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304 Interstitial Lung Disease

gases. However, this schema may have more utility in the emer­ gency department than in the outpatient setting. TREATMENT OF ACUTE EXACERBATIONS Bronchodilators  Typically, patients are treated with inhaled beta agonists and muscarinic antagonists. These may be administered separately or together, and the frequency of administration depends on the severity of the exacerbation. Patients are often treated initially with nebulized therapy, as such treatment is often easier to administer in those in respiratory distress. It has been shown, however, that conversion to metered-dose inhalers is effective when accompanied by education and training of patients and staff. This approach has significant economic benefits and also allows an easier transition to outpatient care. Antibiotics  Patients with COPD are frequently colonized with potential respiratory pathogens, and it is often difficult to identify conclusively a specific species of bacteria responsible for a particu­ lar clinical event. Bacteria frequently implicated in COPD exacer­ bations include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Chlamydia pneumoniae; viral pathogens are also common etiologies of exacerbations. The choice of antibi­ otic should be based on local patterns of antibiotic susceptibility of the above bacterial pathogens as well as the patient’s clinical condition. Patients with moderate or severe exacerbations are usu­ ally treated with 5–7 days of antibiotics, even in the absence of data implicating a specific pathogen. Glucocorticoids  In patients admitted to the hospital, the use of systemic glucocorticoids reduces the length of stay, hastens recov­ ery, and reduces the chance of subsequent exacerbation or relapse. Current recommendations suggest 40 mg of oral prednisone or its equivalent typically for a period of 5 days. Hyperglycemia, particu­ larly in patients with preexisting diagnosis of diabetes, is the most frequently reported acute complication of glucocorticoid treatment. Oxygen  Supplemental O2 should be supplied with a target oxygen saturation of 88–92%. Studies have demonstrated that in patients with both acute and chronic hypercarbia, the administration of supplemental O2 does not reduce minute ventilation. It does, in some patients, result in modest increases in arterial Pco2, chiefly by altering ventilation-perfusion relationships within the lung. This should not deter practitioners from providing the oxygen needed to correct hypoxemia. Mechanical Ventilatory Support  The initiation of noninvasive positive-pressure ventilation (NIPPV) in patients with acute respi­ ratory acidosis, defined as Paco2 >45 mmHg and pH ≤7.35, results in a significant reduction in mortality rate, need for intubation, complications of therapy, and hospital length of stay. Contraindica­ tions to NIPPV include cardiovascular instability, impaired mental status, inability to cooperate, copious secretions or the inability to clear secretions, or craniofacial abnormalities or trauma precluding effective fitting of the mask. Invasive (conventional) mechanical ventilation via an endotra­ cheal tube is indicated for patients with severe respiratory distress, hypoxemia, severe hypercarbia and/or acidosis despite noninvasive ventilation, markedly impaired mental status, respiratory arrest, hemodynamic instability, or other complications. The goal of mechanical ventilation is to correct the aforementioned conditions. Factors to consider during mechanical ventilatory support include the need to provide sufficient expiratory time in patients with severe airflow obstruction and the presence of auto-PEEP (positive end-expiratory pressure), which can result in patients having to generate significant respiratory effort to trigger a breath during a demand mode of ventilation. The mortality rate of patients requiring mechanical ventilatory support for a COPD exacerbation is 17–49% for that particular hospitalization. Owing to the high mortality of invasive mechani­ cal ventilation in COPD exacerbations, patient preferences for advanced directives (e.g., do not resuscitate) should be discussed

in the outpatient setting. Following a hospitalization for COPD, ~20% of patients are rehospitalized in the next 30 days and 45% in the next year. Mortality is ~20% in the year following hospital discharge.

Acknowledgment James Crapo and Barry Make contributed to this chapter in the 21st edition and some material from that chapter has been retained here. ■ ■FURTHER READING Agusti A, Hogg JC: Update on the pathogenesis of chronic obstructive Interstitial Lung Disease CHAPTER 304 pulmonary disease. N Engl J Med 381:1248, 2019. Celli CR, Wedzicha JA: Update on clinical aspects of chronic obstructive pulmonary disease. N Engl J Med 381:1257, 2019. Global Strategy for the Diagnosis, Management and Preven­ tion of COPD: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024. Available at http://goldcopd.org. Kheradmand F et al: Contribution of adaptive immunity to human COPD and experimental models of emphysema. Physiol Rev 103:1059, 2023. Lynch D et al: CT definable subtypes of COPD: A statement of the Fleischner Society. Radiology 277:192, 2015. Regan E et al: Clinical and radiologic disease in smokers with normal spirometry. JAMA Intern Med 175:1539, 2015. Sakornsakoplat P et al: Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations. Nat Genet 51:494, 2019. Sandhaus RA et al: The diagnosis and management of alpha-1 anti­ trypsin deficiency in the adult. Chronic Obstr Pulm Dis 3:668, 2016. Stanojevic S et al: ERS/ATS technical standard on interpretive strate­ gies for routine lung function tests. Eur Respir J 60:2101499, 2022. Stolz D et al: Towards the elimination of chronic obstructive pulmo­ nary disease: A Lancet Commission. Lancet 400:921, 2022. Gary M. Hunninghake, Ivan O. Rosas

Interstitial Lung Disease Diffuse parenchymal lung diseases include a large number (>200) of heterogeneous conditions that affect the lung parenchyma with varying degrees of inflammation and fibrosis. While remodeling of the intersti­ tial space, the region between the epithelium and endothelium, tends to be the dominant site of involvement for most of the interstitial lung diseases (ILDs), it is important to recognize the prominent role of the alveolar epithelium and endothelial cells (including both airways and vessels) in the pathogenesis of these ILDs. Despite the diverse array of conditions, most patients ultimately diagnosed with an ILD will come to medical attention with reports of progressive exertional dyspnea or a persistent dry cough. However, because some ILDs are part of multisystem disorders, some patients will be identified based on nonrespiratory symptomatology (e.g., skin thickening in the setting of systemic sclerosis, Chap. 372) or physical examination findings (e.g., ulnar deviation of the fingers in the setting of rheumatoid arthritis [RA], Chap. 370). Additionally, ILDs can also be identified incidentally based on the results of abnormal pulmonary function tests, chest x-rays (CXRs), and computed tomography (CT) studies of both the chest and abdomen (which can both visualize at least a portion, of the lung parenchyma), and positron emission tomography (PET) scans. It is important to remember that ILDs can be associated with high rates of morbidity and mortality, and although prognosis depends on both disease extent and specificity, this fact makes these important disorders to recognize in a timely manner.

TABLE 304-1  Common Interstitial Lung Disease (ILD) Findings NONSPECIFIC INTERSTITIAL PNEUMONIA   IPF Clinical symptoms Gradual onset of SOB, dry cough. More common in older adults. Subacute onset of SOB, dry cough. Frequently associated with other conditions. Physical exam findings Frequent rales at lung bases; digital clubbing is common. Frequent rales. Clubbing is less common. PART 7 Disorders of the Respiratory System Exposures Idiopathic but many exposed to smoke. Genetic findings may explain more than one-third of the risk of the disease. Can be idiopathic but should prompt consideration for associated conditions. HRCT findings Bilateral subpleural reticular changes most prominent in lower, posterior lung zones. Traction bronchiectasis and honeycombing common. Classic usual interstitial pneumonia (UIP) pattern is considered diagnostic. Peripheral subpleural ground-glass and reticular patterns. Traction bronchiectasis is common, but honeycombing is rare. HRCT not diagnostic. Histopathology UIP pattern including fibroblastic foci, temporal and spatial heterogeneity, honeycombing. Cellular or fibrotic pattern of NSIP. More uniform than a UIP pattern. Clinical course 50% 3- to 5-year mortality. 18% 5-year mortality. 25% 7-year mortality. 20–30% 10-year mortality. Generally low but varies by state. Abbreviations: HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; SOB, shortness of breath. Owing to a variety of clinical presentations, as well as overlapping imaging and histopathologic findings (Table 304-1), ILDs can be difficult to diagnose. A generally accepted central tenet of ILD diag­ nosis is that the combined weight of clinical data, laboratory studies, pulmonary function testing, imaging findings, and histopathology (if obtained) are jointly required to make a confident diagnosis. No sin­ gle piece of data confers a diagnosis alone. For example, a lung biopsy demonstrating the usual interstitial pneumonia (UIP) pattern is helpful in diagnosing a patient with idiopathic pulmonary fibrosis (IPF) but can also be present in some connective tissue diseases (CTDs) (e.g., RA-associated ILD, Chap. 370). In light of this challenge, most ILD centers recommend a multidisciplinary approach to the diagnosis (and, in some cases, the management) of ILDs. An example of a multidisci­ plinary approach is a conference attended by pulmonologists, rheuma­ tologists, radiologists, and pathologists where all of the data generated on a patient can be discussed and reviewed jointly by those with unique sets of expertise in the care of patients with ILD. While there are numerous ways to categorize the ILDs, one classic approach is to divide them into those of known and unknown causes (Fig. 304-1). Although even this approach has limitations (e.g., a grow­ ing number of genetic studies demonstrate that a significant portion of familial and sporadic pulmonary fibrosis or IPF may be explained, in part, by genetic factors), it is a useful place to start. Known causes of ILD include occupational exposures (e.g., asbestosis), medications (e.g., nitrofurantoin), and those related to an underlying systemic dis­ ease (e.g., cryptogenic organizing pneumonia [COP] in the setting of polymyositis). Unknown causes of ILD include groups of rare disorders often with classic presentations (e.g., a spontaneous pneumothorax in a young female with diffuse cystic changes on a chest CT might sug­ gest lymphangioleiomyomatosis [LAM]) and the most common group of ILDs, the idiopathic interstitial pneumonias (IIPs). Granulomatous lung diseases straddle both known (e.g., hypersensitivity pneumonitis [HP] due to chronic bird exposure, Chap. 299) and unknown (e.g., sarcoidosis, Chap. 379) causes and are often separated due to their unique presentations, imaging findings, and diagnostic evaluation.

RESPIRATORY BRONCHIOLITIS– ASSOCIATED ILD SYSTEMIC SCLEROSIS– ASSOCIATED ILD SARCOIDOSIS Can be asymptomatic, or have SOB and cough. Gradual onset of SOB, dry cough. Fatigue, tightening of skin, exaggerated cold response, reflux, and difficulty swallowing. Can be asymptomatic, or have SOB and cough. Can also have fatigue, palpitations, and eye, skin, and joint findings. Rales common. Clubbing is rare. Can have rales in isolation. Also skin thickening, joint swelling, and telangiectasias. Can be normal; rales may be present. Can have skin findings, joint pain, and enlarged lymph nodes. Strong association with smoking. Mostly unknown; some debate about solvent and silicate exposures. Mostly unknown, although silicate dusts thought to play a role in some cases. Diffuse patchy centrilobular ground glass nodules. Can have UIP or nonspecific interstitial pneumonia (NSIP) patterns, also dilated esophagus, occasional mediastinal calcifications, and pulmonary vascular enlargement. Can have mediastinal and hilar lymphadenopathy. Peribronchovascular reticular-nodular findings. Respiratory bronchiolitis with adjacent inflammatory and fibrosing changes. Pigment-laden macrophages. Both UIP or NSIP patterns can occur. Noncaseating granulomas. Equally important to knowledge of disease classification is knowledge of disease prevalence. Although there is variability within different demographic groups, most studies demonstrate that IPF, sarcoidosis (Chap. 379), and ILDs related to CTDs (Chap. 425) as a group are among the most common forms of ILD. DIAGNOSTIC APPROACH The initial diagnostic approach to diffuse parenchymal lung disease is often broader than a focus on ILD and should include an evalua­ tion for alternate causes, including cardiovascular disease (e.g., heart failure, Chap. 265), diffuse infections (e.g., pneumocystis pneumonia, Chap. 227), and malignancy (e.g., bronchoalveolar cell carcinoma). This chapter will focus on the diagnostic evaluation that helps to dis­ tinguish among the various forms of ILD. ■ ■HISTORY Age  The age of onset of clinical symptoms has a strong influence on the pretest probability that IPF, in particular, is present. For example, IPF occurs most commonly in patients aged >60 and is quite rare among patients aged <50. In fact, in patients aged >65 without strong evidence for an alternate diagnosis, atypical chest CT findings are still more likely to result in a histopathologic diagnosis of UIP (a pathologic hallmark of IPF) than they are to result in an alternate IIP diagnosis. Other common ILDs, such as sarcoidosis and CTD-associated ILD, and less common ILDs, such as LAM and pulmonary Langerhans cell histiocytosis (PLCH), tend to present between the ages of 20 and 40. Sex  Although less influential than age, sex has some influence on the likelihood of various ILDs. LAM (and the related disorder tuberous sclerosis) is a disorder that is frequently diagnosed in young women. Many CTD-associated ILDs are more common among women, except for RA-associated ILD, which is more common among men. IPF and occupational/exposure-related ILDs (likely due to work-related expo­ sures that tend to differ between men and women) are more common among men.

ILD of known cause ILD of unknown cause Systemic disease Exposure Occupational: Asbestosis Silicosis Connective tissue disease: Rheumatoid arthritis Scleroderma Polymyositis/ Dermatomyositis Treatment related: Radiation Methotrexate Amiodarone Nitrofurantoin Chemotherapeutics Granulomatous disease with vasculitis: Granulomatosis with polyangiitis Churg-Strauss Granulomatous lung disease: Sarcoidosis Hypersensitivity pneumonia FIGURE 304-1  Classification of interstitial lung disease. This algorithm represents a common approach to subclassifying the interstitial lung diseases. It is typical to divide the interstitial lung diseases into those of known and unknown causes (although it is important to note that genetic studies demonstrate that a significant portion of familial and idiopathic pulmonary fibrosis [classically described as diseases of unknown cause] may be explained, in part, by genetic factors). The idiopathic interstitial pneumonias were more precisely defined by a 2002 study as described in Am J Respir Crit Care Med 165:277, 2002, referenced in the Further Reading list. Duration of Symptoms  Acute presentations (days to weeks) of ILD are unusual and are commonly misdiagnosed as more com­ mon diseases such as pneumonia, a chronic obstructive pulmonary disease (COPD) exacerbation, or heart failure. ILDs that can present acutely include eosinophilic pneumonia, acute interstitial pneumonia (AIP), HP, and granulomatosis with polyangiitis (GPA). An acute exacerbation of IPF as the initial presentation of this disease should also be a consideration given its prevalence. ILDs most commonly have a chronic indolent presentation (months to years) typified by IPF. However, subacute presentations (weeks to months) can occur in most of the ILDs but, in the right context, could suggest sarcoidosis, CTDassociated ILD, drug-induced ILD, or COP. Respiratory Symptoms  Progressive dyspnea, most frequently noted with exertion, is the most common complaint in patients pre­ senting with an ILD. Despite this fact, both research studies of general population samples and clinical experiences of asymptomatic patient referrals with abnormal chest CT imaging patterns have also demon­ strated that some patients, even those with more extensive disease, may not report dyspnea. Cough, particularly a dry cough, is also common and can be the most prominent symptom in patients with IPF. Cough is often reported in other ILDs, particularly those with prominent airway involvement including sarcoidosis and HP. Cough with hemoptysis is rare and could suggest an ILD associated with diffuse alveolar hemor­ rhage (DAH) (e.g., Goodpasture’s syndrome), GPA, or LAM. Cough with hemoptysis could also suggest a secondary pulmonary infection that can be seen in patients with traction bronchiectasis and in those receiving immunosuppressive therapy. Chest pain is rare in most of the ILDs, with the exception of sarcoidosis, where chest discomfort is not uncommon. Fatigue is common to all of the ILDs. Past Medical History  The most pertinent history includes a per­ sonal history of a CTD or a history of symptoms commonly associated with a CTD (e.g., Raynaud’s phenomena). It is also important to remem­ ber that ILD associated with a CTD can be the initial presenting symptom of the disease and can precede the development of additional symptom­ atology by many years. A history of malignancy is important, because some malignancies can be associated with dermatomyositis-associated

Idiopathic interstitial pneumonias Other Idiopathic pulmonary fibrosis Interstitial Lung Disease CHAPTER 304 Nonspecific interstitial pneumonia Respiratory bronchiolitis—associated interstitial lung disease Desquamative interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Lymphocytic interstitial pneumonia Lymangioleiomyomatosis Pulmonary alveolar proteinosis Langerhan’s cell histiocytosis Pleural parenchymal fibroelastosis COP and sarcoid-like reactions. A history of asthma and allergic rhinitis might suggest a diagnosis of eosinophilic GPA. Medications  Many medications have been associated with ILD, and to complicate matters further, many medications commonly used to treat inflammatory and granulomatous lung disease are also associated with ILD development (e.g., methotrexate, azathioprine, rituximab, and the tumor necrosis factor α–blocking agents). Specific medications in many classes are also known to cause ILD, including antibiotics (e.g., nitrofurantoin), antiarrhythmics (e.g., amiodarone), and many of the antineoplastic agents (e.g., bleomycin). Family History  A family history of ILD (of almost any type) is important to ascertain. The percentage of pulmonary fibrosis that is familial, as opposed to idiopathic, varies by study, and could be as high as 20%. Despite the variability, most studies suggest the presence of a close relative with an IIP is among the strongest risk factors for IPF. Family studies have consistently noted familial aggregation of diverse forms of IIP (such as IPF, nonspecific interstitial pneumonia [NSIP], and desquamative interstitial pneumonia [DIP] running in the same family) and, in some cases, other forms of ILD. To date, the most wellreplicated genetic factors for pulmonary fibrosis (a promoter variant of a mucin gene [MUC5B]) and various genetic determinants known to influence telomere length (e.g., variants in the telomerase reverse tran­ scriptase gene [TERT]) (Chap. 495) appear to be associated with both familial and idiopathic forms of pulmonary fibrosis similarly. Social History  A history of smoking is nearly always present in some forms of ILD (e.g., respiratory bronchiolitis and DIP—sometimes referred to by pathologists jointly as smoking-related ILD) where it is felt to be causative. A history of smoking is also noted in approxi­ mately three-quarters of IPF patients. Occupational and environmental exposure histories are also important to obtain as they might identify exposures known to cause pulmonary fibrosis (e.g., significant asbestos exposure) or HP (pigeon breeder’s lung). ■ ■PHYSICAL EXAMINATION End-inspiratory fine crackles, or rales, noted at the lung bases are found in most patients with IPF and may be one of the earliest signs of

the disease. However, rales are nonspecific and can be found in many forms of ILD and other disorders. Wheezing is uncommon in most forms of ILD but can be present in some disorders, such as sarcoidosis, HP, and eosinophilic GPA. Signs of advanced disease include cyanosis, digital clubbing, and cor pulmonale.

■ ■LABORATORY STUDIES Laboratory studies can be particularly helpful in the workup for an underlying CTD-associated ILD. As noted previously, these tests can reveal the presence of an underlying CTD as the cause of an ILD (e.g., a positive anti-cyclic citrullinated peptide [anti-CCP] antibody for RA) even when no other symptomatology or physical examination findings suggestive of the disorder are present. However, the cost-effectiveness and the extent of laboratory testing that should be ordered in various clinical contexts have yet to be determined (as there is a relatively long list of autoantibody tests that could be ordered). PART 7 Disorders of the Respiratory System ■ ■PULMONARY FUNCTION TESTS Most forms of ILD will eventually result in a restrictive deficit in pul­ monary function testing. A restrictive deficit is typified by a reduced total lung capacity (TLC) and symmetrically reduced measures of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). A reduction in the diffusing capacity of the lung for carbon monoxide (DlCO) is also common and may precede a reduction in lung volumes; however, there is more measurement variability in DlCO measurement and the test is less specific for ILD. A reduced FEV1 to FVC ratio, which is diagnostic of airway obstruction, is unusual in many forms of ILD but can be present as an isolated finding or in conjunction with an additional restrictive deficit in ILDs involving the airways such as sarcoidosis, HP, and LAM. Although pulmonary function testing is rarely diagnostic, reductions in lung function help to characterize the extent of disease, and evidence for a decline in repeated measures of pulmonary function (e.g., FVC) has been correlated with an elevated mortality rate. ■ ■CHEST IMAGING STUDIES Chest X-Ray  Findings on CXR can be the first clinical indication that an ILD might be present. For example, enlarged hilar lymph nodes and a pattern of central nodular opacities in the mid to upper lung zones can suggest sarcoidosis. A basilar reticular pattern, with small cystic spaces, in the absence of clinical evidence for heart failure, might suggest IPF. With a few exceptions, CXRs alone rarely lead to a specific diagnosis. Chest CT  High-resolution CT (HRCT) chest imaging is now con­ sidered to be standard of care in the initial evaluation of a patient with a suspected ILD. HRCT can be diagnostic for some ILDs (e.g., IPF) in the right clinical context and may preclude the need for, and spare the patient the risk of, a lung biopsy. HRCT also helps to define the extent of the ILD, determine the presence of more concerning features sug­ gestive of advanced disease (e.g., honeycombing), provide information on coexisting diseases (e.g., emphysema and lung cancer), and when not diagnostic, provide the most useful locations for obtaining lung biopsy specimens. ■ ■LUNG BIOPSY Fiberoptic Bronchoscopy  A bronchoscopy can be helpful in establishing a specific ILD diagnosis, and can help to establish an alternate diagnosis, in select cases. Examination of serial lavage fluid can be helpful in establishing DAH, which can be present in ILDs with vasculitis (e.g., GPA), and in some cases, cellular examination can sug­ gest a specific diagnosis (eosinophilia >25% in chronic eosinophilic pneumonia or fat globules in macrophages in lipoid pneumonia). Transbronchial lung biopsies and lymph node biopsies (particularly in sarcoidosis) can lead to a confident diagnosis in patients with likely granulomatous lung disease (e.g., sarcoidosis and HP). However, in general, bronchoscopically obtained tissue samples are often felt to be insufficient to diagnose most of the IIPs. To date, studies have been mixed on whether bronchoscopically obtained cryobiopsies, which can

result in yields larger than those obtained by transbronchial forceps biopsies, could improve the diagnostic yield of bronchoscopy; however, the precise role of cryobiopsies in the diagnostic workup of ILD has yet to be determined. Surgical Lung Biopsy  A surgically obtained lung biopsy specimen can help solidify the diagnosis of ILD. In many cases, these are now obtained through a video-assisted thoracoscopic (VATS) approach (as compared to an open thoracotomy), which tends to reduce the length of operative times and hospital stays. The diagnostic yield of biopsies tends to be higher if obtained prior to treatment. The desire to obtain a surgical lung biopsy should be weighed against the risks, which can include a short-term mortality rate of as high as 5%. These risks are reported to be higher in biopsies of patients ultimately diagnosed with IPF and in those presenting acutely. ■ ■INDIVIDUAL FORMS OF ILD The ILDs include a diverse group of lung pathologies that can be subclassified into those disorders of unknown cause (e.g., IIPs) and those of known cause (e.g., sometimes referred to as secondary inter­ stitial pneumonias [CTD-associated ILDs]) (see Fig. 304-1). Although this remains a useful approach to classifying these disorders, it is important to recognize that genetic studies are challenging this clas­ sic categorization. For example, numerous ILDs commonly listed as having an “unknown cause” have been determined to have significant genetic underpinnings (e.g., IPF and LAM), while the pathophysiologic processes that result in ILDs of “known cause” (e.g., CTD) remain incompletely understood. Diagnosis is based on combined information obtained from a patient’s clinical presentation, measures of pulmo­ nary function, imaging, immune serologies, and histopathology. It is important to remember that prognosis and treatment vary widely by disorder (and disease extent). In some cases, medical therapy that is felt to be effective for some ILDs has been proven to be harmful for others. Medical treatments range from immune modulators to antifibrotic medications, whereas lung transplantation remains the standard of care for patients with advanced and rapidly progressive ILDs. IDIOPATHIC INTERSTITIAL PNEUMONIAS ■ ■IDIOPATHIC PULMONARY FIBROSIS Clinical Manifestations  IPF is the most common ILD of unknown cause. Prevalence increases with age and is estimated at 50–200:100,000. IPF is commonly diagnosed in the fifth or sixth decade of life, affects men more than women, and is frequently associ­ ated with a history of smoking or other environmental exposures. IPF is a variably progressive disease that carries a poor prognosis with an estimated 50% 3- to 5-year survival. HRCT Image Findings  Chest CT findings include subpleural reticulation with a posterior basal predominance usually including more advanced fibrotic features, such as honeycombing and traction bronchiectasis. Collectively, these imaging findings are referred to as a UIP pattern. The presence of extensive ground-glass opacities, bronchovascular changes, micronodules, mosaic attenuation, or an upper lung predominance should raise suspicion for an alternative diagnosis (Fig. 304-2). Histopathology  Diagnostic VATS biopsy findings include sub­ pleural reticulation associated with honeycomb changes and fibro­ blast foci (subepithelial collections of myofibroblasts and collagen). These fibrotic changes alternate with areas of preserved normal alveolar architecture consistent with temporal and spatial heteroge­ neity (Fig. 304-3). Collectively, these pathologic findings are referred to as UIP. Treatment  Historically, IPF was felt to be refractory to medical therapy, with lung transplantation the only viable therapeutic option. This dogma changed in 2014 with large clinical trials that demon­ strated that antifibrotic therapy (pirfenidone and nintedanib) can slow the decline of lung function in IPF patients. Further meta-analyses

A B C D FIGURE 304-2  Chest CT imaging and interstitial lung disease. A. Idiopathic pulmonary fibrosis (IPF): Classic findings of IPF (apparent on this image) include a posterior, basilar predominance of subpleural reticular markings and more advanced features of pulmonary fibrosis including traction bronchiectasis and honeycombing. This constellation of findings is often referred to as a usual interstitial pneumonia (UIP) pattern. B. Nonspecific interstitial pneumonia (NSIP): Chest CT findings of NSIP can overlap with those of a UIP pattern but tend to include a bilateral, symmetric pattern that presents with a greater percentage of ground-glass opacities than is apparent in a UIP pattern. Additional unique findings include more diffuse imaging abnormalities with a predominance not limited to the lung bases, imaging abnormalities that spare the subpleural regions, and thickening of the bronchovascular bundles (as is apparent in the right mid lung zone on this image). C. Cryptogenic organizing pneumonia: Chest CT findings include patchy, sometimes migratory, subpleural consolidative opacities (as is apparent on this image) often with associated ground-glass opacities. Peribronchiolar or perilobar opacities can be present, and sometimes a rim of subpleural sparing (often referred to as a reversed halo or atoll sign) can be seen, which can help to aid in the diagnosis. D. Sarcoidosis: Sarcoidosis can present with varied imaging abnormalities, but a pattern of mediastinal and hilar lymphadenopathy with a pattern of reticular-nodular opacities involving the bronchovascular bundles (apparent in this image) is a common feature. Additional findings can include diffuse small nodules in a miliary pattern, larger nodular opacities, extensive ground-glass infiltrates, and mosaic attenuation suggestive of small airways involvement, and, in more advanced cases, signs of pulmonary fibrosis. have suggested that antifibrotic therapy may also improve survival. More recent trials suggest that antifibrotic therapy may also be effective in other forms of progressive pulmonary fibrosis. In contrast, treat­ ment with immunosuppression, which had been commonly prescribed to many IPF patients, has been shown to be associated with increased morbidity and mortality. Physical therapy and supplemental oxygen, when indicated, can improve exercise tolerance and reduce the likeli­ hood of developing pulmonary hypertension. Lung transplantation can extend survival and improve the quality of life in a subset of IPF patients who meet the criteria to undergo transplant. ■ ■NONSPECIFIC INTERSTITIAL PNEUMONIA Clinical Manifestations  Idiopathic NSIP is a distinct clinical entity with characteristic clinical, radiologic, and pathologic features; however, NSIP is also commonly observed in patients with CTD and less frequently with familial interstitial pneumonia, drug toxicity, and infection. Although the prevalence of NSIP is not well established, it is commonly diagnosed in nonsmoking females in their fifth decade of life. Positive serologic tests for CTD are frequently observed. Idio­ pathic NSIP has a relatively good prognosis, with a 5-year survival of

80%; patients with a predominant cellular NSIP pattern have a more favorable prognosis than those with a fibrosing NSIP pattern. HRCT Image Findings  Diffuse subpleural, symmetric, groundglass, and reticular opacities are common. Volume loss and traction bronchiectasis involving the lower lung zones can also be found.

Interstitial Lung Disease CHAPTER 304 Occasionally subpleural sparing is noted, while peribronchiolar thick­ ening and honeycombing are uncommon. Histopathology  Diagnostic lung biopsy findings include vary­ ing amounts of interstitial inflammation and fibrosis with a uniform appearance. Honeycomb changes are usually absent, and fibroblast foci are rare. NSIP is often referred to histopathologically as being either predominantly cellular (and potentially more responsive to medical therapy) or fibrotic (and potentially less likely to resolve with medical therapy). Treatment  Pulmonary fibrosis associated with CTD is commonly treated with immunosuppression despite the paucity of randomized clinical trials to demonstrate efficacy. Idiopathic NSIP is often treated with oral steroids (prednisone), cytotoxic agents (mycophenolate, azathioprine, and cyclophosphamide), or biologics (rituximab and tocilizumab). Recent trials suggest that NSIP patients with progres­ sive pulmonary fibrosis may benefit from antifibrotic therapy. Oxygen therapy, pulmonary rehabilitation, and lung transplantation may be required in patients with progressive disease. ■ ■SMOKING-RELATED ILD Although smoking-related ILDs, including respiratory bronchiolitis with interstitial lung disease (RB-ILD), and DIP are frequently subclas­ sified with the IIPs, these disorders (along with PLCH, an ILD with unique clinical, imaging, and histopathologic manifestations) are com­ monly felt to be the result of active or prior tobacco smoke exposure.

A
B
PART 7 Disorders of the Respiratory System C
D
FIGURE 304-3  Histopathology of interstitial lung disease. A. Idiopathic pulmonary fibrosis (IPF): Histopathologic findings include subpleural reticulation associated with honeycomb changes alternating with areas of preserved normal lung architecture referred to as temporal and spatial heterogeneity (as is apparent in the low-power image above). Additional important diagnostic findings include fibroblast foci, which are subepithelial collections of myofibroblasts and collagen (as is apparent in the higherpowered inset of this image). Collectively, these pathologic findings are referred to as usual interstitial pneumonia (UIP). B. Nonspecific interstitial pneumonia (NSIP): Histopathologic findings of NSIP include varying amounts of interstitial inflammation and fibrosis with a uniform appearance (as is apparent in this image). Honeycomb changes are usually absent and fibroblast foci are rare. NSIP is often referred to histopathologically as being either predominantly cellular or fibrotic. C. Cryptogenic organizing pneumonia (COP): Histopathologic findings of COP include patchy regions of organizing pneumonia with granulation tissue that commonly involves the small airways, alveolar ducts, and alveoli with surrounding inflammation that can involve the alveolar walls (as is apparent in this image). D. Sarcoidosis: The hallmark histopathologic feature of sarcoidosis is presence of granulomas (as are apparent numerously in the low-powered image and more closely visualized in the higher-powered inset image). Typically, these are referred to as noncaseating, which suggests the absence of necrosis. Caseating granulomas are rare in sarcoid and should prompt additional evaluation for an underlying infection. Because malignancy can result in a granulomatous reaction, it is important to closely survey biopsy specimens with granulomatous involvement for additional signs of malignancy. DIP has also been known to occur in children with familial pulmonary fibrosis (FPF). Smokers, particularly elderly smokers, frequently have radiologic (centrilobular) interstitial abnormalities. These interstitial abnormalities are often incidentally found on routine CXR or chest CT studies in asymptomatic or minimally symptomatic individuals. Respiratory bronchiolitis is felt to correlate histopathologically with these imaging findings. However, in some cases, these imaging findings can progress to more advanced radiologic changes where more diffuse signs of interstitial pneumonia tend to be present. Clinical Manifestations  These disorders predominantly occur in active, and in many cases heavy, smokers who are typically between 40 and 50 years of age. In those ultimately diagnosed with RB-ILD or DIP, dyspnea and cough are relatively common and symptomatic wheezing is not rare. The prevalence of smoking-related ILDs is not well under­ stood, but they are generally felt to account for <10% of the IIPs. While there are minimal data on the natural histories and prognoses of these conditions, prolonged survival can be expected in most patients with RB-ILD and death secondary to progressive ILD is felt to be rare. HRCT Image Findings  Prominent and common findings in RBILD include central bronchial wall thickening, peripheral bronchial wall thickening, centrilobular nodules, and ground-glass opacities. Septal lines and a reticular pattern are also not uncommon. Honey­ combing is generally felt to be rare (and indicates a worse prognosis). Similar findings are noted in patients with DIP where diffuse (or patchy) bilateral symmetric ground-glass opacities tend to be even more prominent.

Histopathology  Common features of RB-ILD include the accu­ mulation of pigmented macrophages within the lumens of respiratory bronchioles and alveolar ducts, accompanied by chronic inflammation of the respiratory bronchiolar walls and both bronchiolar and peri­ bronchiolar alveolar fibrosis causing architectural distortion. These features are patchy and confined to the peribronchiolar region. DIP tends to include similar changes but has a more diffuse pattern charac­ terized by pigmented macrophage accumulation, pneumocyte hyper­ plasia, and prominent interstitial thickening. Treatment  Patients with smoking-related ILD should be counseled to discontinue smoking and/or encouraged to enroll in a formal smok­ ing cessation program. Small studies have evaluated treatment with immunosuppressive (e.g., prednisone) and cytotoxic (e.g., azathioprine and cyclophosphamide) agents and, in some cases, bronchodilators. To date, there is no strong evidence that these therapies result in signifi­ cant improvements in symptoms or measures of pulmonary function or prevent clinical deterioration. ■ ■CRYPTOGENIC ORGANIZING PNEUMONIA Clinical Manifestations  COP typically involves patients in their 50–60s and often presents as a subacute flulike illness with cough, dyspnea, fever, and fatigue. Inspiratory rales are often present on examination, and most patients are noted to have restrictive lung deficits on pulmonary function testing with hypoxemia. COP is com­ monly mistaken for pneumonia. It is important to note that this syn­ drome can occur in isolation, can be secondary to an underlying CTD

(e.g., polymyositis) or medications, or can result from an underlying malignancy. Laboratory testing for various CTDs is helpful as testing can both be diagnostic and suggest the need for prolonged medical therapy. HRCT Image Findings  The most common imaging findings include patchy, sometimes migratory, subpleural consolidative opaci­ ties often with associated ground-glass opacities. Peribronchiolar or perilobar opacities can be present, and sometimes a rim of subpleural sparing (often referred to as a reversed halo or atoll sign) can be seen, which can aid in the diagnosis. Histopathology  Surgical lung biopsy specimens tend to reveal patchy regions of organizing pneumonia with granulation tissue that commonly involves the small airways, alveolar ducts, and alveoli with surrounding inflammation that can involve the alveolar walls (see Fig. 304-3). Treatment  Corticosteroids can result in substantial clinical improvement in many patients but usually need to be continued for at least 6 months as relapse rates are high. Evidence is growing that alter­ nate cytotoxic (e.g., mycophenolate, cyclophosphamide) or biologic (e.g., rituximab) therapies can be helpful in both treating the disease and reducing the need for steroids. In some patients with secondary forms of the disease, long-term therapy may be needed. ACUTE OR SUBACUTE IIPS ■ ■ACUTE INTERSTITIAL PNEUMONIA (HAMMAN-RICH SYNDROME) Clinical Manifestations  AIP is a rare and often fatal lung dis­ order that is characterized by an acute onset of respiratory distress and hypoxemia. A prodromal period of symptoms consistent with an acute upper respiratory infection is common. The mortality rate within 6 months of presentation can be quite high (>50%), and recur­ rences are common. In those who recover, lung function improvement can be substantial. AIP can be difficult to distinguish from acute respiratory distress syndrome (ARDS) and an acute exacerbation of an unsuspected underlying pulmonary fibrotic process. HRCT Image Findings  The most common imaging findings are patchy bilateral ground-glass opacities. Dependent regions of air-space consolidation are also common. Histopathology  Similar to ARDS and acute exacerbations of underlying pulmonary fibrosis, AIP presents histopathologically as diffuse alveolar damage (DAD) demonstrated on a surgical lung biopsy. Treatment  Treatment is mostly supportive and often includes mechanical ventilation. There is no proven drug therapy for AIP. Glu­ cocorticoids are often given, but they are not clearly effective, and data on their use in other forms of DAD (e.g., ARDS) is controversial. ■ ■ACUTE EXACERBATIONS OF IIPS Clinical Manifestations  Acute exacerbations are not separate dis­ orders, but rather an accelerated phase of lung injury that can occur in any form of ILD with pulmonary fibrosis. Acute exacerbations are most common and most severe in patients with known IPF. Acute exacer­ bations are characterized by an acute onset (<30 days) of respiratory distress and hypoxemia occurring in a patient with underlying pulmo­ nary fibrosis not explained by an alternate cause (e.g., pneumonia, left heart failure). Reported mortality rates are very high (>85%), and mean survival periods range from as little as days to months. HRCT Image Findings  The most common imaging findings include patchy bilateral ground-glass opacities and dependent regions of air-space consolidation that can be appreciated on the background of the imaging findings characteristic of the underlying IIP. However, at times, they obscure the preceding imaging findings. Histopathology  Acute exacerbations of underlying pulmonary fibrosis present histopathologically as DAD, although sometimes orga­ nizing pneumonia can also be demonstrated on a surgical lung biopsy.

Treatment  Overall, treatment is supportive. Mechanical ventila­ tion, when not being used as a bridge to lung transplantation, is con­ troversial as the survival rate in these patients tends to be poor. There is some evidence that drug therapy (e.g., nintedanib) may reduce the rate of acute exacerbations in patients with IPF. Drug therapy, in the con­ text of an acute exacerbation, is also controversial. Immunosuppressive (e.g., prednisone) and cytotoxic (e.g., cyclophosphamide) therapies are commonly used without proven benefit.

ILD ASSOCIATED WITH CONNECTIVE TISSUE DISEASE ILD is a common disease manifestation of many CTDs. Disease pro­ gression, response to therapy, and survival are variable and associated with specific radiologic and histopathologic patterns. ILD occurs most commonly in patients with scleroderma (systemic sclerosis form, or SSc), RA, polymyositis/dermatomyositis, and less frequently Sjögren’s syndrome and systemic lupus erythematosus (SLE). ILD may pre­ cede the development of extrapulmonary manifestations of a specific CTD or may present as part of a poorly defined CTD. In rare cases, lung manifestations may be the sole feature of the patient’s clinical presentation. Interstitial Lung Disease CHAPTER 304 ■ ■SYSTEMIC SCLEROSIS Clinical Manifestations (Chap. 372)  ILD is the most common pulmonary manifestation of SSc. ILD occurs in ~50% of SSc patients with diffuse disease and in ~30% of patients with limited disease. Pul­ monary hypertension can occur separately or concomitantly with ILD and is more frequent in patients with limited SSc. HRCT Image Findings  Imaging features observed in patients with NSIP and IPF can be present, although less common findings present in COP and DAD may also be found. Additional HRCT findings may include a dilated esophagus and pulmonary artery enlargement. Histopathology  Comparable to the imaging overlap, histopatho­ logic changes commonly noted in patients with NSIP and IPF are frequently identified. COP and DAD patterns may be observed and could be secondary to aspiration due to esophageal dysmotility, which is common in SSc. Treatment  Cyclophosphamide has a modest benefit in the pres­ ervation of lung function and is associated with significant toxicity. Mycophenolate has recently been shown to have similar efficacy and improved tolerability. Recent trials suggest that SSc patients with ILD may benefit from anti–interleukin 6 therapy (e.g., tocilizumab) and antifibrotic therapy (e.g., nintedanib). Minimizing the risk of reflux by using high-dose proton pump inhibitors or antireflux surgery should be considered in SSc with progressive ILD, as gastroesophageal reflux disease may contribute to lung injury and fibrosis. Lung transplanta­ tion can potentially be offered to select patients without significant aspiration or chest wall restriction. ■ ■RHEUMATOID ARTHRITIS Clinical Manifestations (Chap. 370)  A common extraarticular complication of RA is ILD. Although RA is more common in females, RA-ILD is more frequent in males and in patients with a history of tobacco exposure. In a small subset of patients, ILD is the first disease manifestation of RA. Clinically evident RA-ILD occurs in nearly 10% of the RA population; however, up to 40–50% of RA patients have radiologic abnormalities on chest CT, suggesting that ILD in the con­ text of RA may be underdiagnosed. HRCT Image Findings  The most common imaging pattern of ILD in patients with RA is a UIP pattern, although NSIP patterns are not uncommon. There is evidence that survival in patients with RA is decreased in patients with a UIP pattern and among those with more extensive fibrosis in general. Histopathology  Histopathologic findings of UIP and NSIP are the most common. Some studies suggest that UIP in the context of RA

(as compared to IPF) may present with a reduced number of fibroblas­ tic foci and an increased amount of germinal centers. Comparable to the imaging findings, UIP (and DAD) patterns in patients with RA are associated with reduced survival.

Treatment  In contrast with SSc, there are no published clinical trials testing the role of immune suppression in RA-ILD. Extrapolating from the scleroderma experience, immunosuppressive (e.g., predni­ sone) and cytotoxic (e.g., mycophenolate, azathioprine, cyclophospha­ mide, and calcineurin inhibitors) agents have been used with variable success. However, RA patients with progressive pulmonary fibrosis may have less of a decline in lung function in response to antifibrotic therapy. Lung transplantation is a viable therapeutic approach for eli­ gible patients with progressive disease that is not responsive to medical therapy. PART 7 Disorders of the Respiratory System ■ ■DERMATOMYOSITIS/POLYMYOSITIS Clinical Manifestations (Chap. 377)  The idiopathic inflam­ matory myopathies are disorders characterized by immune-mediated destruction and dysfunction of muscle; however, these disorders can affect the skin, joints, cardiovascular system, and lungs. The prevalence of ILD associated with inflammatory myopathy varies by report; however, ILD is present in up to 45% of patients with positive anti-synthetase antibodies. The anti-synthetase syndrome is character­ ized by positive anti-synthetase antibodies, myositis, fever, Raynaud’s phenomenon, mechanic’s hands, arthritis, and progressive ILD. There is a subset of anti–Jo-1 antibody–positive individuals who develop a rapidly progressive form of ILD consistent with an acute exacerbation. Some studies have suggested that ILD may be more common in those with other antibodies (e.g., anti-PL-12). Dermatomyositis/polymyositis can occur as an isolated CTD or as a process associated with an under­ lying malignancy. HRCT Image Findings  Common imaging patterns of ILD in patients with dermatomyositis/polymyositis include those consistent with NSIP with or without evidence for COP. A UIP pattern can also occur. Some studies have suggested that a UIP pattern may be more common among those with anti-PL-12 antibodies. Histopathology  The anti-synthetase syndrome is associated with multiple histopathologic subtypes including NSIP, COP, and UIP. DAD, a histopathologic pattern observed in AIP and acute exacerbations, is associated with rapidly progressive ILD in myositis patients. Treatment  Immunosuppressive (e.g., prednisone) and cytotoxic (e.g., mycophenolate, azathioprine, cyclophosphamide, and calcineurin inhibitors) agents are often used in patients with progressive ILD. Some patients (particularly those with less fibrosis) have been noted to have improved or resolved ILD in response to medical therapy. In small studies, relapses have been more common in patients treated with prednisone alone. Patients who fail immune-suppressive therapy can benefit from lung transplantation. ■ ■GRANULOMATOUS ILDS The most common granulomatous ILD is sarcoidosis, a multisystem disorder of unknown cause where lung involvement is often the most dominant feature; sarcoidosis is discussed in Chap. 379. HP, a granu­ lomatous reaction due to inhalation of organic (e.g., bird fancier’s lung secondary to exposure to bird feathers) and inorganic (e.g., coal worker’s pneumoconiosis secondary to exposure to coal dusts) dusts, is also an important and common cause of ILD and is discussed in Chap. 299. Granulomatous Vasculitides (See Chap. 67)  These disor­ ders are characterized by blood vessels with inflammatory infiltrates and associated granulomatous lesions with or without the presence of tissue necrosis. The lungs are commonly involved, and a unique feature of these disorders is that hemoptysis can be a presenting symp­ tom. Although laboratory testing is helpful and can provide specific information, biopsies of involved tissue can be essential for making a diagnosis. Many of these disorders include additional systemic

manifestations. GPA, previously referred to as Wegener’s disease, is an example of a granulomatous vasculitis that commonly affects the lung (including inflammatory infiltrates in small to medium-sized vessels), ears, nose, throat, and kidney (resulting in glomerulone­ phritis). Common imaging abnormalities of GPA include nodules, patchy ground-glass and consolidative opacities that can be migratory, and hilar lymphadenopathy. Eosinophilic GPA (EG; also referred to as Churg-Strauss syndrome) is another example of a granulomatous vasculitis that affects the lung (including eosinophilic infiltrates in small to medium-sized vessels) and can result in numerous clinical manifestations but frequently includes chronic sinusitis, asthma, and peripheral blood eosinophilia. Common imaging abnormalities of EG include peripheral consolidative opacities that can be migratory and small pleural effusions. ■ ■GENETICS AND ILD Studies of genetic epidemiology have led to important insights in our understanding of ILD. First, studies of families with FPF have demonstrated that unique IIPs can cosegregate with specific genetic variants known to be associated with IPF. This suggests that many genetic variants appear to predispose to interstitial lung injury pat­ terns more broadly than to unique diagnoses specifically. Second, most of the genetic variants associated with FPF are also associated with more sporadic forms of the disease. Third, at least one of the genetic factors most strongly associated with FPF and IPF is common and confers a large increase in the risk of these diseases. At least one copy of a mucin 5B (MUC5B) promoter variant is present in ~20% of Caucasian populations and 35–45% of patients with IPF and confers an approximate sixfold increase in the risk of this disease. Fourth, studies of general population samples demonstrate that imaging abnormalities suggestive of an early stage of pulmonary fibrosis in research partici­ pants without known ILD are not uncommon (occurring in ~7–9% of adults) and are also associated with the same genetic variants known to be associated with IPF (e.g., the MUC5B promoter variant). This latter finding suggests a path forward toward an early detection of IPF. Additional genetic findings demonstrating replicable associations with pulmonary fibrosis include numerous genetic variants in, and adjacent to, genes known to be involved in the regulation of telomere length (e.g., the TERT gene, the telomerase RNA component [TERC] gene, and the regulator of telomere elongation helicase 1 [RTEL1] gene) and surfactant protein genes (e.g., surfactant protein A2 [SFTPA2] gene) (Chap. 495), and aggregates of effect estimates from the combined effect of thousands of genetic variants (polygenic risk) score. Genetic studies have also provided some insights into other forms of ILD. Genome-wide association studies of sarcoidosis have demon­ strated numerous variants in genes and in genomic regions that are associated with the disease. Some of these disease-associated vari­ ants in sarcoidosis fall in human leukocyte antigen (HLA) regions, in regions of genes involved in immune regulation (e.g., interleukin 12B [IL12B]), and in regions of genes that are less well understood (butyrophilin-like 2 [BTNL2]) but also appear to be involved in T-cell activation. LAM is often associated with genetic variants in the tuberous sclerosis complex genes (e.g., TSC1 and TSC2), consis­ tent with the known evidence that this disease can occur in isolation but also in patients with known tuberous sclerosis. Many genetic factors for rare diseases such as Hermansky-Pudlak syndrome (a rare autosomal recessive disorder that results in pulmonary fibrosis but also includes oculocutaneous albinism, bleeding diatheses, and horizontal nystagmus) have also been discovered (e.g., HSP1 and HSP3–7). ■ ■GLOBAL CONSIDERATIONS The prevalence, clinical presentation, and natural history of most ILDs in European countries resemble those described in the United States. However, as expected, there is growing evidence for racial differences in clinical (rate of acute exacerbations) and genetic (MUC5B) attributes between Caucasian and Asian populations. To date, there are limited data on the prevalence of ILD in Hispanics, subjects of African descent, and many other ethnic groups.