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Respiratory bronchiolitis-associated interstitial lung disease

Respiratory bronchiolitis-associated interstitial lung disease
Literature review current through: Jan 2024.
This topic last updated: Jul 13, 2022.

INTRODUCTION — Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) is categorized as a smoking-related interstitial pneumonia and is one of the idiopathic interstitial pneumonias (IIPs) [1]. The other major IIPs include idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP; another smoking-related IIP), acute interstitial pneumonia (AIP), and cryptogenic organizing pneumonia (COP).

The clinical presentation, diagnosis, treatment, and prognosis of RB-ILD will be reviewed here. The evaluation and diagnosis of ILD (including IIP) and bronchiolitis are discussed separately. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Treatment and prognosis of nonspecific interstitial pneumonia" and "Acute interstitial pneumonia (Hamman-Rich syndrome)" and "Lymphoid interstitial pneumonia" and "Cryptogenic organizing pneumonia" and "Overview of bronchiolar disorders in adults".)

DEFINITION

Respiratory bronchiolitis – Respiratory (or "smoker's") bronchiolitis (RB) is a well-recognized pathologic lesion found in the lungs of cigarette smokers that is generally not associated with respiratory symptoms. The key histopathologic features of RB are the presence of tan-pigmented macrophages (also known as smokers' macrophages) in the respiratory bronchioles, a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes, and peribronchiolar fibrosis that extends into contiguous alveolar walls. (See 'Histopathology' below.)

Respiratory bronchiolitis-interstitial lung disease – RB-ILD is defined by the presence of changes of RB as the sole pathologic finding in a current or former cigarette smoker with clinical evidence of ILD [1-8]. The degree to which fibrosis extends into the alveolar wall has sometimes been used to distinguish RB from RB-ILD, but most pathologists believe that the two processes cannot be distinguished on pathologic grounds alone [2,9-12]. Thus, RB-ILD probably represents a subset of individuals with a more severe stage in the spectrum of RB and is much less common than RB.

EPIDEMIOLOGY — RB is a common histopathologic finding among smokers [2]; RB-ILD is uncommon, but the exact incidence is not known.

RB is often identified in cigarette smokers who undergo lung biopsy for another reason. In a series of 79 smokers with spontaneous pneumothorax requiring surgical intervention, RB was found in 70 (89 percent) lung biopsies [13]. Associated emphysematous lesions or desquamative interstitial pneumonitis were noted in approximately half of the patients with RB. Histopathologic assessment of lung tissue from a cohort of patients who underwent surgical resection for suspicious lung nodules/masses (89 percent were ever-smokers) identified radiographic pattern RB-ILD in 3.1 percent and histopathologic RB in 12.8 percent of these subjects, respectively [14].

Other estimates are based on the relative frequency of RB-ILD among patients with idiopathic interstitial pneumonias (IIPs) [15-21]. In a review of 168 lung biopsies performed for suspicion of idiopathic pulmonary fibrosis, 10 were RB-ILD [15]. In reviews of series from individual countries, RB-ILD was specifically identified in approximately 2 to 13 percent of cases of IIP [17,20]. In a study from Greece, the incidence of RB-ILD was estimated to be 0.04 per 100,000 [19]. (See 'Histopathology' below and "Idiopathic interstitial pneumonias: Classification and pathology".)

PATHOGENESIS — The exact pathogenesis of RB-ILD is unknown, although almost all patients with RB-ILD are current or former cigarette smokers, suggesting a key etiologic role of cigarette smoking. The role of cigarette smoking is supported by the improvement in disease manifestations that often accompanies smoking cessation. In addition, radiologic studies suggest a relationship between the duration and intensity of cigarette smoking and the presence on chest radiographs of the small irregular opacities (so-called "dirty lungs") associated with RB and RB-ILD [22-25].

Histopathologically, a lack of fibroblastic foci and bronchiolocentric distribution strongly differentiates RB-ILD from usual interstitial pneumonia, the pattern seen in interstitial pulmonary fibrosis. These differences suggest distinct underlying pathologic processes. In contrast, desquamative interstitial pneumonitis (DIP), which is highly associated with cigarette smoking, has similar pathologic changes to RB-ILD and may share a common pathogenesis. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Pathology' and "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Mechanisms of fibrosis'.)

CLINICAL FEATURES — Virtually all patients with RB-ILD are current or former cigarette smokers (>30 pack years) [2,3,15]. Rarely, patients have been reported who have substantial passive cigarette smoke exposure or heavy use of electronic cigarettes (vaping) [26-28].

Patients typically present in their 30s to 50s with subacute symptoms of dyspnea (94 percent), wheeze (69 percent), cough (66 percent), and/or sputum production (50 percent) (figure 1) [29]. Pneumothorax, hemoptysis, and acute respiratory failure are less common initial manifestations [13,30,31]. (See "Treatment of secondary spontaneous pneumothorax in adults".)

Fine, bibasilar end-inspiratory crackles are common findings (40 to 70 percent) on chest examination [29,32]. The crackles are described as being more coarse than those heard in other ILDs, such as idiopathic pulmonary fibrosis; they occur throughout inspiration and sometimes continue into expiration. Clubbing of the digits is unusual but has been reported in a small number of patients with RB-ILD [29,33]. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

DIAGNOSTIC EVALUATION — RB-ILD is typically suspected when a current or recent cigarette smoker presents with nonspecific respiratory symptoms, such as dyspnea or cough, and has an abnormal chest radiograph. The most important diagnostic (and therapeutic) step is cessation of cigarette smoking and avoiding exposure to cigarette smoke.

Laboratory studies — Routine laboratory studies are nonspecific in RB-ILD and are more helpful in excluding alternative diagnoses than in making a diagnosis of RB-ILD. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests'.)

An alpha-1 antitrypsin (AAT) level is commonly obtained in cigarette smokers with progressive dyspnea to exclude AAT deficiency. Other testing for rheumatic disease or hypersensitivity pneumonitis depends on the presence of extrapulmonary clinical findings suggestive of rheumatic disease and a history of occupational or other exposures that might cause hypersensitivity pneumonitis. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis' and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Laboratory tests'.)

Pulmonary function tests — Pulmonary function tests (PFTs) are obtained to ascertain the pattern and magnitude of ventilatory impairment. The most common PFT finding in RB-ILD is a mixed obstructive-restrictive pattern with mild to moderate reduction in diffusing capacity for carbon monoxide (DLCO) [1,32]. The mixture of obstructive and restrictive patterns is attributed to the airway inflammation from heavy cigarette smoke exposure, which causes obstructive physiology, and the interstitial disease associated with RB-ILD, which causes restriction and a gas transfer abnormality. Occasionally, an isolated increase in residual volume (ie, mild air trapping) is noted. (See "Overview of pulmonary function testing in adults".)

Few studies of gas exchange in RB-ILD have been reported. In a series of 10 patients with RB-ILD, the DLCO was moderately reduced (mean 57 percent of predicted) in eight patients in association with abnormalities in spirometry or lung volume [32]. One patient had a reduced DLCO without other PFT abnormalities and one had completely normal PFTs. (See "Diffusing capacity for carbon monoxide" and "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Diffusing capacity'.)

Pulse oximetry is mildly reduced at rest or with exercise in most patients, but may occasionally be severely reduced [29,32-34]. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Gas exchange at rest and on exertion'.)

Imaging — Chest radiographs are usually obtained to evaluate dyspnea or cough in a cigarette smoker. The chest radiograph in RB-ILD often demonstrates diffuse, fine reticular or nodular opacities with preserved lung volumes (image 1), although the plain radiograph is normal in up to 28 percent [32,35]. Bronchial wall thickening, prominence of the peribronchovascular markings, small regular and irregular opacities, and small peripheral ring shadows are other common features of RB-ILD [36]. (See "Evaluation of diffuse lung disease by conventional chest radiography", section on 'Basic patterns'.)

High-resolution computed tomography (HRCT) findings are nonspecific and include diffuse or patchy ground-glass opacities, centrilobular nodules, and air trapping (image 2 and image 3) [1,35,37-40]. In a series of 21 patients, HRCT findings included central bronchial wall thickening (90 percent), peripheral bronchial wall thickening (86 percent), centrilobular nodules (71 percent), and ground-glass opacity (67 percent). Ill-defined centrilobular nodules with upper lung zone predominance and without tree-in-bud opacities were noted in five patients with RB-ILD [39].

Centrilobular emphysema is reported in 57 percent of patients with RB-ILD, usually in the upper lung zones; septal lines and a reticular pattern are noted in 33 percent [29,35]. Atelectasis, intralobular lines, interlobular septal thickening, and peripheral blebs have been reported less commonly. (See "High resolution computed tomography of the lungs", section on 'HRCT patterns' and 'Differential diagnosis' below.)

Ground-glass nodules may be seen on HRCT scans of asymptomatic smokers due to RB, so this finding does not necessarily imply RB-ILD in the absence of symptomatic or physiologic impairment.

Bronchoscopy — Bronchoscopy with bronchoalveolar lavage (BAL) is typically reserved for patients with diagnostic uncertainty in the setting of moderate to severe disease on the basis of symptoms, pulmonary function impairment, or imaging or progressive disease despite smoking cessation. For patients with mild disease, it is reasonable to await a response to smoking cessation before proceeding with BAL. The main purpose of BAL is to exclude other processes in the differential, as the BAL findings of RB-ILD are nonspecific [29,41]. (See 'Differential diagnosis' below.)

BAL specimens are obtained from areas of radiographic abnormality and sent for total and differential cell counts, microbiologic studies, and cytology. (See "Basic principles and technique of bronchoalveolar lavage", section on 'Cell counting' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

The BAL in patients with RB-ILD shows similar cell counts to those of healthy cigarette smokers, such as an increased number of macrophages with golden- (most common), brown-, or black-pigmented inclusions, and proportionately lower percentages of other cellular constituents. Absence of pigmented macrophages is atypical and should lead to consideration of an alternate diagnosis. Neutrophilia and eosinophilia in the BAL fluid are rare in RB-ILD. (See 'Histopathology' below.)

Transbronchial biopsy is obtained during bronchoscopy when technically feasible. As with BAL, the main purpose is to exclude other diseases. A larger biopsy sample than can be obtained with transbronchial biopsy is typically needed to confirm a diagnosis of RB-ILD. Tissue samples are sent for histopathologic and microbiologic analysis. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy'.)

Surgical lung biopsy — Surgical lung biopsy is not always necessary in RB-ILD. If the diagnosis is strongly suspected based on clinical features, pulmonary function test results, and imaging studies, a trial of smoking cessation should precede lung biopsy. In contrast, surgical lung biopsy is typically obtained when the diagnosis remains unclear after the above studies, the patient has moderate to severe respiratory impairment, and does not improve following smoking cessation. Lung biopsy can exclude other ILDs and provide corroborative evidence of RB-ILD [42,43]. (See 'Differential diagnosis' below and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Overview'.)

Lung biopsy may be obtained via video-assisted thoracoscopic surgery (VATS) or open thoracotomy. Ideally, samples are obtained from more than one lobe, targeting areas of varying severity of radiographic disease, as determined by HRCT. Alternatively, transbronchial cryobiopsy is an emerging technique for lung biopsy, where available. A confident diagnosis of RB-ILD or desquamative interstitial pneumonia by transbronchial cryobiopsy has only been reported in a small number of patients [44,45]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Specimen collection' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy'.)

Histopathology — The classic lesion in RB-ILD is the accumulation of tan-pigmented macrophages (ie, smokers' macrophages) within the lumens of first and second order respiratory bronchioles (table 1) [5,7,9,11,46,47]. These intraluminal macrophages are accompanied by a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes. The interstitial histiocytes may contain dusty brown cytoplasmic pigment identical to that seen within the intraluminal macrophages, or they may contain coarse black anthracotic pigment [7,47]. The bronchioles may be ectatic and mucus filled. Peribronchiolar fibrosis expands in a stellate fashion into contiguous alveolar septa, which are lined by hyperplastic type II cells and cuboidal bronchiolar-type epithelium (picture 1). The changes are patchy at low magnification and have a bronchiolocentric distribution. The pulmonary parenchyma away from the airway is usually normal or may demonstrate mild hyperinflation. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Respiratory bronchiolitis-associated ILD'.)

Differentiating RB and RB-ILD – It is controversial whether RB-ILD can be differentiated from RB on pathologic grounds. Like RB-ILD, RB is characterized by accumulation of tan- or golden-pigmented "smokers'" macrophages in the bronchiolar lumens and chronic inflammation and fibrosis in membranous and respiratory bronchioles [9,46]. Variable, but generally mild fibrosis is described in the adjacent alveolar walls [11]. The lesions seen in RB-ILD may be more pronounced than the mainly mild clusters of brown-pigmented macrophages in respiratory and membranous bronchioles in otherwise healthy cigarette smokers with RB [7,10]. The more extensive the alveolar wall fibrosis, the more likely that the patient has RB-ILD rather than RB, although the pathologic changes require compatible clinical manifestations for confirmation of RB-ILD [11].

Differentiation from desquamative interstitial pneumonia – One challenge for the pathologist is to differentiate RB-ILD from desquamative interstitial pneumonia (DIP), another form of idiopathic interstitial pneumonia (IIP) that is strongly associated with cigarette smoking [3,7,13,48]. DIP is characterized by a prominent and diffuse accumulation of intra-alveolar macrophages (that may show fine granular positivity with iron stains), hyperplasia of type II pneumocytes, and mild interstitial chronic inflammation (table 2 and picture 2) [49]. A semiquantitative histologic evaluation comparing RB-ILD to DIP disclosed significantly more lymphoid follicles, interstitial fibrosis, and eosinophils in DIP [3]. The main feature that distinguishes DIP from RB-ILD is that DIP affects the lung in a more uniform and diffuse manner, lacking the bronchiolocentric distribution seen in RB-ILD, but there is considerable clinical, radiologic, and histologic overlap between these entities. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Desquamative interstitial pneumonia'.)

Airspace enlargement with fibrosis – Airspace enlargement with fibrosis has been identified as a pathologic feature in smokers that may be distinct from RB-ILD and may be difficult to distinguish from usual interstitial pneumonia (UIP) [12,50,51]. A case series described the HRCT imaging features in seven patients with histologically identified airspace enlargement with fibrosis; patchy areas of mild reticulation were noted around predominantly subpleural upper zone emphysematous changes, usually associated with patchy ground-glass opacities [52-54].

Differentiation from dust-related environmental lung disease – Accumulation of pigmented alveolar macrophages is not entirely specific to cigarette smoking or RB; similar abnormalities have been demonstrated in patients with other conditions (table 3) [55,56]. As an example, pigmented macrophages are noted in dust-related environmental lung disease (eg, pneumoconioses due to asbestos, silica, aluminum oxide, iron oxide). However, while reminiscent of RB, these macrophages lack the characteristic tan pigmentation of the smokers' macrophages of RB and are usually associated with dust nodules. (See "Silicosis", section on 'Pathology'.)

Radiographic-histopathologic correlation — The correlation between HRCT and histopathologic findings in RB-ILD can aid in diagnosis [57]. In a study of cigarette smokers undergoing lung resection for various pulmonary conditions, preoperative features on HRCT scans were correlated with histologic abnormalities of the small airways and parenchyma in the surgical lung specimens [58]. Parenchymal micronodules on the preoperative computed tomography (CT) scan correlated with the histopathologic presence of bronchiolectasis and peribronchiolar fibrosis [35,58]. Areas of ground-glass attenuation were noted on CT scans from 11 patients and were related to three different histopathologic features:

The accumulation of pigmented macrophages and mucus in the alveolar spaces, associated with mild interstitial inflammation and/or fibrosis (64 percent)

Thickening of the alveolar walls with inflammatory cells, but normal alveolar spaces (27 percent)

The presence of an organizing alveolitis (9 percent)

In a separate study of 21 patients with RB-ILD, the extent of ground-glass opacity correlated with the amount of macrophage accumulation in the alveoli and alveolar ducts [35].

DIAGNOSIS — A definitive diagnosis of RB-ILD requires histopathologic confirmation of tan-pigmented macrophages within the lumens of first and second order respiratory bronchioles and exclusion of other interstitial pneumonias in combination with clinical evidence of interstitial lung disease (see 'Radiographic-histopathologic correlation' above). However, a clinical diagnosis of RB-ILD is often sufficient and is based upon [1]:

A history of current or recent (within the past six months) cigarette smoking (eg, >30 pack years) with symptomatic and radiographic improvement following cigarette smoking cessation. However, lack of improvement with smoking cessation does not exclude RB-ILD [29,32,41].

Subacute onset of cough or dyspnea, accompanied by crackles on chest examination.

Pulmonary function test findings of a restrictive or mixed obstructive and restrictive pattern and a decreased diffusing capacity for carbon monoxide (DLCO) and/or pulse oxygen desaturation on ambulation. (See 'Pulmonary function tests' above.)

High-resolution computed tomography (HRCT) manifestations consistent with RB-ILD, especially upper lung zone patchy ground-glass opacities, or ill-defined centrilobular nodules, and bronchial wall thickening. (See 'Imaging' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of RB-ILD includes a number of bronchiolar disorders and diffuse parenchymal lung diseases, such as nonspecific interstitial pneumonia (NSIP), idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), pulmonary Langerhans cell histiocytosis, hypersensitivity pneumonitis, and diffuse alveolar hemorrhage (table 3). (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Pulmonary Langerhans cell histiocytosis" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis" and "The diffuse alveolar hemorrhage syndromes".)

NSIP and IPF – The clinical manifestations (eg, subacute onset of cough, dyspnea, and crackles) of NSIP resemble those of RB-ILD, although NSIP is characterized by basilar reticular and ground-glass radiographic changes, rather than the more upper lung zone, centrilobular changes of RB-ILD [1,29]. In addition, the mosaic ground-glass appearance of some cases of RB-ILD is not seen in IPF and the honeycomb change seen in IPF does not occur in RB-ILD [5,7]. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Usual interstitial pneumonia'.)

Desquamative interstitial pneumonia – RB-ILD shares several overlapping clinicopathologic features with DIP, a less common form of idiopathic interstitial pneumonia also associated with smoking, and may represent a spectrum of the same disease process [3,32,37,48,59]. On high-resolution computed tomography (HRCT), the ground-glass opacities of DIP tend to be more diffuse than centrilobular and have a lower lobe predilection. These processes are typically differentiated based on the histopathologic findings. (See 'Histopathology' above and "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Desquamative interstitial pneumonia'.)

Pulmonary Langerhans cell histiocytosis – Pulmonary Langerhans cell histiocytosis (PLCH; also known as eosinophilic granuloma), like RB-ILD, is strongly associated with cigarette smoking. Radiographically, PLCH, like RB-ILD, has ill-defined nodular opacities, but unlike RB-ILD, PLCH typically has upper lung zone cysts and honeycomb change. Areas of RB may be seen on pathologic examination of biopsies from patients with PLCH, but these areas are associated with the other features of PLCH. The key pathologic feature of PLCH is Langerhans cells, which are CD1a stain positive and can often be identified in bronchoalveolar lavage (BAL) samples. (See "Pulmonary Langerhans cell histiocytosis", section on 'Lung biopsy'.)

Hypersensitivity pneumonitis – Hypersensitivity pneumonitis can have similar clinical manifestations to RB-ILD, including centrilobular ground-glass nodules on HRCT. However, the histopathology of hypersensitivity pneumonitis is characterized by poorly formed, noncaseating granulomas or a prolific mononuclear cell infiltrate, neither of which are seen in RB-ILD. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Surgical lung biopsy' and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Diagnosis'.)

Other interstitial lung diseases – Other interstitial lung diseases that may have a similar radiographic appearance to RB-ILD (eg, centrilobular nodules) include foreign body granulomatosis, follicular bronchiolitis associated with rheumatic disease, sarcoidosis, berylliosis, and metastatic pulmonary calcification. (See "Foreign body granulomatosis" and "Overview of bronchiolar disorders in adults", section on 'Follicular bronchiolitis' and "Clinical manifestations and diagnosis of sarcoidosis" and "Chronic beryllium disease (berylliosis)" and "Calcification and ossification of the lungs", section on 'Metastatic pulmonary calcification'.)

Diffuse alveolar hemorrhage – Diffuse alveolar hemorrhage is characterized by the accumulation of pigmented macrophages, similar to RB-ILD. However, the macrophages in alveolar hemorrhage contain hemosiderin pigment, which forms large, coarse, refractile granules, while the pigment in RB-ILD is more finely distributed and indistinct. Additionally, the pigmented macrophages in alveolar hemorrhage are randomly distributed, whereas the pigmented macrophages in RB-ILD have a bronchiolocentric distribution. (See "Idiopathic interstitial pneumonias: Classification and pathology", section on 'Respiratory bronchiolitis-associated ILD'.)

INITIAL THERAPY — The initial management of RB-ILD is largely focused on smoking cessation and supportive care.

Smoking cessation — Smoking cessation is strongly advised for patients with RB-ILD, although data regarding the likelihood of symptomatic and physiologic improvement following smoking cessation are conflicting [5,29,32,41,43]. In a retrospective cohort study of RB-ILD, among the 18 patients who discontinued smoking, less than a third had symptomatic and/or physiologic improvement [29]. On the other hand, data from case reports and small case series suggest that approximately two-thirds of those who quit smoking have clinical improvement [5,7,15,32]. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation" and "Benefits and consequences of smoking cessation", section on 'Benefits of smoking cessation'.)

Improvements in the high-resolution computed tomography (HRCT) findings of ground-glass opacities and centrilobular nodules have been reported among five patients with RB-ILD who quit smoking [41]. These radiographic improvements were associated with modest improvements in symptoms and diffusing capacity, but not in spirometry or lung volumes. Based on a cohort of lung cancer subjects with smoking-related interstitial fibrosis, RB may regress following cessation of smoking [60].

Supportive therapy — Supportive care, although not formally examined in RB-ILD, generally includes supplemental oxygen, pulmonary rehabilitation, and vaccination with influenza and pneumococcal vaccines. (See "Long-term supplemental oxygen therapy", section on 'Indications' and "Pulmonary rehabilitation" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)

Some patients with RB-ILD also have a component of chronic obstructive pulmonary disease (COPD) that may respond to specific therapy, such as inhaled anticholinergic agents, beta-agonist bronchodilators, or glucocorticoids. (See "Stable COPD: Initial pharmacologic management".)

Some patients with RB-ILD will meet criteria for lung cancer screening with annual low-dose CT. (See "Screening for lung cancer".)

LACK OF RESPONSE TO INITIAL THERAPY — Effective pharmacologic therapy for RB-ILD has not been established.

Glucocorticoid therapy — For patients who have progressive RB-ILD despite smoking cessation, glucocorticoid therapy is sometimes used, but data supporting its efficacy are conflicting [29,32,33,35]. We typically reserve oral glucocorticoid therapy for patients who have advanced disease or progressive deterioration despite smoking cessation. When initiating oral glucocorticoid therapy, we typically begin with prednisone at 0.5 mg/kg ideal body weight per day up to a maximum of 30 mg/day for one month followed by 20 mg/day for an additional two months, although the optimal dosing has not been formally studied [61].

When a patient responds or stabilizes with treatment, the prednisone dose is gradually tapered, aiming to reach 5 to 10 mg daily or on alternate days, by the end of six to nine months, with attempted cessation after approximately 12 months. Even among patients with an initial response, worsening during tapering or discontinuing glucocorticoids is not uncommon.

When no apparent improvement is noted after the first three months of treatment, we taper and discontinue glucocorticoids as quickly as possible.

Glucocorticoid treatment is associated with a variety of side effects. We support ongoing assessment of the risks and benefits of continued steroid use, as well as proactive measures to reduce adverse effects (eg, prevention of bone loss and opportunistic infection). (See "Major adverse effects of systemic glucocorticoids".)

Case series of glucocorticoid therapy have yielded mixed results:

In the retrospective cohort study described above (see 'Smoking cessation' above), the 15 patients who were treated with oral prednisone experienced progressive deterioration in pulmonary function over several years, and one patient died of respiratory failure [29]. It is unclear whether the progression of disease on glucocorticoid therapy reflects the initiation of therapy in more advanced or clinically progressing patients, or an adverse effect of the therapy.

In an observational study of 12 patients with RB-ILD, of whom 11 received glucocorticoid therapy, initial improvement in symptoms was noted in 6, but over the long term only 3 remained improved, while 8 had disease stabilization, and 1 experienced disease progression [32]. However, only four of the patients successfully quit smoking.

In a series of nine patients, who discontinued smoking and took oral glucocorticoid therapy, all had clinical and functional improvement and some had radiographic improvement [35].

In a case series, two patients who continued to smoke had progressive disease despite therapy with prednisone in one patient and prednisone with azathioprine in the other [33]. Subsequently, both improved with smoking cessation while no longer taking immunosuppressive therapy.

Second-line immunosuppressive agents — Only rare use of immunosuppressive therapy has been reported for RB-ILD, generally for patients with advanced disease and without reported success [15,29]. We only add immunosuppressive therapy (eg, azathioprine) when a patient has had a response to glucocorticoid therapy and needs a glucocorticoid-sparing agent. When a glucocorticoid-sparing agent is added, we favor azathioprine as it is associated with the least toxicity among the immunosuppressive agents. The use of azathioprine in interstitial lung disease is discussed separately. (See "Treatment and prognosis of nonspecific interstitial pneumonia", section on 'Azathioprine' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

Lung transplantation — Lung transplantation has not been reported for RB-ILD, in particular. The guidelines for lung transplantation for ILD (eg, diffusing capacity [DLCO] <39 percent, oxygen desaturation <88 percent on six-minute walk test, or decrease in forced vital capacity of 10 percent or greater within six months) are discussed separately [62]. (See "Lung transplantation: General guidelines for recipient selection" and "Lung transplantation: Disease-based choice of procedure", section on 'Interstitial lung disease'.)

PROGNOSIS — Long-term survival is common among patients with RB-ILD [5,7,15,29,32]. However, the clinical course of symptoms, pulmonary function, and radiographic abnormalities is variable:

Several small case series suggest that RB-ILD has a good prognosis and is often reversible with smoking cessation [5,7,15,32,41]. (See 'Smoking cessation' above.)

In contrast, the retrospective cohort study of 25 patients found symptomatic improvement, stabilization, and deterioration in 28, 44, and 28 percent, respectively [29]. Physiologic improvement occurred in only 10 percent of patients.

Patients with RB-ILD may have a considerable risk for lung cancer [63].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

Respiratory bronchiolitis (RB) is an asymptomatic pathologic finding in cigarette smokers that is characterized by accumulation of tan- or yellow-pigmented macrophages in the bronchiolar lumens with associated chronic inflammation and fibrosis extending from respiratory bronchioles to the alveolar walls (table 1). (See 'Definition' above.)

Respiratory bronchiolitis-interstitial lung disease (RB-ILD) is a distinct form of interstitial lung disease (ILD) in which the pathologic changes of RB are associated clinical evidence of ILD (eg, symptoms and abnormalities on chest imaging studies and pulmonary function tests). (See 'Definition' above.)

The distinction between RB and RB-ILD is largely based on the clinical evidence of ILD, as the histopathologic extent of alveolar wall fibrosis is not an adequate discriminative feature. (See 'Definition' above and 'Histopathology' above.)

Patients with RB-ILD are typically current or former cigarette smokers who present in their 30s to 50s with subacute symptoms of cough and dyspnea. Fine, bibasilar end-inspiratory crackles are common on chest examination. (See 'Clinical features' above.)

High-resolution computed tomography (HRCT) findings are nonspecific and include diffuse or patchy ground-glass opacities, centrilobular nodules, and air trapping (image 3). Bronchoscopy with bronchoalveolar lavage (BAL) can help identify compatible findings (ie, tan- or yellow-pigmented macrophages) and exclude alternative diagnoses, such as hypersensitivity pneumonitis. (See 'Bronchoscopy' above.)

When respiratory impairment is mild, the diagnosis of RB-ILD may be based on strong clinical suspicion and compatible pulmonary function test and HRCT findings. Stabilization or improvement with smoking cessation can obviate the need for invasive studies. For more severe or progressive respiratory impairment despite smoking cessation, lung biopsy is often obtained to confirm the diagnosis and exclude other treatable interstitial lung diseases. (See 'Diagnostic evaluation' above.)

The differential diagnosis of RB-ILD includes a number of diffuse parenchymal lung diseases, such as idiopathic pulmonary fibrosis (IPF), desquamative interstitial pneumonia (DIP), pulmonary Langerhans cell histiocytosis, hypersensitivity pneumonitis, and diffuse alveolar hemorrhage. (See 'Differential diagnosis' above.)

For all patients with a suspected or firm diagnosis of RB-ILD, every effort should be made to facilitate smoking cessation, as a significant portion of patients who stop smoking will have improvement or stabilization of disease. (See 'Initial therapy' above.)

Supportive care for RB-ILD includes pulmonary rehabilitation, vaccination with influenza and pneumococcal vaccines, and supplemental oxygen (if indicated). For patients with a component of chronic obstructive pulmonary disease (COPD), specific therapy, such as inhaled anticholinergic agents, inhaled beta-agonist bronchodilators, or inhaled glucocorticoids, may be of benefit. (See 'Supportive therapy' above and "Long-term supplemental oxygen therapy" and "Pulmonary rehabilitation" and "Stable COPD: Initial pharmacologic management".)

For patients with a new diagnosis of RB-ILD and mild to moderate respiratory impairment, an observation period of three months or longer after smoking cessation is reasonable before initiating pharmacologic therapy (ie, glucocorticoids), as many patients will improve with smoking cessation alone. (See 'Smoking cessation' above.)

For patients who have more advanced disease without improvement after smoking cessation or have progressive deterioration, we suggest a trial of oral glucocorticoid therapy (Grade 2C). The usual dose of oral glucocorticoid is the equivalent of prednisone at 0.5 mg/kg ideal body weight per day up to a maximum of 30 mg/day for one month, followed by 20 mg/day for an additional two months. Subsequent dosing is based on the response to therapy. Alternatively, it is reasonable to continue with supportive care alone, due to the potential side effects of glucocorticoid therapy and the lack of data to suggest benefit. (See 'Glucocorticoid therapy' above.)

Long-term survival is common among patients with RB-ILD and almost 50 percent experience disease stabilization. (See 'Prognosis' above.)

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Topic 4319 Version 21.0

References

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