Diffuse panbronchiolitis

INTRODUCTION — Diffuse panbronchiolitis (DPB) is a rare clinicopathologic syndrome characterized by bronchiolitis and chronic sinusitis [1,2]. In the disease name, "diffuse" refers to the distribution of the lesions throughout both lungs and "pan" refers to the pathologic finding that the inflammation involves all layers of the respiratory bronchioles [1].

The predisposing factors, clinical manifestations, evaluation, diagnosis, and treatment of diffuse panbronchiolitis will be discussed here. The clinical features, diagnosis, and management of other types of bronchiolitis in adults and children are reviewed separately. (See "Overview of bronchiolar disorders in adults" and "Bronchiolitis in infants and children: Clinical features and diagnosis" and "Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

PATHOGENESIS — The exact pathogenesis of DPB is not known. A variety of genetic, environmental, and systemic factors appear to contribute.

Genetic factors — Genetic factors are suspected to contribute to the pathogenesis of DPB based on the observation of familial cases and the association of specific human leukocyte antigen (HLA) haplotypes with the disease. In addition to familial cases noted in Japan, it is also common to identify chronic sinusitis without bronchiolitis in first-degree relatives of afflicted individuals [3-5].

Specific HLA haplotypes, such as HLA-B54 in Japan and HLA-A11 in Korea, are associated with the development of DPB [5,6]. In one report, for example, HLA-B54 was identified in 63 percent of Japanese patients with DPB versus 11 percent of normal Japanese controls (relative risk 13.3) [5]. This HLA haplotype has been reported almost exclusively in natives of Japan, China, and Korea, where it is also associated with rheumatoid arthritis and silicosis.

The association of particular HLA-A and HLA-B haplotypes with DPB suggests that a disease susceptibility gene might be located between these loci in the major histocompatibility complex (MHC) class I region on chromosome 6 [7,8]. In a study of this candidate region, affected patients were found to have polymorphisms in two novel mucin-like genes called panbronchiolitis-related mucin-like 1 and 2 (also known as mucin 22 or MUC22) [7].

A separate study similarly suggests a contribution from mucin-related genes. An insertion/deletion polymorphism of the mucin gene MUC5B on chromosome 11 is associated with DPB [9]. Immunohistochemical staining of lung biopsy samples from patients with DPB demonstrated markedly increased expression of MUC5B-positive secretions in the lower respiratory tract of patients with DPB, compared to normal control samples.

Several other candidate genes, including those encoding interleukin (IL)-8 and tumor necrosis factor-alpha have been associated with an increased risk of DPB in small studies [10,11].

Despite clinical similarities (eg, sinusitis, bronchiectasis) to the genetic disorder cystic fibrosis (a disease not described in the Japanese population), abnormalities in exocrine function, the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and sweat electrolytes have not been identified in patients with DPB [12].

Other factors — Nongenetic factors have also been considered in the etiology and pathogenesis of DPB.

●Environmental cofactors appear to play a role, since DPB is rarely seen in people of East Asian ancestry living abroad.

●The possibility of an underlying systemic disease is suggested by a case reports in which DPB recurred in the lung allograft within 10 to 16 weeks after lung transplantation [13,14].

●A potential role for lymphocytes in the pathogenesis of DPB is suggested by the prominence of lymphocytes in and around the bronchioles on histopathology and in the bronchoalveolar lavage fluid (BALF). Macrolide antibiotics, used to treat DPB, significantly reduce the number of lymphocytes and activated CD8+ cells in BALF of patients with DPB, and also increase the CD4/CD8 ratio [15]. These findings suggest activation of CD8+ cells in the airway lumen of DPB patients, further supporting the hypothesis that lymphocytes are important contributors to the bronchial inflammation.

●BALF also usually shows an increase in the number of neutrophils, although the role of neutrophils in DPB is unclear [15-18]. On histopathology, they are not significant components of tissue-based inflammation. It is possible that the presence of neutrophils in the lumen is a response to airway bacterial colonization. Neutrophils may contribute to development of bronchiectasis proximal to the affected bronchioles.

●Abnormal regulation and expression of human beta-defensins (antimicrobial peptides involved in innate host defense) may play a role in the pathogenesis of DPB. This theory is supported by the finding that patients with DPB have elevated levels of human beta-defensin-1 and -2 in BALF, and increased serum levels of human beta-defensin-2, compared to control subjects [18]. Serum levels of human beta-defensin-2 appear to correlate with disease activity, and therapy with macrolide antibiotics reduced serum human beta-defensin-2 in one small study [18].

EPIDEMIOLOGY — DPB occurs mainly among the Japanese and has rarely been reported outside East Asia [19-22]. However, cases of DPB have been recognized in the United States, Canada, Latin America, and Europe, raising concerns that it might be under-diagnosed in these populations [23-31]. As clinicians, radiologists, and pathologists become familiar with this entity, the number of cases identified worldwide may substantially increase. The disorder is slightly more prevalent in men (approximately 1.4 to 2:1, male to female ratio) [2,32]. The majority of patients are nonsmokers.

CLINICAL FEATURES — Symptoms of DPB typically develop in the second to fifth decade (mean age at presentation 40 years) and are slowly progressive over months to years [2,21,31,32]. Occasionally, DPB develops in childhood and can be mistaken for asthma [33,34]. Often patients have failed prior short-term treatment courses with nonmacrolide antibiotics. In case series, the time from onset of symptoms to diagnosis was in the range of one to four years [21].

Common symptoms and signs at presentation include the following [2,19,32,35]:

●Chronic sinusitis, found in at least 75 percent of Japanese patients with DPB, often preceding chest symptoms by years or even decades

●Cough, usually productive of copious amounts of purulent sputum, exceeding 50 mL/day in half of untreated patients [2]

●Breathlessness with exertion, which usually develops several months after the onset of cough

●History of wheezing

●Weight loss, especially when pulmonary symptoms become progressive and severe

Chest examination may reveal decreased breath sounds, coarse crackles, or wheezes. Clubbing is uncommon. Rarely, immune-mediated peripheral neuropathy, including vasculitic neuropathy, has been associated with DPB. Further study is required to clarify this finding in DPB [36].

EVALUATION — The evaluation for possible DPB is typically initiated in adults with a chronic cough, particularly when the cough is productive and the patient is at risk for DPB due to genetic, clinical, and/or geographic factors (eg, East Asian descent, sinusitis, residence in Asia).

Laboratory testing — No specific laboratory abnormalities are diagnostic for DPB. However, when evaluating patients with chronic sinusitis and lower respiratory tract symptoms, laboratory testing can help identify processes in the differential diagnosis. (See 'Differential diagnosis' below.)

Laboratory testing typically includes the following:

●Complete blood and differential cell counts (looking for eosinophilia or abnormal leukocytes that would suggest an alternate diagnosis).

●Cold agglutinins, which are usually obtained when suspicion for DPB is high due to the clinical setting or radiographic findings, are frequently positive in DPB. However, we do not obtain serologic testing for M pneumoniae, which is typically negative.

●Serum immunoglobulin levels (to exclude common variable immunodeficiency).

Other laboratory testing that may occasionally be appropriate includes:

●Antineutrophil cytoplasmic antibody test (for possible granulomatosis with polyangiitis [GPA] or eosinophilic granulomatosis with polyangiitis [EGPA; Churg-Strauss]). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●Sweat test for cystic fibrosis or genetic testing for mutations in the CFTR gene. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation'.)

●In areas endemic for human T-cell lymphotropic virus type 1 (HTLV-1), a screening enzyme-linked immunosorbent assay (ELISA) is usually obtained due to similar clinical presentations of DPB and HTLV-1-associated bronchiolitis. (See 'Differential diagnosis' below and "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment", section on 'Diagnosis'.)

●In the absence of clinical findings to suggest underlying systemic lupus erythematosus, we do not routinely obtain serology for antinuclear antibodies, although these may be positive at a low level. Similarly, rheumatoid factor may be obtained, as bronchiolitis obliterans associated with rheumatoid arthritis can have a similar radiographic appearance and can rarely precede the onset of frank arthritis. However, rheumatoid factor can be present at a low level in DPB.

Among patients with DPB, the following nonspecific findings may be seen [2,19,37]:

●Mild peripheral blood neutrophilia

●Increased serum IgA

●Positive C-reactive protein

Sputum stain and culture — For patients with a chronic productive cough, sputum samples are usually obtained for gram stain, acid fast stain, and cultures (including mycobacterial). Sputum cultures have grown Haemophilus influenzae in 44 percent and Pseudomonas aeruginosa in 22 percent of patients with DPB [2,19]. The frequency of P aeruginosa can increase to 60 percent after four years of treatment. In early disease, Streptococcus pneumoniae and Moraxella catarrhalis may be seen, but less commonly than the above organisms. Mycobacterial cultures are obtained as infection with these organisms is in the differential diagnosis. (See 'Differential diagnosis' below.)

Pulmonary function tests — Pulmonary function tests are obtained in most patients to evaluate whether a patient with a chronic cough or dyspnea has a pattern consistent with asthma or chronic obstructive pulmonary disease (COPD), whether there is a concomitant gas transfer defect, and also to assess the severity of the respiratory impairment.

In DPB, an obstructive defect is common [26], although a mixed obstructive-restrictive pattern may also be seen. Patients with DPB exhibit a smaller increase in forced expiratory volume in one second (FEV₁) after inhaled bronchodilator and less airway hyperresponsiveness (less responsive to methacholine challenge), than those with chronic obstructive pulmonary disease [38]. The diffusing capacity (DLCO) is variably reduced.

Hypoxemia is common, while hypercapnia occurs in the terminal stages of the disease.

Imaging — A conventional chest radiograph is typically obtained to evaluate adults with dyspnea and a persistent productive cough. In DPB, the chest radiograph can reveal several different abnormalities [26,39-41]. These include normal or hyperinflated lung volumes, diffuse ill-defined nodules up to 3 mm in diameter, and/or an increase in bronchovascular markings (reticular "airway" pattern). (See "Evaluation of diffuse lung disease by conventional chest radiography", section on 'Basic patterns'.)

High-resolution computed tomography (HRCT) scanning is usually obtained to evaluate abnormalities seen on chest radiograph or abnormal gas exchange on pulmonary function testing. In DPB, the HRCT scan may show centrilobular nodular opacities, nodular and linear (tree-in-bud) opacities corresponding to bronchioles with intraluminal mucous plugs (image 1), thickened and dilated bronchiolar walls (bronchiolectasis), and, as a late finding, large cystic opacities accompanied by dilated proximal bronchi [39-42]. A diffuse pattern, uniformly identifiable throughout the lungs is suggestive of panbronchiolitis, while a focal pattern is more commonly seen with allergic bronchopulmonary aspergillosis, cystic fibrosis, or mycobacterial infection. (See "High resolution computed tomography of the lungs", section on 'Centrilobular nodules' and "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Inhomogeneity in lung density, as a result of peripheral air trapping, may also be seen, although this is less common. Expiratory images may enhance the airway trapping due to the obstructed airways. (See "High resolution computed tomography of the lungs", section on 'Mosaic attenuation'.)

Bronchoscopy — Bronchoscopy with bronchoalveolar lavage is often performed in patients with centrilobular nodular and tree-in-bud opacities on chest imaging to exclude infection (eg, mycobacterial, nocardial), particularly when the patient is not raising sufficient quantities of sputum for culture. (See "Basic principles and technique of bronchoalveolar lavage" and "Overview of nontuberculous mycobacterial infections".)

In DPB, bronchoalveolar lavage findings are nonspecific, as are transbronchial biopsies [35]. Cellular analysis of bronchoalveolar lavage fluid (BALF) usually shows increased numbers of lymphocytes and neutrophils, although the presence of neutrophils may be a response to local bacterial superinfection [16,17,43].

Transbronchial biopsy is more helpful to identify other processes (eg, hypersensitivity pneumonitis, sarcoidosis), than to secure a diagnosis of DPB. The low sensitivity of transbronchial biopsy for DPB was illustrated in a study of eight patients who underwent transbronchial biopsy prior to a surgical lung biopsy that showed DPB; all eight transbronchial biopsies showed nonspecific inflammation [35]. (See 'Differential diagnosis' below.)

Lung biopsy — Lung biopsy is often NOT necessary in patients with typical clinical, physiologic, and radiographic features who live in countries where the prevalence of DPB is high. However, for patients living in countries with a low prevalence of DPB and those with atypical features, lung biopsy is typically obtained by video-assisted thoracoscopic surgery or thoracotomy in order to confirm the diagnosis because no other findings are specific for the diagnosis.

Pathology — The histologic lesion of DPB is centered around the respiratory bronchiole and consists of a transmural infiltrate composed of lymphocytes, plasma cells, and distinctive lipid-laden "foamy" macrophages, also known as foam cells (picture 1 and picture 2) [24,32,44-46]. Mucus and acute inflammatory cells fill the lumen of affected airways and alveoli, although the alveolar walls are spared.

Narrowing of the lumen of these small airways occurs as the disease progresses. However, obliterative bronchiolitis with submucosal fibrosis is not a prominent feature. Persistent inflammation and superinfection combine to produce secondary ectasia of more proximal bronchioles in advanced disease. Hyperplasia of bronchus-associated lymphoid tissue is also common [45].

The panbronchiolitis (PB) lesion (chronic inflammation of membranous and respiratory bronchioles and prominent interstitial foam cells) is a not a specific histologic finding. A PB-like lesion has been reported in pathologic specimens of at least 11 other diseases (eg, constrictive bronchiolitis, follicular bronchiolitis, cystic fibrosis, bronchiectasis, aspiration pneumonia, hypersensitivity pneumonia, bronchocentric granulomatosis) [46]. However, when a PB-like lesion is found in these other diseases, the airways with the most marked changes are the proximal membranous bronchioles rather than the respiratory bronchioles. Alternatively, the PB-lesion is a minor finding and other histologic lesions (eg, poorly formed granulomas, lymphoma, vasculitis) lead to the specific diagnosis. Thus, the diagnosis of DPB can be made only in the appropriate clinical setting, with careful histopathologic analysis, and when other conditions have been carefully ruled out [46].

DIAGNOSIS — In countries where DPB is prevalent, a lung biopsy is often not needed to make the diagnosis, and clinical criteria for DPB are used instead [37]. Definite cases should fulfill the first three criteria and at least two of the remaining (table 1):

●Persistent cough, sputum, and exertional dyspnea

●History or current symptoms of chronic sinusitis

●Bilateral, diffuse, small nodular shadows on a plain chest radiograph or centrilobular micronodules on chest CT images

●Coarse crackles

●Forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) less than 70 percent and arterial oxygen tension (PaO₂) less than 80 mmHg (10.64 kPa)

●Titer of cold agglutinins of 64 or greater

For patients who reside in an area where DPB is not prevalent, the diagnosis is based on the clinical criteria described above and histopathologic examination of a lung biopsy. The characteristic histopathologic features of DPB are centered on the respiratory bronchiole and consist of a transmural infiltrate composed of lymphocytes, plasma cells, and distinctive lipid-laden "foamy" macrophages, also known as foam cells (picture 1 and picture 2). (See 'Pathology' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of DPB includes a variety of sinopulmonary processes as well as infectious and inflammatory causes of bronchiolitis, which are more common than DPB outside East Asia. (See "Overview of bronchiolar disorders in adults".)

●Granulomatosis with polyangiitis (GPA) – Patients with GPA often have chronic sinusitis and occasionally have bronchiectasis, although the pattern of diffuse centrilobular nodules seen in DPB would be atypical for GPA. In addition, the non-sinopulmonary manifestations of GPA (eg, renal, neurologic, cutaneous) would not be expected in DPB. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

●Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) – Patients with the eosinophilic granulomatosis with polyangiitis (EGPA) typically have a combination of chronic rhinosinusitis and asthma. Migratory pulmonary opacities reflecting acute eosinophilic pneumonia may be seen. Radiographic findings suggestive of bronchiectasis would be unlikely in EGPA, although centrilobular nodules have been reported [47]. Peripheral eosinophilia would be a clue to the diagnosis of EGPA. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Evaluation'.)

●Aspirin-exacerbated respiratory disease – Aspirin-exacerbated respiratory disease (AERD) refers to the combination of asthma, chronic rhinosinusitis with nasal polyposis, and reactions to aspirin ingestion that include bronchospasm and nasal congestion. Chronic sinusitis and obstructive airways disease are common in both AERD and DPB, but other clinical manifestations, such as crackles on physical examination and centrilobular nodules on chest imaging, are atypical in AERD (but characteristic of DPB). (See "Aspirin-exacerbated respiratory disease", section on 'Diagnosis'.)

●Immunodeficiency syndromes − Selective antibody deficiency (polysaccharide non-response) and the various forms of hypogammaglobulinemia typically present with chronic rhinosinusitis and bronchiectasis. Deficiency of immunoglobulins (eg, IgG, IgA, IgM, or IgG subclasses) or lack of specific antibody responses to pneumococcal vaccine will identify the responsible immunodeficiency. Thymoma combined with adult-onset immunodeficiency (Good syndrome) may present with DPB or DPB-like pulmonary manifestation [48,49]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

●Primary ciliary dysplasia (PCD) – PCD is associated with chronic sinusitis and bronchiectasis like DPB and can occasionally present in adulthood [50,51], although the clinical presentation of PCD is usually in childhood. The evaluation and diagnosis of PCD are discussed separately. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)".)

●Cystic fibrosis – The sinopulmonary manifestations of cystic fibrosis (CF) include chronic sinusitis, chronic productive cough, and as the disease progresses, radiographic findings of peribronchial cuffing, mucous plugging with subsegmental atelectasis, and saccular bronchiectasis. Unlike DPB, patients with CF often have extrapulmonary manifestations: in childhood, failure to thrive, steatorrhea, and meconium ileus are common, while in adulthood, pancreatitis, nonspecific gastrointestinal symptoms, diabetes mellitus, and infertility are common. The diagnosis of CF is made based on sweat chloride results and analysis for mutations in the CF transmembrane regulator (CFTR) gene. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●Allergic bronchopulmonary aspergillosis – Allergic bronchopulmonary aspergillosis (ABPA) typically occurs in patients with asthma or cystic fibrosis. The presentation is usually recurrent episodes of bronchial obstruction, fever, malaise, and expectoration of brownish mucus plugs. The affected airways are typically more central in ABPA (manifest on HRCT), than in DPB. Some patients with ABPA also have nasal polyposis. Peripheral blood eosinophilia and elevation of the total IgE are the typical findings of ABPA that help to differentiate it from DPB. (See "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)

●Mycobacterium avium complex – In non-HIV infected individuals, Mycobacterium avium complex (MAC) lung infection can cause chronic cough, sputum production, and HRCT findings of tree-in-bud opacities and bronchiectasis. Chronic sinusitis is typically absent. The diagnosis of MAC is typically made by sputum acid fast stains and mycobacterial culture. (See "Overview of nontuberculous mycobacterial infections".)

●Sarcoidosis – Sarcoidosis can present with chronic sinusitis, chronic cough, and radiographic findings of scarring and traction bronchiectasis [52]. A tree-in-bud pattern can be seen on HRCT but would typically be associated with beading of the interlobular septae. The diagnosis of sarcoidosis is typically made on the basis of granulomas on biopsy specimens from the lung or mediastinal lymph nodes. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Diagnostic approach'.)

●Inflammatory bowel disease-associated bronchiolitis – The pathologic finding of panbronchiolitis can also be seen in bronchiolitis associated with inflammatory bowel disease. Panbronchiolitis may precede bowel manifestations in patients with ulcerative colitis [53]. (See 'Pathology' above and "Pulmonary complications of inflammatory bowel disease".)

●Obliterative bronchiolitis in rheumatoid arthritis − Considerable overlap exists in the clinical features of DPB and obliterative bronchiolitis associated with rheumatoid arthritis (RA). Both groups of patients typically manifest productive cough, exertional dyspnea, wheezing and/or coarse crackles, but chronic sinusitis is absent in RA [54]. A similar HRCT appearance to DPB has been reported in RA [55]. However, the histopathology is different: the primary obstructive lesion is in the respiratory bronchioli in DPB and in the membranous bronchioli and the proximal small bronchi in RA. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Obliterative bronchiolitis'.)

●Human T-cell lymphotropic virus type 1 associated bronchiolitis − Human T-cell lymphotropic virus type 1 (HTLV-1) infection is endemic in certain parts of Japan and occurs sporadically elsewhere. It has several features in common with DPB, such as radiographic findings (eg, centrilobular nodules, thickening of the bronchovascular bundle, bronchiectasis), bronchoalveolar lavage fluid lymphocytosis, and lymphocytic bronchiolitis on histopathology [2,56-60]. Identification of HTLV-1-associated bronchiolitis is based on a positive screening enzyme-linked immunosorbent assay (ELISA) with a confirmatory Western blot or polymerase chain reaction (PCR)-based testing to detect proviral DNA in peripheral blood mononuclear cells. (See "Human T-lymphotropic virus type I: Disease associations, diagnosis, and treatment", section on 'Diagnosis'.)  

TREATMENT AND PROGNOSIS — The natural history of untreated DPB is characterized by the development of diffuse bronchiectasis, progressive respiratory failure leading to cor pulmonale, and ultimately death over the course of a few years. However, long-term treatment with macrolide antibiotics has markedly improved outcomes.

Macrolide antibiotics — We recommend using a macrolide antibiotic in all patients diagnosed with DPB, based on the dramatic improvement in prognosis associated with the use of macrolide antibiotics. Nearly 50 percent of untreated patients die within five years of diagnosis and 75 percent after ten years [37,61,62]. In contrast, the use of long-term treatment with macrolide antibiotics has resulted in a greater than 90 percent 10-year survival rate. Importantly, a Cochrane review on the efficacy and safety of macrolides for DPB topic emphasized that this treatment recommendation for DPB is based on evidence from retrospective and non-randomized studies. The Cochrane review did conclude that the use of low-dose macrolides according to current guidelines was a reasonable approach [63].

Mechanism of action of macrolides — The mechanisms by which macrolide antibiotics exert their beneficial effect in DPB may include both antimicrobial and anti-inflammatory effects [64-67]. In the treatment of DPB, the serum and sputum erythromycin levels are below the minimum inhibitory concentrations of the common superinfecting organisms, suggesting that antimicrobial effects may be less important than anti-inflammatory effects. In addition, other antibiotics with greater activity against the specific organisms in the sputum (eg, quinolones) had less effect on the overall disease control [43].

On the other hand, novel antimicrobial effects of macrolides, such as impairment of biofilm formation and inhibition of flagellar function of P aeruginosa, may contribute to the overall efficacy of these agents [64,68]. Furthermore, macrolides in general and azithromycin and clarithromycin in particular are concentrated intracellularly in alveolar macrophages to levels approximately 400 to 800 fold above serum concentrations [68]. Intracellular concentration may enhance both antimicrobial and anti-inflammatory effects and explain why relatively low doses are effective.

Erythromycin — Erythromycin is the drug of first choice in the treatment of DPB, due to the greater clinical experience with it and lower cost. Most patients respond to erythromycin 400 to 600 mg per day [2,43,63,69-72]. The following studies provide support for the use of erythromycin in the treatment of DPB:

●One study reported that the long-term administration (average 19.8 months) of oral low-dose erythromycin (600 mg/day) resulted in improvements in dyspnea, body weight, chest radiographic findings, pulmonary function, and arterial oxygen (PaO₂) level [69]. The same group of investigators retrospectively found a significant survival advantage among 63 patients who received erythromycin compared with 24 patients who did not [71]. However, these results do not definitively demonstrate an effect of erythromycin because the study was nonrandomized and most deaths were due to causes other than DPB.

●Another study showed that an erythromycin dose of 400 to 600 mg daily for more than two months relieved the productive cough and dyspnea, and improved the pulmonary radiographic manifestations in 16 of 19 patients [43].

●In a case series of patients who had high-resolution computed tomography (HRCT) before initiation of erythromycin and after three months of therapy found a significant reduction in the extent of small nodular opacities, the severity of peri-airway thickening, and the amount of mucous plugging [42].

Other macrolides — For patients who are unable to tolerate erythromycin due to an adverse effect and those who are unimproved after several weeks of therapy, an alternate macrolide may be substituted, although data regarding dose and efficacy are limited. (See "Azithromycin and clarithromycin".)

In case series, clarithromycin (200 to 400 mg orally once per day) [73-76] and roxithromycin (150 to 300 mg orally once per day) [77,78] show beneficial effects against DPB [37]. One group treated 10 patients with DPB with clarithromycin 200 mg per day for four years [74]. Treatment was associated with clinical improvement that peaked at 6 months in most patients and a significant increase in forced expiratory volume in one second (FEV₁) at six months. In this study, long-term clarithromycin was not associated with clinically significant side effects. In a separate report, a patient had progressive disease on clarithromycin 200 mg daily, but improved with an increase to 400 mg per day [76].

Azithromycin has also been assessed in patients with DPB [79-82]. In a case series, azithromycin was administered to 51 patients with DPB, initially at a dose of 500 mg intravenously daily for one to two weeks, then orally for three months, and then three times a week orally for 6 to 12 months [79]. Clinical cure was achieved in 27 percent and improvement in 71 percent. The five-year survival was 94 percent. In a separate series, azithromycin was administered to 60 patients at a dose of 250 mg twice a week for three months [80]. Sputum volume and dyspnea decreased, but details about pulmonary function and radiographic improvements were limited [37,80]. A retrospective case series showed that azithromycin (500 mg, once a day) was associated with improvements in dyspnea, lung function, and opacities on HRCT (small nodular shadows, dilated peripheral bronchi, bronchial wall thickening, and tree-in-bud pattern) [82].

Duration of therapy — The optimal duration of therapy is unknown, but most patients are treated for a minimum of six months [2,82]. Macrolide therapy is continued until clinical manifestations, radiographic findings, and pulmonary function measurements are improved or stable. In the majority of patients, therapy is stopped after two years. However, in patients with advanced bronchiectasis, therapy is continued indefinitely.

After discontinuation of macrolide therapy, patients are monitored clinically for any increase in dyspnea, cough, or sputum production. If symptoms reappear, the patient is evaluated for recurrent DPB or evidence of an intercurrent illness, such as a flare of bronchiectasis or sinusitis. A sputum culture and a chest radiograph are usually obtained. Macrolide therapy is resumed if recurrent DPB is diagnosed.

Other therapies — Other therapies, such as bronchodilator medications, and bronchial hygiene, may be useful in selected patients. We recommend not using systemic glucocorticoids, due to their adverse effects and lack of evidence of benefit [2].

Inhaled short-acting beta agonists and anticholinergic agents are sometimes used to promote bronchodilation and reduce bronchorrhea, particularly in patients who do not respond promptly to macrolide therapy and those with bronchiectasis [83]. Their use is generally empiric and symptom based. Bronchial hygiene measures may be beneficial in patients who have radiographic evidence of bronchiectasis. (See "Bronchiectasis in adults: Maintaining lung health", section on 'Airway clearance therapy'.)

Exacerbations of bronchiectasis — Patients whose DPB is advanced enough that airway scarring has led to bronchiectasis may periodically develop an exacerbation that is due to bacterial overgrowth rather than recurrent or worsening DPB [84]. These exacerbations may occur during ongoing macrolide therapy or after discontinuation. Exacerbations are usually manifest by an increase in sputum production, more purulent appearing sputum, and dyspnea. Depending on the severity of symptoms and degree of concern for recurrent DPB, a chest radiograph may be needed to exclude recurrent DPB or intercurrent pneumonia.

Prompt treatment of exacerbations of bronchiectasis is important to prevent further scarring. The choice of antibiotics should be guided by sputum gram stain and culture results, although it is often difficult to distinguish colonization from infection. Treatment of exacerbations is similar to that for other causes of bronchiectasis and is discussed in detail separately. (See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)

Chronic sinusitis — The optimal treatment of chronic rhinosinusitis (CRS) in patients with DPB is not known, although it tends to improve with chronic macrolide therapy [85]. Treatment of CRS may also help alleviate symptoms such as cough and sputum production. We typically follow the treatment outlined for CRS without nasal polyposis, which includes oral antibiotics (eg, prolonged macrolide therapy), intranasal glucocorticoids, and sometimes a course of oral glucocorticoids. The management of CRS is described in detail separately. (See "Chronic rhinosinusitis without nasal polyposis: Management and prognosis".)

Lung transplantation — Despite improved survival with current treatment, patients with DPB can progress to respiratory failure and may eventually become candidates for lung transplantation. To date, lung transplantation for DPB has been rare and the outcome in these patients remains uncertain [13,14,86,87]. One report describes the experience of five patients who progressed despite long-term macrolide therapy and underwent lung transplantation at a single center [86]. Bilateral cadaveric lung transplantation was performed in four patients, and living-donor lung transplantation in one. All five patients survived with a median follow-up period of 4.9 years (3.7 to 12.3 years) and none developed recurrence of DPB. Recurrence of DPB after transplant has been noted in other reports [13,14]. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

SUMMARY AND RECOMMENDATIONS

●Definition – DPB is a distinct clinical and pathologic syndrome that involves the upper and lower respiratory tracts. It has rarely been reported outside East Asia. The etiology of DPB is unknown; genetic, environmental, and immunologic factors appear to play a role. (See 'Introduction' above and 'Pathogenesis' above.)

●Epidemiology – DPB is slightly more prevalent in men; peak incidence is in the second to fifth decades of life (mean age at presentation is 40 years); most patients are nonsmokers. (See 'Epidemiology' above.)

●Clinical features – Common symptoms and signs include chronic sinusitis, cough, wheeze, dyspnea, and weight loss. Chest examination may reveal decreased breath sounds, coarse crackles, or wheezes. Clubbing is uncommon. (See 'Clinical features' above.)

●Evaluation

•Laboratory studies – No specific laboratory abnormalities are diagnostic of DPB. In patients with a suggestive clinical picture, we typically obtain a complete cell count and differential, serum cold agglutinins, serum immunoglobulin levels with IgG subclasses, and sputum cultures. In selected patients, testing for cystic fibrosis and human T-cell lymphotropic virus type 1 (HTLV-1) infection, rheumatoid factor, and antineutrophil cytoplasmic antibodies may be appropriate. (See 'Laboratory testing' above.)

•Pulmonary function testing – Pulmonary function tests typically show an obstructive defect, although a mixed obstructive-restrictive pattern may also be seen. Diffusing capacity (DLCO) is variably reduced. (See 'Pulmonary function tests' above.)

•Chest imaging – The chest radiograph findings in DPB include normal or hyperinflated lung volumes, diffuse ill-defined nodules up to 3 mm in diameter, and/or an increase in bronchovascular markings. High-resolution computed tomography (HRCT) scanning typically shows centrilobular nodular, linear opacities corresponding to thickened and dilated bronchiolar walls with intraluminal mucous plugs, and evidence of air-trapping (image 1). (See 'Imaging' above.)

●Diagnosis – In countries where the prevalence of DPB is high, the diagnosis is based on the presence of specific clinical criteria (table 1). In countries where DPB is infrequent, lung biopsy is generally needed to exclude alternative causes. (See 'Lung biopsy' above and 'Diagnosis' above.)

●Histopathology – The characteristic histopathologic features of DPB are centered on the respiratory bronchiole and consist of a transmural infiltrate composed of lymphocytes, plasma cells, and distinctive lipid-laden "foamy" macrophages, also known as foam cells (picture 1 and picture 2). (See 'Pathology' above.)

●Differential diagnosis – The differential diagnosis of DPB includes a variety of sinopulmonary processes as well as infectious and inflammatory causes of bronchiolitis obliterans. (See 'Differential diagnosis' above.)

●Treatment

•Macrolide therapy – We suggest using a macrolide antibiotic in all patients diagnosed with DPB rather than observation alone (Grade 2C). The agent of first choice is erythromycin 400 to 600 mg/day due to greater clinical experience with it. Alternative macrolides include clarithromycin, roxithromycin, and azithromycin. (See 'Macrolide antibiotics' above.)

-The optimal duration of therapy is unknown, but most patients are treated for 6 to 24 months. The longer duration of therapy is used in patients with extensive bronchiectasis or a recurrence of disease after cessation of therapy. Occasional patients with recurrent disease need indefinite therapy. (See 'Macrolide antibiotics' above.)

•Other therapies – Inhaled beta-2 agonists and/or anticholinergic agents may be helpful adjunctive therapy for symptomatic control of cough and sputum production. Systemic glucocorticoids are not beneficial in DPB. (See 'Other therapies' above.)

•Bronchiectasis and chronic rhinosinusitis – Treatment of bronchiectasis and CRS due to DPB follow the usual management strategies for these diseases. (See 'Exacerbations of bronchiectasis' above and 'Chronic sinusitis' above and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis" and "Chronic rhinosinusitis without nasal polyposis: Management and prognosis" and "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)