial or pulmonary infection, clinical review needs to be followed by definitive investigation. A CT pulmonary angiography will prove or exclude pulmonary embolism; it will give some clear indication whether carcinoma or tuberculosis are likely, indicating the need for proceeding to bronchoscopy or microscopy for mycobacteria in sputum. The CT can also identify or suggest other rarer diagnoses such as pulmonary arteriovenous malformation, or some forms of pulmonary vasculitis (e.g. polyangiitis with granulomatosis, where pulmonary nodules with or without cavitation may be shown). Diagnosis of Goodpasture’s syndrome or lupus depends on clinical suspicion, and serology for antiglomerular basement membrane (anti-​GBM) and antinuclear autoantibodies. Table 18.2.2  Causes of cough Cause Example Upper airway Inhaled foreign body Paranasal sinus disease Upper respiratory tract infection Upper respiratory tract tumour Airways disease Asthma Cough variant asthma Lung disease Bronchial carcinoma or adenoma Inflammatory parenchymal lung disease (e.g. sarcoidosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis) Inhalation of noxious fumes or gases Pneumonia (some) Gastro-oesophageal reflux Medication ACE inhibitors Functional

Section 18  Respiratory disorders 3950 In massive haemoptysis, immediate resuscitation is paramount, and treatment may run concurrently with or precede definitive in- vestigation. While blood loss can be substantial, the greatest risk is from asphyxiation owing to widespread clotting of blood in the air- ways rather than blood loss per se, and efforts should be made to prevent blood flooding the unaffected lung. This is best performed, where available, via rigid bronchoscopy under general anaesthetic, allowing the use of topical vasoconstrictors or of balloon tam- ponade. In practice this is rarely immediately available, and large volume blood loss can make visualization virtually impossible. Double lumen endotracheal tubes allow isolation of the affected lung, and where bleeding does not settle, radiological therapeutic embolization of a bronchial artery or arteriovenous pulmonary mal- formation can be performed as appropriate or, in extremis, surgical resection of the bleeding lobe. Chest pain Pain associated with respiratory disease is usually pleuritic in na- ture. Caused by inflammation or irritation of the parietal pleura (the visceral pleura is insensate), it is sharp and ‘catching’ in nature, and made worse by anything that increases pleural friction (e.g. deep inspiration, coughing). Most often that irritation arises from lung disease with extension to the pleura—​infection, infarction, tumour—​but primary pleural disease is also seen—​infection (e.g. from subdiaphragmatic or blood-​borne spread), asbestos (inflam- matory effusions and mesothelioma), tumour (e.g. metastatic from breast or other cancer), serositis (in lupus or rheumatoid disease), trauma (fractured rib, pneumothorax and its tube drainage). Pleuritic pain, with audible pleural rubs on auscultation (Table 18.2.4), occurs with or without the presence of pleural fluid. By contrast, pleural effusions resulting from transudation from oe- dematous lungs in heart failure produce neither pleuritic pain nor audible rub, hence their presence under such circumstances sug- gests compounding disorder such as pulmonary embolism and infarction. Pleuritic pain needs to be distinguished from chest wall pain due to injury of the ribs, or associated muscles from unusual use, trauma, or from forceful repeated coughing. Such chest wall pain can cause diagnostic confusion, particularly when cough is a prominent fea- ture. The absence of audible pleural rub and of pleural effusion, to- gether with marked localized tenderness on palpation at the site of the pain, suggests chest wall disorder. In Bornholm’s disease (epidemic pleurodynia due to Coxsackie virus strains B1–​5) there is pleuritic-​type pain with accompanying malaise and fever and marked local chest tenderness, but normally no audible rub. Chest pain of a nonpleuritic type is not often a feature of lung disease. The exceptions are when tumour invades sensitive tissues in the thorax to cause a dull but often severe pain, and sarcoidosis, where inexplicable fleeting chest pains often occur. Other symptoms Respiratory disease may also present with nonthoracic symptoms, and the dominant features vary. Examples include constitutional symptoms (chills and prostration in pneumonia; fever and sweati- ness in thoracic empyema; drowsiness, headache, and fatigue in respiratory failure; daytime somnolence in sleep apnoea); gastro- intestinal symptoms (anorexia and weight loss in lung cancer and tuberculosis); neurological symptoms (headache, weakness, seiz- ures, or cerebellar signs in cerebral metastases; neuromuscular disorder in lung cancer or respiratory muscle weakness; seizure and hyponatraemia in inappropriate antidiuretic hormone syn- drome); musculoskeletal symptoms (underlying connective Table 18.2.4  The onset and duration of different causes of pleuritic pain Onset Cause Acute (respiratory) Costochondritis Muscular pain Pleural infection Pneumonia Pneumothorax Pulmonary embolism Rib fractures Acute (other) Angina Aortic dissection Gastro-​oesophageal reflux Myocardial infarction Oesophageal rupture Pericarditis Sickle cell crisis Chronic Autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis) Benign musculoskeletal pain Malignant pleural disease Pleural infection Recurrent pulmonary embolism Sarcoidosis (often flitting) Table 18.2.3  Causes of haemoptysis Cause Examples Infection Abscess Acute purulent bronchitis Aspergillus and other fungi Bronchiectasis Pneumonia (typical and atypical) Tuberculosis (active and inactive) Malignancy Benign tumours and adenoma Carcinoid tumour Karposi’s sarcoma in AIDS Lung cancer Pulmonary and bronchial metastases Vasculitides Churg–​Strauss Goodpasture’s syndrome Lung transplant rejection (capillaritis) Polyangiitis with granulomatosis Systemic lupus erythematosus Cardiovascular Heart failure with pulmonary oedema Mitral stenosis Pulmonary arteriovenous malformations Pulmonary embolism Clotting disorders Anticoagulation Disseminated intravascular coagulation Haemophilia Thrombocytopaenia Other Endometriosis Foreign body aspiration Iatrogenic (transbronchial biopsy; surgery) Idiopathic pulmonary haemosiderosis Trauma (inhalation; contusion)

18.2  The clinical presentation of respiratory disease 3951 tissue or collagen vascular diseases in interstitial lung disease); and dermatological manifestations, which may present before re- spiratory symptoms become evident (e.g. erythema nodosum in sarcoidosis). Other features of the history Past medical history The past medical history should include questions on premature birth (bronchopulmonary dysplasia), a history of childhood asthma or atopy, recurrent infections, connective tissue disease, previous cancers, cardiac disease, allergies, previous thoracic and gastro- intestinal surgery, as well as nasal polyps and other upper airway pathology. Recent surgery or immobilization predisposes to venous thromboembolism. Cigarette smoking can have devastating results on respiratory health, pulmonary disease and emphysema, and lung cancer. Evidence for inherited disease may emerge from the family history. Affected siblings with premature emphysema due to α1-​ antitrypsin or with cystic fibrosis exemplify autosomal recessive disease. Dominant inheritance, but with variable penetration of disease, can sometimes be traced in deep vein thrombosis and pul- monary embolism—​for example, resistance of coagulation factor V to protein C inhibition (factor V Leiden). Atopic asthma with rhin- itis and eczema is a common polygenic clinical complex which can show familial aggregation. It is important to consider environmental respiratory disease due to exposures at work and home. Such factors include: contact with others with respiratory infection (e.g. tuberculosis, mycoplasma, in- fluenza); place of residence or travel predisposing to acquisition of infections such as coccidioidomycosis, legionella, and tuberculosis; the presence at home of pet animals (e.g. cats and dogs) which can trigger asthmatic reactions or underlie hypersensitivity pneumon- itis (e.g. psittacines or pigeons). A thorough history of occupational exposures is required, and prompting is often needed for jobs performed years previously. Asbestos causes inflammatory effusions, benign pleural thickening, mesothelioma, pulmonary fibrosis, and carcinoma of the bronchus. Coal and stone mining cause pneumoconiosis and silicosis. Several inorganic agents (e.g. isocyanates, acid anhydrides) and organic agents (e.g. bread flour, antibiotics) can cause occupational asthma; beryllium exposure in electronics manufacturing causes sarcoid-​ like granulomatous disease; acute isocyanate exposures can cause pulmonary oedema. Spores from thermophilic bacteria and fungi on vegetable matter are an important agricultural cause of hypersen- sitivity pneumonitis (e.g. farmer’s lung). Industrial accidents include inhalation of noxious gases and fumes. Medication history Previous or current drug use—​prescribed, or otherwise—​can be an important cause of lung symptoms and diseases, notably cough, interstitial disease, and bronchospasm. β-​adrenergic blockers ex- acerbate asthma, sometimes catastrophically. Aspirin and non-​ steroidal inflammatory drugs can cause asthma and rhinitis in susceptible individuals, thought to be caused by an anomaly in the arachidonic acid metabolizing cascade and increased production of pro-​inflammatory cysteinyl leukotrienes. Chemotherapy agents and immunosuppressive or anti-​inflammatory regimens (e.g. bleomycin, tyrosine kinase inhibitors, methotrexate) can cause or exacerbate diffuse lung diseases, or can predispose to both pathogenic and op- portunistic pulmonary infections (e.g. prolonged high-​dosage cor- ticosteroids and pneumocystis, anti-​TNF therapy and tuberculosis). Drugs (e.g. dapsone, isoniazid) as well as parasitic worms can cause pulmonary eosinophilia syndromes, and interstitial changes can be seen with some cardiac drugs (e.g. amiodarone, statins). Use of illicit drugs must also be considered. They may cause in- jury directly, as seen in smoking of marijuana (bullous emphysema) and crack cocaine (interstitial disease, or ‘crack lung’), and sedatives causing respiratory failure, or by association (e.g. intravenous drug abuse with dirty needles causing lung abscess by haematogenous spread, or opportunistic infections in those with advanced HIV). A thorough drug history includes over-​the-​counter or homeopathic preparations (e.g. St John’s Wort), and oxygen therapy (long-​term and ambulatory). Clinical examination The purpose of physical examination is to elicit signs of disease. The underlying diagnosis is often evident from thorough h istory taking, and signs can be observed from the moment the patient comes into view. Observations such as obesity, cachexia, obvious skeletal de- formities, and the smell of cigarette smoke are all instantly apparent. Immediate pointers to respiratory disorder, whatever its origin, are repeated cough, wheeze, or stridor, painful breathing, laboured or ineffective breathing, or evident cyanosis. A thorough physical examination of the patient using a systematic approach is essential. Accurate monitoring and documentation of respiratory rate, pulse rate, and temperature are essential for any pa- tient who is acutely unwell. The sputum pot can be inspected for the colour, consistency and (in some cases) smell of the sputum therein. The four basic procedures of respiratory examination are inspection, palpation, percussion, and auscultation. Inspection The trachea and lymph nodes are better assessed by palpation, but obvious abnormalities such as a tracheostomy, substantial tracheal tug, or massive lymphadenopathy are apparent on observation. Other signs include engorgement of veins in the neck and superior chest accompanying superior vena cava obstruction; poor dentition is especially relevant when considering pleural infection; conjunc- tival pallor of anaemia; Horner’s syndrome (ptosis, meiosis, and anhydrosis), a rare accompaniment to respiratory disease but one that can occur in Pancoast’s tumour or as a rare complication of intercostal tube insertion. Breathing pattern The use of accessory muscles of respiration is seen when diaphragm function is insufficient to maintain adequate airflow, and is classic- ally seen in patients with severe airflow obstruction (chronic ob- structive pulmonary disease, asthma). Accompanying signs include a barrel-​shaped chest; reduced cricosternal distance; tracheal tug on inspiration; purse-​lipped breathing (airway splinting by creating positive expiratory airway pressure); prolonged expiration. The dia- phragm, already flattened by hyperinflated lungs, may even reduce

Section 18  Respiratory disorders 3952 the intrathoracic volume by pulling in the lower ribs to which it at- taches (Hoover’s sign). Inspiratory stridor and supraclavicular recession are seen in sig- nificant obstruction of the larger airways or larynx, either acute (epiglottitis, inhaled foreign body, laryngeal oedema) or chronic (intra-​ or extraluminal growths). Fast, deep breathing is consistent with severe pneumonia, other inflammatory parenchymal lung disease (diverse alveolitides), pul- monary embolism, or pulmonary oedema. Waxing and waning of respiratory rate and volume, and including spells of apnoea, can occur in severe heart failure, in neurological disease, or at high alti- tude (Cheyne-​Stokes breathing). A patient’s insistence on sitting upright is a regular feature of heart failure with pulmonary oedema (limiting dependent alveolar oe- dema to the lower zones of the lungs) or severe asthma or chronic obstructive pulmonary disease (gaining mechanical advantage by fixing the upper thorax with rigid arms clutching the bedside). By contrast, many patients with pulmonary embolism and inflamma- tory lung disease (pneumonia, interstitial disease) seem ready to lie fairly flat on their back or side. The classic deep, laboured, sighing breathing of Kussmaul res- piration is characteristic of metabolic acidosis, while shallow, often erratic, respiration is seen in states of anxiety or dysfunctional breathing. The presence of abdominal paradox indicates significant dia- phragm weakness (e.g. neuromuscular disease, neuropathy in lupus, the inherited myopathy of Pompe’s disease), and usually requires both hemidiaphragms to be affected. Cyanosis Cyanosis is a blue discoloration of the skin (especially nail beds, ear lobes, and lips) and mucous membranes of the mouth, tradition- ally said to occur when there is greater than 5 g/​dl of deoxygenated haemoglobin in the blood, but can be seen at levels lower than this. It indicates a failure of oxygenation through a variety of circula- tory, ventilatory, neurological, or haematological causes, although is often not seen until the blood oxygen saturations drop below 85%. Polycythaemia and anaemia, respectively, increase and decrease the likelihood of visible cyanosis for any degree of hypoxaemia, and significant hypoxaemia can occur without clinically detectable cyanosis, emphasizing the value of simple pulse oximetry as part of the examination. Central cyanosis is a more reliable sign of poor blood oxygenation than peripheral cyanosis, which can occur when there is poor peripheral circulation alone. In chronic respiratory disease, where breathlessness and disability are to be assessed, walking with the patient and observing exercise tolerance and distress can provide particularly valuable information. This can be supplemented by recording the haemoglobin–​oxygen saturation by simple pulse oximetry before, during, and after some modest exercise in the clinic room. An uncommon but important cause of cyanosis is methaemo- globinaemia, due to oxidation of haemoglobin by a variety of drugs, or due to inherited haemoglobin M or deficiency of meth- aemoglobin reductase. Methaemoglobin binds oxygen poorly and can lead to symptoms of hypoxaemia, with fatigue and dizziness, which can be treated by intravenous methylene blue (depending on cause). Extrapulmonary features Impairment of cerebral function Just as significant hypoxaemia can occur without evident cyanosis, it is important to realize that respiratory failure can present as a torpid or drowsy state, and without clear respiratory distress—​as in severe chronic obstructive pulmonary disease, asthma, sedative overdose, brain stem disorders and encephalitis, neuromuscular disorder, and extreme obesity. Arterial blood gases are therefore a vital investiga- tion in the torpid or drowsy patient, providing vital information on possible respiratory failure or metabolic acidosis. Cerebral disturb- ance as the presenting feature in respiratory failure is one important example of unexpected presentation. Peripheral stigmata The hands can be a tremendous source of clinical signs in respiratory disease. Clubbing (Table 18.2.5) may occur without the presence of disease, but about half of all cases are seen in patients with non-​ small cell lung cancer. In hypertrophic pulmonary osteoarthropathy (clubbing, periostitis of the long bones, and arthritis) patients pre- sent with clubbing and sore ankles or wrists. Unilateral wasting of the thenar eminence is seen in apical lung tumours involving or compressing the brachial plexus (Pancoast’s Table 18.2.5  Causes of clubbing Respiratory Cardiovascular Gastrointestinal Haematological Other Chronic suppurative lung disease Cyanotic congenital heart disease Inflammatory bowel disease Hodgkin’s lymphoma Idiopathic empyema Subacute bacterial endocarditis Cirrhosis of the liver CML Hereditary bronchiectasis Atrial myxoma Hepatopulmonary syndrome Myelofibrosis Thyroid acropachy cystic fibrosis Coeliac disease Axillary artery aneurysm lung abscess Tropical sprue Secondary hyperparathyroidism tuberculosis Hepatocellular carcinoma Pachydermoperiostitis Pulmonary fibrosis Pregnancy Yellow nail syndrome Oesophageal cancer Mesothelioma AV malformations Note—​There are many other causes of clubbing that appear in the literature, but the main causes are listed here.

18.2  The clinical presentation of respiratory disease 3953 tumour), whereas bilateral signs point to underlying neuromuscular conditions (respiratory muscle weakness, aspiration). The skin should be examined for rashes associated with respira- tory disease (Table 18.2.6), and the legs for erythema nodosum (tu- berculosis, sarcoidosis), oedema (right heart disease), and unilateral swelling (DVT). Hyperpigmentation of the lower thighs may be seen in those with severe emphysema (Dahl’s sign), owing to pressure from the arms when the patient is in the ‘tripod’ position. A crude assessment of gas exchange can be made by measuring the oxygen saturations and observing for asterixis (the flap of carbon dioxide retention). Orthopnoea is usually readily elicited, and measuring the saturations with the patient both supine and erect may detect platypnoea and orthodeoxia, seen in a variety of cardiac, pulmonary, or hepatic diseases where there is right to left shunting that is more marked in the upright position (although a rare phe- nomenon). Other peripheral stigmata are listed in Table 18.2.7. Skeleton and muscles Signs may include kyphoscoliosis as the basis of respiratory failure; immobile stiff neck and back of ankylosing spondylitis as the basis for progressive upper lobe fibrosis; stiff and deformed joints of the hand in rheumatoid disease as the basis for pulmonary nodules, fibrosing alveolitis, and pleural effusion; muscle wasting and weakness from motor neurone disease as the basis of respiratory failure; diplopia and muscle fatigability of myasthenia as the basis for respiratory Table 18.2.6  Skin manifestations of respiratory diseases Disease Skin manifestation Allergy and anaphylaxis Urticaria Arteriovenous malformations Telangectasia Dermatomyositis Heliotrope rash Eczema Red bumpy rash becoming scaly and dry Illicit drug use Scarred veins of forearms (and elsewhere) Lung cancer Palpable nodules Neurofibromatosis Cafe-​au-​lait spots; neurofibromas Paracoccidioidomycosis Violaceous facial lesions Pneumonia (esp. Mycoplasma) Erythema multiforme Pneumothorax Subcutaneous emphysema Psoriasis Plaques Rheumatoid arthritis Nodules; livedo reticularis; vasculitic rash Sarcoidosis Erythema nodosum; lupus pernio Scleroderma Telangiectasia; sclerodactyly SLE Malar rash; discoid lesions Tuberculosis Erythema nodosum; lupus vulgaris Tuberous sclerosis Shagreen patches; ash-​leaf spots; adenoma sebaceum Vasculitis Purpuric rash; palpable purpura Table 18.2.7  Peripheral signs in respiratory disease Hands Face Neck Legs Sign Association Sign Association Sign Association Sign Association Tar staining Smoking Central cyanosis Hypoxaemia Lymphadenopathy Malignancy; infection (tuberculous, viral) Oedema Right heart failure, hypoproteinaemia Clubbing see Table 18.2.5 Conjunctival pallor Anaemia Elevated jugular venous pulse Cor pulmonale Erythema nodosum Tuberculosis, sarcoidosis Peripheral cyanosis hypoxaemia Horner’s syndrome Pancoast’s tumour; trauma Suprasternal notch scar Previous mediastinoscopy Unilateral swelling Venous thromboembolism Small muscle wasting Neuromuscular disease; Pancoast tumour Pharyngeal injection Infection, HIV seroconversion Supraclavicular scar Phrenic nerve crush (tuberculosis) Dahl’s sign (darkened and thickened skin on lower thighs and elbows) Emphysema Asterixis carbon dioxide retention Malar flush Systemic lupus erythematosis; mitral stenosis Tremor anxiety states Parotid enlargement Uveoparotid fever (Herefordt’s syndrome) (sarcoidosis) Koilonychia Iron deficiency anaemia Microstomia Systemic sclerosis Leukonychia Protein deficiency (pleural effusions) Xerostomia Sjorgren’s syndrome Raynaud’s phenomenon Connective tissue diseases Oral telangiectasia Hereditary haemorrhagic telangiectasia Sclerodactyly Systemic sclerosis Nasal crusting Granulomatosis with polyangiitis Joint deformity Rheumatoid arthritis Saddle nose Granulomatosis with polyangiitis; polychondritis

Section 18  Respiratory disorders 3954 failure. A full neurological examination is essential where there are signs or symptoms of respiratory muscle weakness. Cardiovascular signs The heart and lungs are intimately connected, and disease in one organ not infrequently produces effects in the other. Specific cardiac examination findings can help determine the presence of, or indicate the severity of, respiratory disease. Other than findings associated with left ventricular dysfunction (pulmonary oedema, third heart sound), and perhaps with the exception of mitral stenosis in cases of haemoptysis (owing to pulmonary venous hypertension), most signs in respiratory disease relate to the development of right heart dysfunction or pulmonary hypertension (Table 18.2.8). One should also look for signs of deep vein thrombosis as the origin for pul- monary embolus. Palpation The neck is examined for lymphadenopathy, tracheal deviation (best assessed at the suprasternal notch), and the carotid pulsation. Aside from examination of areas of pain or tenderness (rib fracture, cough trauma, vertebral collapse), or obvious or patient-​reported lumps, the palpation of the chest is divided predominantly into the assessment of expansion and detection of chest wall vibrations (transmission of the voice, or fremitus). The hemithorax with dis- ease always expands less than the healthy hemithorax. Anything between the lung and the chest wall (air, fluid, or solid) will de- crease the transmission of vibrations to the chest wall, while con- solidated lung increases transmission and hence the detection of vocal fremitus. The same information can be obtained during aus- cultation by the assessment of vocal resonance. Palpation of the heart can reveal displacement of the apex beat, ventricular heaves, and valvular thrills. In women, a thorough breast examination is essential in cases of pleural effusion or lung masses, and abdominal examination can be useful in selected cases. Percussion Percussion is a simple but valuable clinical technique, at its best in defining a region of intense thoracic dullness and thereby indicating a pleural effusion, haemothorax, or empyema. It can also suggest, with variable accuracy, the presence of pneumo- thorax with resonant percussion note, or lobar collapse or con- solidation with dull percussion note. Pneumonic lung, while being largely solid with fluid, still retains some aeration in most cases and is therefore less dull than in effusion. Percussion of the heart pro- vides information about displacement, enlargement (dilatation or pericardial effusion), and pneumopericardium (diminished area of cardiac dullness). Auscultation Auscultation is essential to establishing a secure clinical diagnosis. It should, however, be recognized that several important lung diseases do not produce auscultatory signs. In some this relates to their early phase (e.g. bronchial carcinoma); in others it typifies the diseases through their course (e.g. sarcoidosis, diverse nodular lung diseases as opposed to diffuse or segmental disorders, some diffuse pneumo- nias such as pneumocystis, and tuberculosis). Findings on clinical examination can be unreliable in small to moderate pneumothorax and in pulmonary embolism. There are three general categories of sound that should be listened for, namely breathing sounds, pleural sounds, and the quality of the transmitted voice. Breath sounds There are two distinct sounds heard during respiration in the healthy chest. Bronchial breath sounds can be heard over the trachea and large airways in areas where there is little or no lung interspersed between the airways and the chest wall. They tend to be of a similar duration in both inspiration and expiration, and there is a distinct gap between the two when auscultating. Bronchial breathing heard anywhere other than as just described indicates a loss of alveolar in- tegrity such that large airway sounds are transmitted unchanged. This can occur in lung collapse, consolidation, cavitary disease, pneumothorax, occasionally over the upper regions of pleural ef- fusions (when it does not necessarily imply underlying consolida- tion), and over small areas of lung in gross pulmonary oedema or pulmonary fibrosis. Vesicular breath sounds are heard over most of the lung fields, the large volume of air in the lungs dampening the transmission of sound. They are longer and louder on inspiration than expiration, continuous in nature, louder towards the bases, and are quieter and lower pitched than bronchial sounds. Breath sounds may be globally reduced in chronic obstructive pulmonary disease and severe asthma. Regions of quiet sounds are important and can denote partial obstruction of the bronchus to the region (when no other signs may be found), an underlying large bulla in emphysema, pulmonary collapse, or pleural effusion. The quality of the transmitted voice can help distinguish these causes. Abnormal breath sounds are known as adventitious sounds. Crackles (rales, crepitations) are short, nonmusical sounds, and are described as fine or coarse. Parallel information from the history and other physical and radiographic signs are often required to help determine a diagnosis. Fine, or dry, crackles are often said to sound like Velcro, and are produced when diseased distal airways and alveoli ‘snap’ open. Of short duration, they are heard only during inspiration. They clas- sically occur (usually bilaterally) over areas of pulmonary fibrosis (often late and very fine; <10 ms). In some severe cases of fibrosis and adult respiratory distress syndrome, short musical sounds on inspiration (squawks), can accompany the crackles. Coarse, or wet, crackles are generated by fluid-​filled alveoli, can be heard in inspiration and expiration, are of a lower pitch, longer duration (close to 20 ms), and are louder than fine crackles. They are heard predominantly in pulmonary oedema, pneumonia, and Table 18.2.8  Cardiac signs in respiratory disease Pansystolic murmur of tricuspid regurgitation Diastolic murmur of pulmonary regurgitation Split second heart sound Loud pulmonary component of second heart sound Right ventricular third heart sound Elevated jugular venous pressure (JVP) Prominent a and v waves in JVP Right ventricular parasternal heave

18.2  The clinical presentation of respiratory disease 3955 bronchiectasis, but occur in any situation where there is excess fluid in the airways. Wheeze is a high-pitched, continuous sound with a whistling quality, (always >80 ms and usually >250 ms) generated by turbulent air travelling through the narrowed airways. It is often considerably more pronounced on expiration, as the negative intrathoracic pres- sure generated during inspiration helps to maintain airway patency. Polyphonic wheeze consists of several differently pitched sounds produced by airways of different calibres and is the classical finding in acute asthma, although certainly not unique to this diagnosis. A monophonic wheeze suggests a single airway is narrowed, usually by tumour (malignant or benign). Rhonchi are low-​pitched wheeze-​ like sounds produced in the larger airways, and often have a gurgling or rattling quality. Stridor is a loud, high-​pitched, continuous inspiratory sound that indicates upper airway obstruction. It should prompt urgent further investigations to establish its cause. Pleural sounds Anything which interrupts the normal smooth gliding action of the parietal pleura over the visceral pleura will create friction between the two surfaces. This can be heard as a pleural rub, a dry rubbing or crunching sound during respiration often likened to the sound made when walking in crisp snow, or the creaking of leather. Pleural inflammation, tumour, pulmonary embolus, and infection can all cause rub which is often heard only in a small part of the chest, is not modified by cough, and can vary hour by hour or day by day throughout the course of disease. Vocal sounds Vocal resonance is the auscultatory equivalent of tactile vocal fremitus, but tends to allow for easier detection of changes, espe- cially when subtle. The significance of changes in vocal resonance parallel those of vocal fremitus, with an increase of consolidation and a reduction when anything is interposed between the lung and the chest wall (air, fluid, solid material). The normal voice has a muffled quality, while being transmitted clearly through consolidated lung. Initial investigations A plain posteroanterior (PA) chest radiograph is an essential ad- junct to early diagnostic assessment in the medical admissions unit or specialist chest clinic, but note that practice varies; in rural and poor global settings, for instance, microscopy of sputum for myco- bacteria is used efficiently instead of radiology in the detection of endemic tuberculosis. In dealing with any patient who is acutely unwell, pulse oxim- etry and (in most cases) arterial blood gas analysis (see deceptive clinical features of respiratory failure, earlier) should be performed. A haemoglobin–​oxygen saturation lower than 94% signifies clinic- ally significant hypoxaemia. Beware carbon monoxide poisoning with tissue hypoxaemia but normal pulse oximetry. Peak expiratory flow measurement is an essential adjunct in acute asthma. In the clinic, well-​conducted but simple spirometry pro- vides an excellent and objective assessment of diverse obstructive and restrictive respiratory disorders, comparing the forced expiratory volume in one second and the forced vital capacity (FEV1 and FVC) to predicted values according to age, gender, height, and ethnic origin. Repeated spirometry can provide the basis for assessing objectively the response to treatments. See Chapter 18.3.1 for further discussion. FURTHER READING Shah PL, et al. (2018). Essentials of Clinical Pulmonology. CRC Press. Von Leupoldt A, et al. (2009). Dyspnea and pain share emotion related brain network. Neuroimage, 48, 200–​6. Vyshedskiy A, et al. (2005). Transmission of crackles in patients with interstitial fibrosis, heart failure and pneumonia. Chest, 128, 1468–​74.