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Overview of bronchiolar disorders in adults

Overview of bronchiolar disorders in adults
Literature review current through: Jan 2024.
This topic last updated: Mar 29, 2023.

INTRODUCTION — Bronchiolitis is a general term used to describe a nonspecific inflammatory injury that primarily affects the small airways (eg, 2 mm or less in diameter without cartilage) (picture 1), often sparing a considerable portion of the interstitium [1-6].

An overview of bronchiolar disorders in adults is provided here. The acute infectious bronchiolitis that occurs predominantly in young children and proliferative bronchiolitis, a component of organizing pneumonia (previously known as bronchiolitis obliterans organizing pneumonia [BOOP]) are described separately. (See "Bronchiolitis in infants and children: Clinical features and diagnosis" and "Bronchiolitis in infants and children: Treatment, outcome, and prevention" and "Cryptogenic organizing pneumonia".)

DEFINITIONS — Bronchiolitis is a broad histopathologic term that refers to inflammation, narrowing, or obliteration of bronchioles (table 1). The nomenclature of bronchiolitis has been confusing because clinicians and pathologists have sometimes used one term to describe different disease processes [3,4,7-9]. The following are definitions of the various descriptors used in reference to bronchiolar disorders:

Acute bronchiolitis – Acute bronchiolitis is histologically characterized by intense inflammation of small bronchioles with associated epithelial necrosis and sloughing. Acute bronchiolitis is rare in adults but has been most commonly associated with infections and inhalational injury.

Bronchiolitis obliterans – The term bronchiolitis obliterans (also called obliterative bronchiolitis) is used by clinicians to describe the clinical syndrome of dyspnea and airflow limitation not reversible with inhaled bronchodilator that is associated with small airways injury due to a spectrum of inhalational agents, infections, systemic diseases, chronic lung allograft dysfunction after lung transplantation, and graft versus host disease in hematopoietic cell transplantation (table 2).

It is typically associated with the histopathologic description of constrictive bronchiolitis (see below). However, in the older literature, pathologists used this term to describe intrabronchiolar polypoid protrusions that obliterate the lumen from within, what is now called proliferative bronchiolitis [9].

Bronchiolitis obliterans syndrome (BOS) – Patients who have undergone lung transplantation or hematopoietic cell transplantation can develop bronchiolitis obliterans (BO). BOS is a clinical term that is used to describe airflow limitation that is a marker for BO in transplant recipients when the patient has not had confirmatory lung biopsy. Thus, following lung transplantation, the diagnosis of BOS can be made on the basis of new airflow limitation, without histologic confirmation. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Constrictive bronchiolitis – Constrictive bronchiolitis is the histopathologic correlate of the clinical syndrome bronchiolitis obliterans and is characterized by fibroproliferative thickening of the bronchiolar walls causing narrowing of the bronchiolar lumen, which may progress to the complete obliteration of bronchioles.

Proliferative bronchiolitis – Proliferative bronchiolitis is a distinct histopathologic pattern in which characteristic intraluminal fibrotic buds, called Masson bodies, extend beyond alveolar ducts to alveoli. When proliferative bronchiolitis is associated with extension of inflammatory cells into the more distal lung parenchyma, the process is called organizing pneumonia. The cryptogenic form of organizing pneumonia, previously called idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) is discussed separately. (See 'Proliferative bronchiolitis' below and "Cryptogenic organizing pneumonia".)

Respiratory bronchiolitis – Respiratory bronchiolitis is seen predominantly in cigarette smokers and is associated with the characteristic finding of tan-pigmented macrophages in the respiratory bronchioles. Respiratory bronchiolitis is typically asymptomatic; when the process advances enough to cause symptoms and radiographic opacities, it is called respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). (See 'Respiratory bronchiolitis' below and "Respiratory bronchiolitis-associated interstitial lung disease".)

Cellular bronchiolitis – Cellular bronchiolitis is a pathologic term that refers to the presence of an inflammatory cell infiltrate (eg, lymphocytes, neutrophils, eosinophils) involving the bronchioles. Follicular bronchiolitis, respiratory bronchiolitis, and diffuse panbronchiolitis are forms of cellular bronchiolitis. Cellular bronchiolitis can also be seen in association with diseases such as hypersensitivity pneumonitis, granulomatosis with polyangiitis, and asthma.

BRONCHIOLITIS OBLITERANS — Bronchiolitis obliterans, also known as obliterative bronchiolitis, refers to the clinical syndrome associated with small airways injury caused by a spectrum of inhalational, infectious, and drug exposures, and also following lung or hematopoietic cell transplantation (table 1) [3]. The clinical syndrome is typically characterized by dyspnea, airflow limitation that is not reversible by inhaled bronchodilator, and a chest radiograph that shows normal or hyperinflated lungs. Histopathologically, bronchiolitis obliterans is associated with constrictive bronchiolitis, and the two terms are sometimes used interchangeably in the literature. (See 'Histopathology' below.)

Pathogenesis — In most instances, the pathogenesis of bronchiolitis remains poorly defined. Injury to the bronchiolar epithelium appears to initiate the process (figure 1). The alveoli immediately adjacent to the small airways are also frequently involved. The repair process may result in complete recovery or may be characterized by excessive proliferation of granulation tissue that causes narrowing or obliteration of the airway lumen. In some cases, fibrosis is primarily submucosal and peribronchiolar in distribution, resulting in extrinsic narrowing or obliteration of the bronchiolar lumen.

Causes — A broad range of agents and disease processes can cause lung injury that leads to bronchiolitis obliterans (table 2) [3,10-31]. Examples include:

Inhalational injury – Inhalation of toxins and irritants, including nitrogen oxides, ammonia, chlorine, welding fumes, volatile food flavorings (eg, diacetyl), volatile organic compounds, ultra-fine particles, vitamin E acetate, mineral or heavy metal dusts, free-base cocaine, and other chemicals via vaping may result in small airway injury. For example, soldiers deployed to the 1991 Gulf War and the post-9/11 conflicts in Iraq and Afghanistan who experienced exposure to airborne hazards (including sandstorms, burn pits, and improvised explosive devices) are at risk for bronchiolitis obliterans.

Infection – Infections including respiratory syncytial virus, adenovirus, influenza, parainfluenza, or Mycoplasma pneumoniae have been linked to small airway disease.

Reactions to pharmaceuticals –Inflammatory reactions to systemic administration of pharmacologic agents including busulfan, gold, penicillamine, and sulfasalazine may rarely result in bronchiolitis obliterans.

Manifestation of systemic disease – Bronchiolitis obliterans may arise in association with systemic diseases including graft-versus-host disease (GVHD) in lung and hematopoietic cell transplantation, rheumatoid arthritis, Sjögren's disease, as well as, rarely, ulcerative colitis/primary biliary cholangitis and paraneoplastic pemphigus.

Idiopathic – Bronchiolitis obliterans may arise without known cause, also referred to as cryptogenic bronchiolitis obliterans.

(See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Airway obstruction' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans' and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Paraneoplastic pemphigus", section on 'Pulmonary disease'.)

Clinical manifestations — The clinical manifestations of constrictive bronchiolitis usually include dyspnea and cough, sometimes with sputum production. Symptoms are generally slowly progressive over weeks to months [3,4,27]. Among patients with rheumatoid arthritis, symptoms typically follow the onset of joint symptoms by several years (mean 9.5 ± 10 years), although they may precede or present concomitantly with the diagnosis in approximately 10 percent [32].

On examination, tachypnea, crackles, and/or wheezing may be present.

Evaluation — When bronchiolitis obliterans is suspected based on symptoms of cough and dyspnea that are not well-explained by asthma or COPD, the most helpful tests are chest imaging, usually a high-resolution computed tomography (HRCT) scan with inspiratory and expiratory images and pulmonary function testing with diffusing capacity and ambulatory oximetry.

The evaluation of possible bronchiolitis obliterans in patients who have undergone lung or hematopoietic transplantation is discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Evaluation for CLAD' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes".)

Pulmonary function testing — Pulmonary function testing (PFT) is helpful for excluding other diagnostic possibilities, providing support for the diagnosis of bronchiolitis, and defining the severity of disease. In bronchiolitis obliterans, spirometry may be normal or show obstructive changes with air trapping, but without reversibility following inhaled bronchodilator [4,16,17]. Given the vast number of bronchioles, a large percentage can be narrowed or obstructed before a significant loss of function occurs [33]. (See "Overview of pulmonary function testing in adults".)

Lung volumes often show air trapping (eg, increased residual volume and functional residual capacity), but occasionally, show a mixed pattern of obstruction and restriction [33] or restriction alone [34]. The restriction is probably related to the proportion of airways that are fully obstructed.

The diffusing capacity for carbon monoxide (DLCO) is usually reduced, particularly as the disease progresses [3,35]. In a case series of soldiers with constrictive bronchiolitis (bronchiolitis obliterans), the most common abnormality on PFT was a reduced DLCO [17]. Resting hypoxemia is frequently present. (See "Diffusing capacity for carbon monoxide".)

Chest imaging — In most cases of chronic bronchiolitis, the plain chest radiograph is normal or shows only increased bronchial wall thickening or hyperinflation (without marked flattening of the diaphragms or hyperlucent areas that would suggest emphysema).

HRCT is more likely to identify findings consistent with bronchiolitis than plain chest radiographs, particularly when inspiratory and expiratory HRCT images are obtained (table 1) [36-39]. The most consistent abnormalities on HRCT are expiratory air trapping (mosaic or diffuse) and bronchial wall thickening (eg, nodules and "v" or "y" shaped branching linear opacities). The nodules are centrilobular, consistent with the anatomic location of bronchioles. In addition, ground glass opacity in a mosaic pattern of attenuation is seen in some patients; the mosaic attenuation may be enhanced on expiratory views due to air trapping [35]. Except for a mosaic pattern of attenuation, which is highly suggestive of bronchiolitis obliterans, it is often difficult to distinguish severe asthma from bronchiolitis [36,40].

Cylindric bronchial dilation or bronchiectasis can be seen with bronchiolitis obliterans, particularly in cases related to transplantation, rheumatic disease, inhalation of toxic fumes, and previous infection [38]. Subpleural distribution of patchy consolidation or ground glass density is a characteristic finding of proliferative bronchiolitis on HRCT. Well or poorly-defined nodules on CT scans may correlate with areas of organizing pneumonia [8].

Rarely, diffuse cystic lung diseases has been reported in patients with evidence of chronic cellular or constrictive bronchiolitis on surgical lung biopsy [41].

Bronchoscopy — Findings on bronchoscopy and bronchoalveolar lavage in bronchiolitis obliterans are nonspecific. However, bronchoscopy can be helpful in identifying features suggestive of other disease processes in the differential diagnosis, such as the high bronchoalveolar lavage lymphocyte counts in hypersensitivity pneumonitis or endobronchial nonnecrotizing granulomas in airway sarcoid. In addition, bronchoalveolar lavage (BAL) can help diagnose infection or other etiologies as a cause of deteriorating lung function. (See "Basic principles and technique of bronchoalveolar lavage".)

Transbronchial lung biopsies generally yield insufficient tissue to make a diagnosis of bronchiolitis obliterans, as the histopathologic findings are subtle and patchy, although they may help exclude other processes [1,42]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy'.)

Diagnosis — The diagnosis of bronchiolitis obliterans should be considered in patients who present with insidious onset of dyspnea and cough, especially when the symptoms and signs do not follow a typical pattern for asthma or COPD. As an example, bronchiolitis should be considered in a nonsmoker when airflow limitation is irreversible or associated with a gas transfer abnormality.

The clinical setting may also alert the clinician to suspect bronchiolitis; for example, recent toxic fume exposure, symptoms of viral infection, history of organ transplantation, or concomitant rheumatic disease. (See 'Causes' above.)

A firm diagnosis of bronchiolitis obliterans usually requires a lung biopsy, although in a high probability clinical setting such as a known predisposing inhalational exposure or hematopoietic cell or lung transplantation (see 'Causes' above), the combination of airflow limitation on spirometry and HRCT showing expiratory air trapping (mosaic or diffuse), bronchial wall thickening, and centrilobular nodules may be sufficient to make the diagnosis. (See "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans' and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Diagnosis'.)

Lung biopsy — An open or thoracoscopic lung biopsy is required to make a definitive diagnosis, although tissue confirmation may not be necessary in patients with a clear predisposition and typical HRCT. A multidisciplinary discussion can help guide the decision-making, balancing the benefit of a clear diagnosis with potential risk of the procedure. Transbronchial lung biopsy is often inadequate for diagnosis because the disease is patchy and involves the respiratory and membranous bronchioles but may be helpful in excluding alternate diagnostic possibilities. (See 'Bronchoscopy' above.)

Histopathology — The histopathologic lesions of bronchiolitis obliterans are often subtle, and specific attention must be placed on examining the small airways. This may include step sectioning of the tissue and using special stains (elastic stains) to identify remnants of the small airway walls. Constrictive bronchiolitis, the histopathologic lesion most commonly seen following inhalation injury, is characterized by alterations in the walls of membranous and respiratory bronchioles, often without extensive changes in alveolar ducts and alveolar walls [7,17]. These changes lead to concentric narrowing or complete obliteration of the airway lumen (picture 2). The associated lesions comprise a spectrum of abnormalities that can include [3,9,43]:

Subtle cellular infiltrates (predominantly T lymphocytes) around the small airways

Bronchiolar smooth muscle hypertrophy

Bronchiolectasia with mucus stasis, distortion, and fibrosis

Total obliterative bronchiolar scarring (picture 3)

Patients with predominant histopathologic features of constrictive bronchiolitis may have concomitant, but less frequent lesions of proliferative bronchiolitis [44]. (See 'Proliferative bronchiolitis' below.)

Differential diagnosis — The differential diagnosis of bronchiolitis obliterans includes severe asthma, COPD, hypersensitivity pneumonitis, sarcoidosis, and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

Aspiration-related bronchiolitis – The diagnosis of aspiration as a cause of small airway injury can be difficult. If untreated, chronic aspiration may result in permanent lung injury with fibrosis and bronchiectasis. Conditions associated with increased risk for aspiration include gastroesophageal reflux disease, neurologic conditions, head and neck cancer, prior irradiation, gastric surgery, and esophageal abnormalities such as dysmotility or hiatal hernia [39,45].

Asthma – Asthma is typically differentiated from bronchiolitis obliterans by the presence of reversible airflow limitation on spirometry. However, severe asthma can be associated with a component of irreversible airflow limitation. A reduction in diffusing capacity is uncommon in asthma, but common in bronchiolitis. While mosaic attenuation may rarely be seen in asthma, it is present in approximately 50 percent of patients with bronchiolitis obliterans. (See 'Chest imaging' above and "Asthma in adolescents and adults: Evaluation and diagnosis".)

A few patients with clinical features of severe asthma have been found to have hypereosinophilic obliterative bronchiolitis. These patients are poorly responsive to inhaled glucocorticoids, have eosinophilia in the peripheral blood (≥1000 cells/microL) and bronchoalveolar lavage (>25 percent), and an HRCT that is more consistent with bronchiolitis obliterans than asthma. (See "Evaluation of severe asthma in adolescents and adults", section on 'Assessing conditions that mimic asthma'.)

As asthma is common, individual patients with bronchiolitis obliterans may have a component of asthma and have a clinical response to inhaled bronchodilators.

COPD – Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation on spirometry that is irreversible or incompletely reversible. Most patients have a significant cigarette smoking history and lack exposure to the typical etiologic agents for bronchiolitis obliterans. While respiratory bronchiolitis is a common finding among cigarette smokers, it is usually asymptomatic, unless it progresses to respiratory bronchiolitis-interstitial lung disease (RB-ILD). (See "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Diagnosis' and 'Respiratory bronchiolitis' below.)

Hypersensitivity pneumonitis – Hypersensitivity pneumonitis, while typically associated with restrictive physiology, can cause small airways narrowing due to compression by epithelial and subepithelial granulomas. The history of exposure to organic dusts or other typical causes of hypersensitivity pneumonitis is a main differentiator from bronchiolitis obliterans. In hypersensitivity pneumonitis, histopathology demonstrates mononuclear cell infiltration and poorly-formed granulomas in the walls of bronchioles, in addition to the interstitial infiltration with lymphocytes [41]. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

Sarcoidosis – Sarcoidosis can have a similar presentation in terms of cough and dyspnea and, on occasion, airway sarcoid is associated with airflow limitation. More commonly, sarcoidosis is associated with a restrictive pattern (reduced vital capacity and total lung capacity) and a reduction in the DLCO; it is also not unusual for lung function to be normal. A lung or mediastinal lymph node biopsy showing well-formed, noncaseating granulomas would make sarcoidosis much more likely. (See "Clinical manifestations and diagnosis of sarcoidosis".)

Bronchocentric granulomatosis – Bronchocentric granulomatosis predominantly affects the bronchi, but bronchiolar inflammation may be present. Identification of fungal hyphae associated with granulomatous inflammation on bronchial biopsy would strongly support the diagnosis. (See "Bronchocentric granulomatosis", section on 'Diagnosis'.)

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) – DIPNECH is a generalized proliferation of pulmonary neuroendocrine cells that can be confined to the mucosa of the airways, invade locally to form "tumorlets," or develop into invasive neuroendocrine tumors (NETs; carcinoid tumors). The tumorlets are intimately related to an airway and are ≤5 mm in diameter. DIPNECH is considered a preinvasive precursor to pulmonary NETs. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Classification, histology, and histochemistry'.)

DIPNECH is predominantly seen in women and typically presents with cough and dyspnea, airflow limitation on spirometry, and multiple small nodules (4 to 10 mm) on computed tomography (CT) [46-49]. In one series of 30 patients with DIPNECH, 44 percent had associated constrictive bronchiolitis [46]. Serum chromogranin A levels may be elevated. Mosaic attenuation with multiple small nodules on chest CT is suggestive of DIPNECH [50]. The diagnosis is usually made by lung biopsy: transbronchial (showing pulmonary neuroendocrine cells), transbronchial cryobiopsy, or surgical. (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging".)

Most patients with DIPNECH remain stable for many years. The optimal treatment for patients who have progressive disease remains unclear. Various options are discussed separately. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis", section on 'Management of patients with DIPNECH'.)

Hypereosinophilic obliterative bronchiolitis – A small number of patients with clinical features of severe asthma have been found to have hypereosinophilic obliterative bronchiolitis. Differentiating characteristics of this condition include a peripheral blood eosinophil count ≥1000 cells/microL (1 x 109/L) and/or bronchoalveolar lavage eosinophils >25 percent; persistent airflow obstruction with a post bronchodilator forced expiratory volume in one second (FEV1) <80 percent predicted and an FEV1/forced vital capacity (FVC) <70 percent not improved after four to six weeks of high dose inhaled glucocorticoids; and a lung biopsy showing prominent bronchiolar wall infiltration by eosinophils and/or HRCT features of bronchiolitis. (See "Evaluation of severe asthma in adolescents and adults", section on 'Assessing conditions that mimic asthma'.)

Other bronchiolar disorders – Other bronchiolar disorders, such as airway-centered interstitial fibrosis (ACIF) and diffuse panbronchiolitis, can present similarly (table 1). ACIF is differentiated from bronchiolitis obliterans based on the pathology, and diffuse panbronchiolitis typically has concomitant symptoms of sinusitis and productive cough, in addition to different histopathologic features, as described below. (See 'Airway-centered interstitial fibrosis' below and 'Diffuse panbronchiolitis' below.)

Treatment — The optimal treatment for bronchiolitis obliterans (constrictive type) is not known, and data in support of the various options are limited. In a portion of patients, the disease is progressive despite all therapies and eventuates in respiratory failure. Other patients may not improve with therapy, but may have stable lung function over several years [51]. Thus, the decision to initiate therapy is often based on the severity of respiratory impairment and evidence of disease progression. When an underlying disease process is present, this may also influence treatment decisions. Unfortunately, bronchiolitis obliterans tends to be relatively refractory to therapy. The following represents our approach.

The treatment of bronchiolitis obliterans in the setting of lung or hematopoietic cell transplantation is discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Treatment of BOS' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)

Symptom-based and supportive therapy — General measures to reduce symptoms include inhaled bronchodilators and cough suppressants (eg, dextromethorphan, codeine), guided by symptomatic response and supplemental oxygen as needed to maintain the pulse oxygen saturation ≥89 percent. In addition, inhaled bronchodilators may be of benefit for dyspnea if the patient has a component of reversible airways obstruction. (See "Long-term supplemental oxygen therapy", section on 'Indications'.)

Supportive therapies that are helpful in other chronic lung diseases are advisable, such as smoking cessation (if needed), pulmonary rehabilitation, and vaccination against influenza and pneumococcus. (See "Overview of smoking cessation management in adults" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults".)

Cessation of culprit drugs and exposures — For patients taking a medication that has been associated with bronchiolitis obliterans, cessation of that medication is recommended although at times it is not clear whether the drug or the disease for which the drug is taken (eg, rheumatoid arthritis) is actually the culprit. In small series of workers exposed to food flavoring fumes (eg, diacetyl used in popcorn and other foods), cessation of exposure was associated with disease stabilization in some workers, although others have experienced progressive disease [11,34,52]. For patients with vaping-associated disease, it has also been reported that cessation of vaping can improve symptoms, with variable impact on lung function and imaging [28].

Pharmacotherapy — Macrolide antibiotics, systemic glucocorticoids, and immunosuppressive agents have been associated with benefit in isolated patients, but responses are variable.  

Macrolide antibiotics – Macrolide antibiotics are increasingly used in the long-term management of nontransplant-related bronchiolitis obliterans because of their success in diffuse panbronchiolitis [42,53-55]. For patients with cryptogenic bronchiolitis obliterans that is symptomatic, we suggest a three- to six-month trial of a macrolide antibiotic, such as a low oral dose of erythromycin (200 to 600 mg/day), azithromycin (250 mg/day), or clarithromycin (250 or 500 mg/day). Patients whose lung function stabilizes or improves can continue on long-term therapy. (See "Diffuse panbronchiolitis", section on 'Macrolide antibiotics'.)

Macrolide therapy has not been formally assessed in patients with bronchiolitis obliterans due to rheumatic disease or inhalational exposures (eg, diacetyl flavoring agents), but a similar trial of macrolide therapy may be reasonable in these patients.

The effect of macrolides may be influenced by the underlying disease.

In a series of 19 patients with bronchiolitis obliterans not related to transplantation, but including rheumatic diseases, 53 percent were treated with macrolide antibiotics; long-term follow-up revealed overall stability in lung function [51]. The associated literature review, which included an additional 104 patients, found a lower rate of macrolide use and greater mortality, providing some additional support for macrolide use.

In a report that included seven patients with cryptogenic bronchiolitis obliterans, none of the patients improved with macrolides, although the dose and duration of therapy were not given [27]. In the same report, pulmonary function did not improve with macrolides in five patients with rheumatoid arthritis. One patient with bronchiolitis obliterans that developed after exposure to dust at the World Trade Center improved with long-term azithromycin [56].

The role of macrolide antibiotics in lung and hematopoietic cell transplant-related BOS is discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Treatment of BOS' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)

Glucocorticoids – The rationale behind glucocorticoid and immunosuppressive therapy comes from the histopathologic identification of lymphocytic infiltrates and the association with diseases such as rheumatoid arthritis that tend to respond to these agents. However, the role and efficacy of systemic glucocorticoid therapy in nontransplant and nonrheumatic disease-related bronchiolitis obliterans is unclear. We typically reserve systemic glucocorticoids for patients with persistent symptoms and progressive deterioration in lung function. If a trial of glucocorticoids (eg, four to six weeks) does not lead to improvement in lung function, we taper and discontinue glucocorticoids.

Most case series of the constrictive type of bronchiolitis obliterans have not shown improvement with systemic glucocorticoids [27,32,43,57]. In a case series that included long-term follow-up of five patients with rheumatoid arthritis associated bronchiolitis obliterans and seven patients with cryptogenic bronchiolitis obliterans, none of the patients exhibited significant improvement with glucocorticoids, although only one patient experienced progressive respiratory impairment [27]. In a separate series of cryptogenic bronchiolitis obliterans, four patients were treated with oral glucocorticoids; none experienced improvement, although all had stable disease over one to five years [57].

Similarly, systemic glucocorticoids have not been of benefit in bronchiolitis obliterans associated with food flavoring (diacetyl)-associated bronchiolitis obliterans [52].

For patients with clinical features that overlap with asthma or a prior diagnosis of asthma (eg, partial response to bronchodilators), a trial of systemic or inhaled glucocorticoids following guidelines for asthma is reasonable. (See "An overview of asthma management", section on 'Initiating pharmacologic treatment'.)

High-dose glucocorticoids are typically part of the treatment of hematopoietic cell transplantation-related BOS, as described separately. (See "Treatment of chronic graft-versus-host disease", section on 'Prednisone'.)

Chronic therapy with systemic glucocorticoids is associated with a number of adverse effects. Steps to monitor, prevent, and treat these side effects are discussed separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Additional immunosuppressive therapy – While immunosuppressive therapy has been used in patients with bronchiolitis obliterans based on the histopathologic pattern and the association with rheumatic disease in some patients, clear benefit has not been demonstrated. Thus, we avoid cytotoxic immunosuppressive agents in patients with nontransplant related bronchiolitis obliterans, unless these agents are indicated to treat the underlying disease.

The use of cytotoxic immunosuppressive therapy (eg, cyclophosphamide, azathioprine, methotrexate) has been described in patients with rheumatoid arthritis [27,32] and food flavoring related bronchiolitis obliterans [52]. Other than the post-transplant experience, cytotoxic immunosuppressive agents have not been associated with significant improvement in lung function [27,52].

The tumor necrosis factor-alpha (TNF-alpha) inhibitors, etanercept and infliximab, have been suggested as possible treatment for bronchiolitis obliterans associated with rheumatoid arthritis and Sjögren's disease, although results are conflicting [27,58]. It is not known whether TNF-alpha inhibitors would be beneficial in other forms of bronchiolitis obliterans. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Obliterative bronchiolitis'.)

In patients with bronchiolitis obliterans syndrome following lung or hematopoietic cell transplantation, intensification of immunosuppression is sometimes successful in reversing or stabilizing bronchiolitis obliterans syndrome based on case series. The management of bronchiolitis obliterans syndrome following transplantation is discussed separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Treatment of BOS' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)

Antireflux therapy – Gastroesophageal reflux disease (GERD) is prevalent in lung transplantation recipients, and non-acid reflux has been associated with the development of bronchiolitis obliterans syndrome [59-63]. Aggressive therapy for GERD, possibly including surgery, has been proposed to prevent progression of lung transplant-related bronchiolitis obliterans syndrome, although additional studies are needed [64]. Whether antireflux therapy has a role in nontransplant bronchiolitis obliterans has not been formally examined. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Etiology and risk factors'.)

Lung transplantation — From 1995 to 2018, approximately 1 percent of primary lung transplantations were for bronchiolitis obliterans [65]. General guidelines for lung transplantation and outcomes are discussed separately. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

ACUTE BRONCHIOLITIS — Acute infectious bronchiolitis in adults has been reported in patients with Mycoplasma pneumoniae, respiratory syncytial virus, measles, influenza, pertussis, parainfluenza, and adenovirus [3,66-69]. The clinical presentation of bronchiolitis in adults is poorly defined. Generally, an upper respiratory illness precedes onset of lower respiratory symptoms of cough, dyspnea on exertion, fever, tachypnea, and wheezing [3]. In one series, computed tomography (CT) showed bronchial wall thickening, centrilobular nodules, and/or a tree-in-bud pattern [68]. The diagnosis is generally clinical, based on the setting and imaging results. Treatment is largely supportive or, when available, directed at the underlying disease (eg, Mycoplasma, influenza). Occasionally, this acute syndrome has been reported to progress to bronchiolitis obliterans. (See "Mycoplasma pneumoniae infection in adults", section on 'Treatment' and "Seasonal influenza in nonpregnant adults: Treatment" and 'Bronchiolitis obliterans' above.)

PROLIFERATIVE BRONCHIOLITIS — Proliferative bronchiolitis is a histopathologic finding characterized by a more cellular appearance than bronchiolitis obliterans with fibroblast proliferation and an organizing intraluminal exudate that occludes bronchioles from within. The characteristic intraluminal fibrotic buds, called Masson bodies, are seen in the respiratory bronchioles; when they extend beyond alveolar ducts to alveoli, the term organizing pneumonia is used. It is more common than constrictive bronchiolitis and is seen in association with many pulmonary disorders (table 1) [44].

Proliferative bronchiolitis is particularly extensive or prominent in patients with cryptogenic organizing pneumonitis (COP), previously called idiopathic bronchiolitis obliterans with organizing pneumonia (idiopathic BOOP). In COP, Masson bodies extend to the alveoli and may extend from one alveolus to another through the pores of Kohn (picture 4). Inflammatory changes in the surrounding alveolar walls and prominent foamy macrophages in alveolar spaces (ie, organizing pneumonia) are commonly present in COP. (See "Cryptogenic organizing pneumonia".)

Proliferative bronchiolitis can also be seen as a minor feature of other interstitial lung diseases, such as chronic eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, and nonspecific interstitial pneumonia.

The high-resolution computed tomography (HRCT) findings of proliferative bronchiolitis include patchy air-space consolidation, ground-glass opacities, and small nodular opacities in the periphery and lower lung zones. When proliferative bronchiolitis is the predominant histopathologic finding, the next step is to determine whether the patient has organizing pneumonia that is cryptogenic or due to another process (secondary organizing pneumonia) (table 3). Proliferative bronchiolitis is typically responsive to glucocorticoids; the specific treatment regimen depends on the clinical features and underlying cause. (See "Cryptogenic organizing pneumonia".)

FOLLICULAR BRONCHIOLITIS — Follicular bronchiolitis is characterized by lymphoid hyperplasia of bronchus-associated lymphoid tissue (BALT) [36,70]. Most cases of follicular bronchiolitis are associated with rheumatic diseases (particularly rheumatoid arthritis and Sjögren's disease), immunodeficiency (eg, HIV infection and acquired immunoglobulin deficiency), or hypersensitivity pneumonitis [71-76]. Follicular bronchiolitis can also be seen in the context of lymphoid interstitial pneumonia and diffuse panbronchiolitis [9]. It is rare for follicular bronchiolitis to present in the absence of one of these predisposing processes. (See "Lymphoid interstitial pneumonia", section on 'Pathologic findings' and "Diffuse panbronchiolitis", section on 'Pathology' and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Follicular bronchiolitis' and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Follicular bronchiolitis'.)

Patients present with progressive dyspnea, and the high-resolution computed tomography (HRCT) typically shows centrilobular and peribronchial nodules 1 to 12 mm in diameter [77,78]. The tree-in-bud pattern may be present. Areas of ground glass opacity and, rarely, bronchial dilation and interlobular septal thickening may be present [36,77]. Thin-walled cysts may also be seen (especially in patients with concomitant lymphocytic interstitial pneumonia); they are thought to be due to check-valve obstruction of small bronchioles by lymphatic tissue [36].

The diagnosis of follicular bronchiolitis is based on a lung biopsy that shows hyperplastic lymphoid follicles with reactive germinal centers distributed along the bronchioles. Sometimes, follicular bronchiolitis is a minor feature in patients with other interstitial lung diseases, such as nonspecific interstitial pneumonia and organizing pneumonia [9,74]. If peribronchiolar granulomas are noted, the possibility of sarcoidosis (tightly formed granulomas), granulomatosis with polyangiitis (necrotizing granulomas), or hypersensitivity pneumonitis (poorly-formed granulomas) should be explored.

Follicular bronchiolitis is usually treated as part of the underlying disease, whether it is associated with a rheumatic disease or immunodeficiency [1,36,79]. Anecdotal success with macrolide antibiotics and systemic glucocorticoids has been reported in primary follicular bronchiolitis [78,80,81].

RESPIRATORY BRONCHIOLITIS — Respiratory bronchiolitis is a well-recognized pathological lesion found in the lungs of many cigarette smokers that is usually asymptomatic. It is recognized by a characteristic finding of tan-pigmented macrophages in the respiratory bronchioles. These intraluminal macrophages are accompanied by a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes. Peribronchiolar fibrosis extends in a stellate pattern into contiguous alveolar walls. More severe, symptomatic disease generally reflects more extensive interstitial involvement and is called respiratory bronchiolitis-associated interstitial lung disease (RB-ILD). On high-resolution computed tomography (HRCT), RB-ILD is associated with diffuse or patchy ground glass opacities in a mosaic pattern or fine nodules and air trapping. RB typically resolves with smoking cessation. The diagnosis and management of RB-ILD is discussed separately. (See "Respiratory bronchiolitis-associated interstitial lung disease".)

AIRWAY-CENTERED INTERSTITIAL FIBROSIS — Airway-centered interstitial fibrosis (ACIF), also called idiopathic bronchiolocentric interstitial pneumonia or chronic bronchiolitis with fibrosis, is a form of bronchiolitis in which the key histopathologic finding is a centrilobular and bronchiolocentric inflammatory infiltrate with peribronchiolar fibrosis and an absence of granulomas [82-85]. Prominent epithelial hyperplasia involving adjacent alveolar septa is usually present. Goblet cell metaplasia, squamous metaplasia, and necrosis have also been described. Many of the cases were thought to be characteristic of hypersensitivity pneumonitis (HP) on clinical grounds, although no specific antigens were identified.

Many of the reported patients had a history of smoking, raising concerns that cigarette smoking may be a contributor to airway injury. Chronic silent microaspiration and toxic or hypersensitivity reactions may contribute to the development of this pattern of injury in some patients [84-86].

The typical patient is a middle-aged woman (40 to 50 years old) with a chronic nonproductive cough [87]. The clinical course is more rapidly progressive than that of most patients with HP, nonspecific interstitial pneumonia (NSIP), or respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), the other diagnoses that have a similar presentation.

Both restrictive and obstructive patterns may be found on lung function testing. High-resolution computed tomography (HRCT) scans of airway-centered interstitial fibrosis show a combination of peribronchovascular ground glass opacities, traction bronchiectasis, and thickening of bronchial walls. Bronchial wall thickening is characteristic of more advanced peribronchiolar fibrosis [44].

Unlike HP, the percentage of lymphocytes on bronchoalveolar lavage is less than 40 percent [84].

The diagnosis of ACIF is based upon lung biopsy showing the above-described findings. The optimal treatment is not known. In some patients, the disease appears to stabilize or improve during treatment with systemic or inhaled glucocorticoid; however, the disease has progressed despite glucocorticoid treatment in about half of the patients reported [44,84].

HYPEREOSINOPHILIC OBLITERATIVE BRONCHIOLITIS — Hypereosinophilic obliterative bronchiolitis (HOB) is a rare, poorly-characterized cause of chronic irreversible airflow obstruction that is associated with blood or bronchoalveolar lavage eosinophilia and bronchiolar nodules on high-resolution computed tomography (HRCT) imaging [88,89]. (See "Evaluation of severe asthma in adolescents and adults", section on 'Assessing conditions that mimic asthma'.)

DIFFUSE ASPIRATION BRONCHIOLITIS — Diffuse aspiration bronchiolitis is a poorly defined, occult entity most commonly found in young to middle-aged subjects with identifiable predisposing factors, eg, gastroesophageal reflux disease (GERD), drug abuse, and dysphagia [90,91]. A retrospective study of 20 consecutive patients found that cough, sputum production, dyspnea, and fever in patients with a history of recurrent pneumonia unresponsive to antimicrobial therapy were the most common manifestations [45]. A high index of suspicion is required to make the diagnosis as only 25 percent of patients were clinically suspected to have aspiration as the underlying cause of their lung disease. Chest computed tomography (CT) findings included micronodules and tree-in-bud opacities. Management of these patients should focus on the treatment of GERD and prevention of recurrent aspiration. (See "Medical management of gastroesophageal reflux disease in adults".)

DIFFUSE PANBRONCHIOLITIS — Diffuse panbronchiolitis (DPB) is a distinct clinicopathologic syndrome that involves the upper and lower respiratory tracts (table 1). It occurs mainly among the Japanese and is rarely reported outside Southeast Asia. The histologic lesion of DPB is centered on the respiratory bronchiole, and consists of a transmural infiltrate composed of lymphocytes, plasma cells, and distinctive lipid-laden "foamy" macrophages. Patients present in their second to fifth decade with sinusitis, productive cough, breathlessness, and wheezing. The clinical manifestations, diagnostic evaluation, and treatment of diffuse panbronchiolitis are discussed separately. (See "Diffuse panbronchiolitis".)

SUMMARY AND RECOMMENDATIONS

Definition – Bronchiolitis is a general term used to describe a nonspecific inflammatory injury that primarily affects the small airways and generally spares the interstitium. The main types are bronchiolitis obliterans (also called constrictive bronchiolitis), acute bronchiolitis, proliferative bronchiolitis, follicular bronchiolitis, respiratory bronchiolitis, airway centered interstitial fibrosis, and diffuse panbronchiolitis. (See 'Introduction' above and 'Definitions' above.)

Bronchiolitis obliterans

Causes – Bronchiolitis obliterans may be caused by inhalation injury, infection, or drugs; associated with organ transplantation, rheumatic disease, or paraneoplastic pemphigus; or may be idiopathic (table 2). Bronchiolitis obliterans syndrome (BOS) is a clinical term that is used after lung or hematopoietic cell transplantation when the patient has airflow limitation but has not had confirmatory lung biopsy. (See 'Causes' above and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Diagnosis' and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)

Evaluation – Bronchiolitis obliterans is typically suspected in a patient with the insidious onset of dyspnea and cough, especially when the patient has a predisposing exposure or condition (table 1).

-Pulmonary function testing (PFT) may be normal or show irreversible airway obstruction with air trapping.

-Radiographic findings consistent with bronchiolitis (eg, air trapping, mosaic attenuation, centrilobular nodules, and "v" or "y" shaped branching linear opacities) are more likely to be identified on high-resolution CT (HRCT) scans than on plain chest radiographs, particularly when inspiratory and expiratory images are obtained; however, HRCT may also be normal. (See 'Chest imaging' above.)

-Bronchoscopy may exclude diseases with a similar presentation, such as sarcoidosis and hypersensitivity pneumonitis. (See 'Bronchoscopy' above.)

Diagnosis – In most patients, open or thoracoscopic lung biopsy is required, although tissue confirmation may not be necessary in patients with a clear predisposition (eg, known inhalational exposure or prior lung or hematopoietic cell transplantation) and typical HRCT features. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of bronchiolitis obliterans includes asthma, COPD, hypersensitivity pneumonitis (HP), sarcoidosis, bronchocentric granulomatosis, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH), and hypereosinophilic obliterative bronchiolitis. (See 'Differential diagnosis' above.)

Treatment – The optimal treatment of bronchiolitis obliterans unrelated to transplantation has not been determined. Symptomatic therapy with cough suppressants (eg, dextromethorphan, codeine) may be beneficial, and inhaled bronchodilators may alleviate cough and/or dyspnea in some patients. (See 'Symptom-based and supportive therapy' above.)

-Potential culprit exposures or medications (table 2) should be stopped in any patient who develops bronchiolitis. (See 'Treatment' above.)

-For patients with cryptogenic bronchiolitis obliterans (constrictive), we suggest a trial of a macrolide antibiotic (eg, erythromycin, azithromycin, or clarithromycin) (Grade 2C). We typically use a low dose for a three- to six-month trial and continue therapy if lung function stabilizes or improves. (See 'Pharmacotherapy' above.)

-The role of systemic glucocorticoid therapy in nontransplant-related bronchiolitis obliterans is unclear. Most case series have not found clear benefit. (See 'Pharmacotherapy' above.)

Other bronchiolar disorders – The clinical, imaging, histopathologic features of the other chronic bronchiolar disorders are listed in the table (table 1). Proliferative, follicular, and respiratory bronchiolitis, and diffuse panbronchiolitis are discussed in greater detail separately. (See "Cryptogenic organizing pneumonia" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis", section on 'Follicular bronchiolitis' and "Interstitial lung disease associated with Sjögren's disease: Clinical manifestations, evaluation, and diagnosis", section on 'Follicular bronchiolitis' and "Respiratory bronchiolitis-associated interstitial lung disease" and "Diffuse panbronchiolitis".)

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References

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