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.