Pathology of small airways disease.
Abstract: Context.--The term small airways disease encompasses a generally poorly understood group of lung diseases that may arise primarily within the small airways or secondarily from diseases primarily affecting the bronchi or lung parenchyma. Their histology may be confusing; however, because treatments and prognoses vary, correct pathologic diagnosis is important.

Objective.--To present a nonexhaustive review of the pathology of primary and secondary small airways diseases, including small airways disease related to tobacco; to various other exposures, including mineral dusts; to diseases involving other areas of the lung with secondary bronchiolar involvement; and to recently described bronchiolitic disorders.

Data Sources.--Current literature is reviewed.

Conclusions.--Small airways diseases include a wide variety of diseases of which the pathologist must consider. Uncommon conditions such as diffuse idiopathic neuroendocrine cell hyperplasia and diffuse panbronchiolitis may show relatively specific diagnostic features histologically; however, most small airways diseases exhibit nonspecific histologic features. Conditions not considered primary pulmonary diseases, such as collagen vascular diseases, bone marrow transplantation, and inflammatory bowel disease, must also be considered in patients with small airways changes histologically. Clinical and radiologic correlation is important for obtaining the best possible diagnosis.

(Arch Pathol Lab Med. 2010;134:702-718)
Article Type: Report
Subject: Blood circulation disorders (Development and progression)
Blood circulation disorders (Diagnosis)
Blood circulation disorders (Care and treatment)
Lung diseases (Development and progression)
Lung diseases (Diagnosis)
Lung diseases (Care and treatment)
CT imaging (Usage)
Author: Allen, Timothy Craig
Pub Date: 05/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: May, 2010 Source Volume: 134 Source Issue: 5
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230246556
Full Text: Although diseases frequently involve the small airways, the concept of small airways disease is one of which many pathologists lack a strong understanding. There are valid reasons for this lack of understanding. The definition of the term small airways disease varies based on the physician's perspective. Pulmonologists and other clinicians often consider small airways disease as a group of lung disorders involving the terminal airways often assessed for airflow obstruction (1-8) or underlying etiology. 9-13 Radiologists generally evaluate small airways disease by evaluating high-resolution computed tomography (CT) scan changes including "direct signs" of small airways disease, such as centrilobular nodules and opacities, centrilobular bronchiolar dilation, and prominent centrilobular branching structures, often yielding a characteristic "tree in bud" pattern; and "indirect signs" of fibrotic narrowing of small airways, including areas of reduced lung density, within which there is pulmonary vessel constriction, bronchial wall thickening, and bronchiectasis. (14-20) In contrast, the pathologists' study of small airways disease is histology-based. (7,21-29) Depending on how broadly or narrowly one defines the term, there are a variable number of diseases that may fall under the heading of small airways disease, including those primary to the bronchioles and those involving the bronchioles secondarily, with bronchiolar involvement only one of several features of the disease. Further, as stated by Katzenstein, (27) "[t]he literature in this area is confusing because many studies combine under one category several pathologically distinct lesions, and terminology tends to be inconsistent."


Hogg and colleagues (21) in 1968 first used the term small airways disease to describe airway disease in patients with variably severe chronic airflow obstruction characterized by loss of bronchioles, mucus plugs, and variable amounts of inflammation and fibrosis that involve "the smallest bronchi as well as the bronchioles, so that neither bronchitis nor bronchiolitis is an appropriate term." Disease severity was noted to correlate with occlusion of airway lumen by mucus and inflammatory cells. (21) This original, limited definition of small airways disease by Hogg and colleagues has given way during the years to an expanded scope of diseases affecting the airways that are considered in various classification schemes as small airways disease. Because classifications of lung diseases are in some respects dynamic and overlapping, classifications of small airways disease vary. There have been several proposed classifications of small airways disease, including, for example, one of the initial classifications by Myers and Colby in 1993 (Table 1) and a relatively recent 2006 classification by Katzenstein (Table 2). (17,23,27,30,31) Another recent classification that is descriptive of the various pathologic patterns is listed in Table 3. One might classify these diseases according to whether the histologic patterns, along with clinical and radiologic correlation, show changes diagnostic of a particular disease; however, except for diffuse idiopathic neuroendocrine cell hyperplasia and diffuse panbronchiolitis, and arguably follicular bronchiolitis and respiratory bronchiolitis-interstitial lung disease, the histologic changes, such as cellular bronchiolitis and fibrotic changes, are typically not specific for a distinctive etiology. One could also classify small airways diseases for whether the disease is primary to the small airways or secondary to other lung disease, such as smoking or asthma. Ultimately, what classification scheme one prefers is less important than an understanding of the histologic features, the disease processes involved, the limitations of histologic diagnosis, and the confidence one can make a specific diagnosis on a biopsy of small airways disease.


Although small airways diseases as a group are relatively common, many patients have straightforward clinical and radiologic diagnoses and are treated without biopsy confirmation of the disease. Pulmonologists performing bronchoscopy typically focus on biopsying discrete masses rather than diseases that involve a diffuse but relatively peripheral portion of the pulmonary airways. Features of the various small airways diseases overlap, and a firm diagnosis may not be possible on limited endobronchial or transbronchial biopsy tissue, and diagnoses are often descriptive rather than specifically diagnostic of a specific entity. Clinical and radiologic correlation is necessary to provide the most accurate diagnosis.

Small airways may be involved with disease primarily or may be involved secondarily by diseases primarily affecting bronchi or lung parenchyma. Although etiologies are numerous, small airways disease may be generally divided into small airways disease related to tobacco; to various other exposures, including mineral dusts; to diseases involving other areas of the lung, with secondary bronchiolar involvement; and to idiopathic causes. In some cases, small airways disease may be extremely subtle histologically and can be missed on examination. (22,24) Although occasionally small airways have been described with sizes other than less than 2 mm, (32) small airways are currently defined as airways having a diameter of less than 2 mm. (7,27,33-35) It is important to keep in mind that the less than 2-mm measurement is of luminal (ie, measuring from mucosa to mucosa) diameter. In terms perhaps more useful for the pathologist on a daily basis, the term small airways includes membranous bronchioles, respiratory bronchioles, and alveolar ducts (29,36) (Figures 1 and 2). Membranous bronchioles, bronchioles ranging from approximately 1 mm down to approximately 0.5 mm in diameter, normally contain a layer of smooth muscle and a layer of adventitia and are lined by ciliated columnar cells and Clara cells. Smooth muscle is diminished distally. They lack cartilage and may contain rare goblet cells or seromucinous glands. The final generation of membranous bronchiole is termed terminal bronchiole and opens into a functional unit of the lung termed an acinus, which is composed of respiratory bronchioles, alveolar ducts, and alveoli. Another functional unit, the lobule, is composed of approximately 3 to 10 acini, enclosed by an interlobular septum. Respiratory bronchioles have alveoli budding from their walls, the number of which increases distally. They are lined by columnar or simple cuboidal epithelium. (26) Small airways have been termed the lung's "Achilles heel" because of their importance in airflow and air distribution and their lack of bronchilike rigidity to protect them from collapsing during exhalation, especially when involved with disease. (37)

The following is a nonexhaustive review of the pathology of some of the small airways diseases, specifically cellular bronchiolitis, including follicular bronchiolitis and diffuse panbronchiolitis; granulomatous bronchiolitis; tobacco smoke-associated small airways bronchiolitic diseases, hypersensitivity pneumonitis; organizing pneumonia; constrictive bronchiolitis; mineral dust exposure and various other exposure-associated bronchiolitic diseases; and 4 recently described bronchiolitic disorders, bronchiolitic disease due to ingestion of Sauropus androgynus, airway-centered interstitial fibrosis, idiopathic bronchiolocentric interstitial pneumonia, and bronchiolitis interstitial pneumonitis.


The term bronchiolitis is a generic term used clinically to define a variety of inflammatory conditions involving the small airways. Bronchiolar and peribronchiolar inflammation may be focal or diffuse and may or may not be associated with scarring and bronchiolar metaplasia. Bronchiolar mucosa may undergo bronchiolar, squamous, or goblet cell metaplasia.







Peribronchiolar Metaplasia

Bronchiolar-type epithelium that grows along the alveolar surfaces adjacent to bronchioles has been termed peribronchiolar metaplasia or lambertosis, in reference to the canals of Lambert through which bronchiolar epithelium was once considered to traverse to grow on alveolar septa (21,29,38-41) (Figures 3 and 4). Peribronchiolar metaplasia may be present in a variety of processes involving the small airways. Bronchiolarization may occur in the setting of healed bronchiolitis or interstitial fibrosis and may also be found in association with chronic hypersensitivity pneumonitis, constrictive bronchiolitis, or bronchiectasis. Idiopathic foci of peribronchiolar metaplasia may also be found; these may represent healed sites of prior infection or other localized injury.


The term cellular bronchiolitis describes disease in which the primary pattern is an inflammatory infiltrate within the bronchioles. The inflammatory infiltrate may be acute, chronic, or both acute and chronic and may or may not be associated with peribronchiolar fibrosis or metaplasia. (39,42)

Acute Bronchiolitis

Acute bronchiolitis is most commonly found in infants and young children. (43-65) It is the most common respiratory ailment during the first year of life. Its etiology is generally infectious, and although approximately three-fourths of cases are due to respiratory syncytial virus, numerous other infections may be causative, including other viruses such as measles, adenovirus, influenza, and parainfluenza; nonviral organisms such as fungi and mycoplasma; and Bordetella pertussis. * It occurs most frequently during the winter months. Infants often present with tachypnea, wheezing, and tachycardia, with more severely ill patients exhibiting chest retraction and nasal flaring. Lung hyperinflation is often found on x-ray. Some cases may show patchy ground glass opacities or small centrilobular nodules as well. High-resolution chest CT scan may show branching linear opacities or small centrilobular nodules. Focal areas of nodularity may be present, representing foci of bronchopneumonia. In obvious cases of acute bronchiolitis, chest radiology is more frequently being omitted. (3) Patients typically do not undergo open biopsy; however, biopsy may be obtained in some cases having unusual presentations. Histologically, acute bronchiolitis consists of bronchioles filled with necrotic debris and purulent exudative material, as well as sloughed bronchiolar mucosal cells. The residual bronchiolar mucosa and surrounding bronchiolar wall contain a neutrophilic infiltrate (23,24,39,66-72) (Figure 5). Most cases are treated symptomatically, with generally excellent prognosis. Rare cases exhibit long-term morbidity or mortality. In a small number of patients, long-term disease results in constrictive bronchiolitis. Drug treatments have not shown convincing benefit; however, oxygen is generally administered in cases with significant hypoxia. Home oxygen therapy is being more frequently used to reduce hospital stay. Also, corticosteroids have reportedly shown benefit in some patients with croup, and nebulized saline has been reported to reduce morbidity and length of hospital stay in patients with acute bronchiolitis. ([double dagger]) It is uncertain what factors contribute to disease severity in infants; however, cell-mediated immune response to disease pathogenesis has been implicated. Recent studies have estimated that 22% of cases in infants have a hereditary contribution to disease severity. Increased risk of severe acute respiratory syncytial virus bronchiolitis has been reported to correspond to a haplotype at the IL13-IL4 locus that is associated with increased interleukin (IL)-13 production. Interleukin-8 levels have been reported to correlate with length of hospitalization, and IL-8 associated airway inflammation has been reported to relate significantly to the severity of acute epidemic bronchiolitis. (45,51,65,66) Acute bronchiolitis in adults has a variety of potential causes, as listed in Table 4.

Acute and Chronic Bronchiolitis

Acute and chronic bronchiolitis is generally found in adults, and potential etiologies are numerous (Table 5). Although many cases are caused by infections, including respiratory syncytial virus, other noninfectious etiologies exist. Some cases are idiopathic. (23,24,39,45,66-72) Patients often have mild symptoms but may present with shortness of breath of variable duration, with or without cough. Pulmonary function tests may show an obstructive pattern. (68,71,72) Histologically, bronchiolar lumen contain purulent exudative material and sloughed bronchiolar mucosal cellular debris and variable amounts of mucus, and bronchiole mucosa and walls contain a mixed neutrophilic infiltrate and chronic inflammatory cell infiltrate made up predominantly of lymphocytes and plasma cells. The mixed acute and chronic inflammatory cell infiltrate extends into peribronchiolar tissue, and edema may be present. (23,24,39,67,68,71,72) In patients with disease caused by respiratory syncytial virus, various chemokines, including regulated upon activation, normal T cell expressed and secreted; IL-8; IL-1; and IL-6 have been implicated in recruitment and activation of inflammatory cells, including neutrophils, macrophages, lymphocytes, and eosinophils, to the infected area. (65,69,70,72) Most patients have a good prognosis with generally full recovery. Patients with idiopathic disease may show therapeutic response to antibiotics and immunosuppressive drugs; however, in these patients residual pulmonary impairment is frequent. (39,66,70-72)

Chronic Bronchiolitis

Chronic bronchiolitis describes a histologic pattern in which bronchioles contain, and peribronchiolar tissues are infiltrated with, chronic inflammatory cells. Germinal centers and constrictive bronchiolitis may or may not be present, and if germinal centers predominate and constriction of the airway lumen is significant, the diagnosis of follicular bronchiolitis should be considered. The histologic features of acute and chronic bronchiolitis may overlap with chronic bronchiolitis. (24,39,71,72) Chronic bronchiolitis may be a feature of various diseases (Table 6) and may be idiopathic. (39,71,72) Fibrosis may or may not be present in association with chronic bronchiolitis. The presence of fibrosis suggests some amount of irreversibility of the process. Although chronic bronchiolitis with fibrosis is a common feature of chronic obstructive pulmonary disease, the lesion is rarely biopsied in that setting.

Bronchiolar Necrosis

Histologically, bronchiolar necrosis describes mucosal necrosis and sloughing of mucosa into the airway lumen, with or without necrosis of the bronchiolar wall. (39) Bronchiolar necrosis may be identified in a variety of diseases, including infections (Table 7).

Follicular Bronchiolitis

Follicular bronchiolitis consists of lymphoid hyperplasia of the bronchus-associated lymphoid tissue. (29,80-90) It is caused by altered immune response or immune stimulus of the bronchus-associated lymphoid tissue and is a feature of various immune-related disorders involving the lungs, including collagen vascular diseases, especially rheumatoid arthritis and Sjogren syndrome; bronchiectasis and middle lobe syndrome; hypersensitivity reactions; and various types of immune deficiency states such as AIDS and congenital immunodeficiency disorders. Some cases are idiopathic. (29,80-83,85-89,91-93) It has been reported to cause posttransplantation bronchiolitis obliterans syndrome. 84 Radiologic features include reticulonodular infiltrates or small nodules on chest x-ray. High-resolution CT scan may show peribronchial nodules, with or without patchy ground glass opacities. Histologically follicular bronchiolitis is characterized by peribronchiolar lymphoid hyperplasia that extends into surrounding lung parenchyma. Reactive germinal centers are present (29,72) (Figure 6). Therapy depends on the underlying causative process. Overall prognosis has been reported to be good. (29,39,83,84,90) Patients with idiopathic disease may benefit from steroids and bronchodilators. (72,80-83,93,94)

Eosinophilic Bronchiolitis

Eosinophilic bronchiolitis is characterized histologically by bronchiolar walls containing increased numbers of eosinophils. Its presence may be secondary to asthma or allergic bronchopulmonary aspergillosis, although patients with these diseases usually have increased eosinophils within bronchi rather than bronchioles. Eosinophilic pneumonia, drug reactions, and parasitic or fungal infections may also occasionally exhibit eosinophilic bronchiolitis, but there is usually a predominant interstitial disease component present. (95-99) One patient with a prior diagnosis of diffuse panbronchiolitis and worsening symptoms despite therapy subsequently was diagnosed as having eosinophilic bronchiolitis. (96)

Diffuse Panbronchiolitis

Diffuse panbronchiolitis, an idiopathic, bilateral, progressive, obstructive, suppurative small airways disease associated with sinusitis, primarily occurs in Japan, has been increasingly identified within other Asian populations, and is uncommon in the United States. (29,100-126) The term diffuse panbronchiolitis refers to its distribution in both lungs (diffuse) and the inflammatory involvement of all layers of the wall or respiratory bronchioles (pan). (122) Because diffuse panbronchiolitis is predominantly found in Japan, a genetic predisposition is assumed to play a role in disease progression. Human leukocyte antigen alleles are thought to cause a genetic predisposition to diffuse panbronchiolitis. Researchers have shown an association with HLA-Bw (54), found predominantly among East Asians, and diffuse panbronchiolitis, with 63% of Japanese patients possessing the antigen compared with 11% of control subjects. Korean patients have been shown to have an association with HLA-A11. These findings suggest a major HLA susceptibility gene for diffuse panbronchiolitis. (122,126-130) Patients average approximately 40 years of age at presentation; however, there is a wide age range from the first to the seventh decades of life. Males predominate, with a male to female ratio in Japan reportedly between 1.4:1 and 2:1. No association with smoking or exposure to fumes or toxins has been proven. Patients typically present with a variable history of chronic sinusitis, cough, and dyspnea. Some patients may produce purulent sputum. Pulmonary function studies show obstructive changes. Radiographically, diffuse panbronchiolitis produces bilateral small nodules on x-ray and centrilobular lesions on high-resolution CT scan. ([section]) On biopsy, yellow bronchiolocentric nodules measuring approximately 1 mm to 3 mm are identified. Histologically, diffuse panbronchiolitis is characterized by transmural infiltration of the bronchiole and surrounding lung interstitium with foamy macrophages, plasma cells, and lymphocytes. The changes involve terminal bronchioles, respiratory bronchioles, and alveolar ducts. Predominantly respiratory bronchiole involvement is a distinctive feature of diffuse panbronchiolitis, as other forms of constrictive bronchiolitis predominantly affect membranous bronchioles. (122,133) Foamy macrophages and other inflammatory cells may fill the bronchiolar lumen and may involve alveolar spaces; however, alveoli are relatively spared in diffuse panbronchiolitis (Figure 7). Neutrophils may be identified in the bronchiolar lumen as well. Follicular bronchiolitis can occur as part of the histologic changes, and superimposed acute or organizing pneumonia and bronchiectasis may be present. Terminal bronchioles may become ectatic as the disease advances. Untreated disease generally progresses to bronchiectasis, with resultant respiratory failure and death. (122,125,126,134,135)

Patients typically have associated infections, and Pseudomonas infection is associated with a poor prognosis. Significantly improved survival has been reported in patients treated with chronic low-dose macrolide antibiotic therapy, with improved survival considered to be caused by the drug's antiinflammatory affects rather than its antibiotic properties. ** Diagnosis is generally made based on the disease's clinical, radiographic, and histologic features. Isolation from the sputum of Haemophilus influenza and Streptococcus pneumoniae, and in advanced stages of disease, Pseudomonas aeruginosa, assists in making the diagnosis. (122,126,134) Differential diagnosis includes xanthomatous bronchiolitis, rheumatoid arthritis-associated bronchiolitis and other collagen vascular disease and autoimmune diseases, human T-cell lymphotropic virus type 1-associated bronchiolitis, and idiopathic bronchiolitis. ([dagger])([dagger])


Granulomatous bronchiolitis is characterized histologically by granulomas within bronchiolar walls, with or without giant cells or necrosis (39) (Figure 8). Granulomatous bronchiolitis is a feature of a variety of pulmonary disorders (Table 8). (39,143-155) Clinical, radiologic, therapeutic, and prognostic features are those of the underlying disease. Although not diagnostic, well-formed noncaseating granulomas suggest sarcoidosis; caseating granulomas suggest infection; poorly formed nonnecrotizing granulomas, especially in association with interstitial lymphocytic infiltrates or organizing pneumonia, suggest hypersensitivity pneumonitis; and noncaseating granulomas with associated foreign body giant cells or foreign material suggest aspiration pneumonia.


Organizing pneumonia with intraluminal polyps, formerly termed bronchiolitis obliterans organizing pneumonia/ organizing pneumonia pattern, may occur secondary to a wide variety of lung injuries (Table 9). (29,39,156-186) It may also be idiopathic, termed cryptogenic organizing pneumonia, formerly termed idiopathic bronchiolitis obliterans organizing pneumonia. (44) Histologically, organizing pneumonia is characterized by plugs of granulation tissue, composed of fibroblasts within a myxoid or edematous stroma, which are located within bronchiolar lumens, alveolar ducts, and associated alveolar airspaces (Figure 9). Within airspaces, these plugs of granulation tissue may form rounded nodules, termed Masson bodies. A variable interstitial lymphocytic infiltrate may be present. If bronchiolar obstruction is a feature of the disease, foamy macrophages may be present within alveolar airspaces. Clinical history is often necessary to determine the etiology; however, histologic features that assist in specific diagnosis include viral inclusions suggestive of viral pneumonia, foreign body giant cells suggestive of aspiration, and poorly formed granulomas with multinucleated giant cells suggestive of hypersensitivity pneumonia. Typically, organizing pneumonia resolves with no or minimal scarring; however, clinical course and prognosis depend on the type of and severity of the underlying disease. (29,39,156-186) If, after clinical correlation and careful histologic examination for viral inclusions, foreign body giant cells, and poorly formed granulomas with associated giant cells, no etiology is determinable, the diagnosis of cryptogenic organizing pneumonia is appropriate. Cryptogenic organizing pneumonia is a clinical syndrome generally occurring in middle-aged to older women who often present with a history of flulike illness and have shortness of breath and persistent nonproductive cough. Radiologically, patchy bilateral alveolar infiltrates may occur transiently and recur in different locations. Therapeutic response to steroid therapy, and prognosis, are usually very good in patients with cryptogenic organizing pneumonia. (11)








Constrictive bronchiolitis, also termed bronchiolitis obliterans and obliterative bronchiolitis, is an obstructive small airways disease identified in a variety of disorders (Table 10). Constrictive bronchiolitis is strongly associated with chronic lung transplant rejection, for which it is a significant cause of morbidity and mortality. It may also occur as idiopathic disease, predominantly presenting as persistent cough and dyspnea, in middle-aged to older women who are never-smokers. Patients with idiopathic constrictive bronchiolitis have variable prognoses, ranging from slowly progressive disease to rapidly deteriorating disease. *** Histologically, constrictive bronchiolitis is characterized by concentric bronchiolar lumen narrowing by submucosal fibrous tissue. The lumen narrowing may range from slight and histologically subtle tomarked, with complete obliteration of the bronchiolar lumen leaving only a residual fibrous scar (Figures 13 and 14). Chronic inflammation may or may not be present in constrictive bronchiolitis, and patients with idiopathic disease often have little or no chronic inflammation within bronchiolar walls or peribronchiolar tissues. Smooth muscle hyperplasia and adventitial fibrosis may occur in membranous bronchioles. The plugs of granulation tissue found with organizing pneumonia with intraluminal polyps are not a characteristic of constrictive bronchiolitis. ([dagger])([dagger])([dagger])


Membranous Bronchiolitis and Respiratory Bronchiolitis

Variably extensive and variably severe inflammatory and fibrotic changes caused by tobacco smoke that are found in the terminal bronchioles and respiratory bronchioles are termed, respectively, membranous bronchiolitis and respiratory bronchiolitis. (29,39,206-208) Patients are typically asymptomatic, but pulmonary function studies may show obstructive change. (29,39,206-208) Other smoking-related lung changes including chronic bronchitis, emphysema, and desquamative interstitial pneumonia may be present along with membranous bronchiolitis and respiratory bronchiolitis. Histologically, both membranous bronchiolitis and respiratory bronchiolitis contain cellular infiltrates made up predominantly of lymphocytes and histiocytes within the bronchioles and infiltrating into surrounding peribronchiolar tissue. Lying within the bronchiolar lumen and also within adjacent alveolar ducts and alveoli, there are collections of macrophages containing finely granular brown cytoplasmic pigment (Figure 10). Pigment-laden macrophages are also often found within the bronchiolar wall. Minimal to mild fibrosis may occur in the bronchial wall and adjacent alveolar septa. Metaplastic bronchiolar epithelium (lambertosis) and type II pneumocyte hyperplasia may be present. Membranous bronchiolitis may contain smooth muscle hyperplasia and adventitial fibrosis (39) (Figure 11). Patients are typically asymptomatic; however, they often show obstructive changes on pulmonary function tests. The diagnosis is often made incidentally, and prognosis in these patients is excellent with smoking cessation, with or without corticosteroid therapy. (29,39,206-208) These histologic changes are on a continuum, and when severe enough, changes of respiratory bronchiolitis are termed respiratory bronchiolitis-associated interstitial lung disease (RBILD).

Respiratory Bronchiolitis-Associated Interstitial Lung Disease

Patients with respiratory bronchiolitis histologically, who are typically heavy smokers, with generally mild nonprogressive symptoms of dyspnea and cough, and with radiologic changes of interstitial lung disease, are diagnosed as having RBILD. ([double dagger])([double dagger])([double dagger]) The differential diagnosis of respiratory bronchiolitis and RBILD is generally based on clinical and radiologic features. Some cases have been reported in nonsmokers, and similar histologic features have been seen in patients with asbestos and nonasbestos mineral dust exposure. (207,221) Chest x-ray results may be normal or may show fine reticulonodular interstitial opacities, corresponding to fibrosis involving the subpleural alveolar septa, that may be diffuse or predominate within the lung bases. High-resolution CT scan shows ground glass opacities, centrilobular nodules, and interstitial thickening with an upper lung zone predominance. ([section])([section])([section]) The histologic features of RBILD and respiratory bronchiolitis are generally indistinguishable, although some cases of RBILD may showmore pronounced changes. Histologic diagnosis of RBILD requires more than mere collections of pigmented macrophages within bronchiolar airspaces, as may be seen in healthy cigarette smokers. (29,39,207,208) More pronounced cases of RBILD merge in the continuum with cases of desquamative interstitial pneumonia (29) (Figure 12).

Pulmonary Langerhans Cell Histiocytosis

Pulmonary Langerhans cell histiocytosis commonly arises within a background of respiratory bronchiolitis and should be considered as a possible concurrent disease process in patients with respiratory bronchiolitis. (39,225) Pulmonary Langerhans cell histiocytosis has recently been reviewed. (226)


Although late-stage hypersensitivity pneumonitis can mimic usual interstitial pneumonia and nonspecific interstitial pneumonia, in earlier stage hypersensitivity pneumonitis cellular bronchiolitis is one of its characteristic histologic features, along with organizing pneumonia and poorly formed nonnecrotizing granulomas. (29,39,227) Hypersensitivity pneumonitis is often in the differential diagnosis of cellular bronchiolitis, with and without fibrotic changes. Detailed reviews of hypersensitivity pneumonitis have been recently published. (228-231)


Mineral Dust-Associated Bronchiolitic Diseases

Numerous mineral dust-associated airway diseases, including asbestosis, silicosis, and coal miner's pneumoconiosis, among others, may cause bronchiolitic disease. (29,39,67,232-257) The histologic changes typically consist of varying degrees of fibrosis that ultimately may obstruct and completely occlude the airway. The exact histologic pattern depends on the specific dust being inhaled and the amount of dust inhaled. Care must be taken to make a correct diagnosis, and clinical and radiologic correlation is necessary. For example, in some patients, especially heavy smokers, anthracotic pigment may be identified along alveolar ducts and respiratory bronchioles; however, there is typically less pigment deposition and less airway fibrosis than in patients with mineral dust-associated bronchiolitic diseases. ****

Exposure to Fumes and Toxins

The most serious pulmonary exposures characteristically cause overwhelming pulmonary edema, with or without diffuse alveolar damage, and frequently cause death. Lesser exposures to fumes and toxins may cause bronchiolitic disease. ([dagger]) ([dagger])([dagger])([dagger]) Patients may have cough and dyspnea, as well as other symptoms such as vomiting, dizziness, and headache. Radiographic studies may show thickened bronchioles. Acutely, histologic changes include necrotic bronchiolar mucosa with a neutrophilic infiltrate and sloughing. Pulmonary edema and changes of diffuse alveolar damage may also be present to variable degrees. The acute stage is followed by an organizing stage characterized histologically by organizing pneumonia (organizing pneumonia with intraluminal polyps). Patients who progress beyond the acute and organizing stages of disease often recover without long-term lung changes. Some patients may, however, progress chronically and show constrictive bronchiolitis. Numerous chemicals may cause bronchiolitic disease, including smoke, chlorine gas, phosgene, and hydrogen fluoride, among others. Reports have recently shown that the inhalation of volatile diacetyl as part of the popcorn manufacturing process has caused bronchiolitis, frequently constrictive bronchiolitis, in some workers. Other exposures may also cause bronchiolitis, including fiber inhalation in the nylon flocking industry. Recent reports have shown that some workers involved with flocking, in which short synthetic fibers are applied to a backing fabric, have been diagnosed with chronic bronchiolitis, often follicular bronchiolitis (Figure 15). Toxin and fume exposure may also show histologic features of organizing pneumonia with intraluminal polyps. That histologic pattern may predominate in cases of acute exposures. ([double dagger])([double dagger]) ([double dagger])

Drug Reactions

A great number of drugs cause drug-induced pulmonary toxicity. There are several histologic patterns that may occur, including diffuse alveolar hemorrhage, diffuse alveolar damage, and nonspecific interstitial pneumonia. Bronchiolitic disease, including organizing pneumonia and hypersensitivity pneumonitis, may also occur as a consequence of pulmonary drug reactions. Methotrexate is one drug commonly associated with hypersensitivity pneumonitis-associated drug-induced lung injury, although many other drugs can give a similar histologic pattern (Figure 16). Numerous drugs may cause an organizing pneumonia pattern of injury. (297-305)


Finally, there are a few related relatively recently described bronchiolitic diseases that bear some discussion.

Airway-Centered Interstitial Fibrosis, Idiopathic Bronchiolocentric Idiopathic Pneumonia, and PeribronchiolarMetaplasia-Related Interstitial Lung Disease

Three recently described airway-centered entities, possibly representing similar manifestations or differing points of progression of the same disease or group of diseases, include airway-centered interstitial fibrosis, idiopathic bronchiolocentric idiopathic pneumonia, and peribronchiolar metaplasia-related interstitial lung disease.

Airway-centered interstitial fibrosis is the term used by Churg et al (306) in 2004 to describe the histologic features of interstitial fibrosis that is centered around bronchioles, with associated peribronchiolar fibrosis extending into surrounding lung parenchyma, increased bronchiolar smooth muscle, and metaplastic bronchiolar epithelium (lambertosis), with little interstitial inflammation. (29,306-312) Increased alveolar macrophages and honeycombing are not characteristics of airway-centered interstitial fibrosis. This uncommon diagnosis remains controversial, as these histologic features may be due to other, established, diseases such as hypersensitivity pneumonitis and RBILD. Whether airway-centered interstitial fibrosis ultimately is classified as an individual, specific form of interstitial lung disease remains to be determined. Usual interstitial pneumonia and nonspecific interstitial pneumonia are also differential diagnoses in these patients. Lung injury due to environmental exposures has been proposed as a cause of disease. Patients reportedly are middle-aged, and the majority are women. Chest x-rays generally show peribronchial and perivascular fibrosis with interstitial thickening. Patients reportedly present with chronic cough and progressive dyspnea. Treatment with bronchodilators and corticosteroids has been generally unsatisfactory. Patients have a generally poor prognosis, with a reported 40% dead of disease with follow-up periods of 1 to 10 years. Airway-centered interstitial fibrosis has features in common with idiopathic bronchiolocentric interstitial pneumonia. (29,306-312)

Idiopathic bronchiolocentric interstitial pneumonia was reported by Yousem and Dacic (313) in 2002. The authors described histologically centrilobular and bronchiolocentric fibrosis with patchy interstitial inflammation. Granulomas are not characteristic of the process. Patients reportedly were predominantly middle-aged women. Prognosis was generally guarded, with 33% of patients dead of disease and 56% alive with persistent progressive disease, with a mean follow-up period of 4 years with 9 patients. Compared with airway-centered interstitial fibrosis, idiopathic bronchiolocentric interstitial pneumonia has a more substantial interstitial inflammatory infiltrate. The diagnosis of idiopathic bronchiolocentric interstitial pneumonia is controversial, and whether these patients represent cases of hypersensitivity pneumonitis or nonspecific interstitial pneumonia remains to be determined. Differential diagnosis also includes usual interstitial pneumonia and RBILD. (29,312-314)

Fukuoka et al (315) reported 15 cases of peribronchiolar metaplasia-related interstitial lung disease. These cases differed from those reported by Churg et al and Yousem et al in that although the patients had interstitial lung disease clinically, the primary histologic finding on biopsy was peribronchiolar metaplasia. The authors designated this finding peribronchiolar metaplasia-related interstitial lung disease because of the analogy with respiratory bronchiolitis and RBILD, in which respiratory bronchiolitis is a common incidental finding in smokers and RBILD is the smoking-associated clinically significant interstitial lung disease. (315) The authors noted that although the cases reported by Churg et al and Yousem et al contained cases with peribronchiolar metaplasia, their cases did not have other features found in the cases reported by Churg et al and Yousem et al, including significant interstitial fibrosis beyond the peribronchiolar region. The authors suggested that the better prognosis identified in their cases relative to those of Churg et al and Yousem et al may be related to the absence of significant interstitial fibrosis beyond the peribronchiolar region. (315) The authors note that peribronchiolar metaplasia frequently occurs as a histologic feature in other interstitial lung diseases and that chronic hypersensitivity pneumonitis is the most important differential diagnosis in cases with these histologic features. (315)

S androgynus Ingestion

Ingestion of S androgynus, a common Malaysian vegetable also termed Sabah vegetable, was first associated with bronchiolitic disease in Taiwan and reported by Lai et al (316) and Lin et al (317) in 1996. (316-336) The plant was ingested as raw leaves or extract juice by predominantly young to middle-aged women for the perceived weight loss benefit. Patients were reported to exhibit dyspnea and cough with progressive respiratory failure developing. Some patients have died of disease. Cases have been reported in other countries, including Japan. Cause is uncertain; however, T-cell mediated immunity is thought to play a role in disease. Familial associations (mother and daughter) have been identified. Intake cessation, corticosteroids, bronchodilators, cytotoxic agents, and plasmapheresis have been attempted; however, lung transplantation has been considered to be the only effective treatment. Reports show histologic changes of segmental necrosis of small bronchi with relative sparing of large bronchi, most bronchioles, and alveoli. As well, bronchial arteries within walls of large bronchi show fibromuscular sclerosis and obliteration. In some cases, constrictive bronchiolitis and organizing pneumonia (organizing pneumonia with intraluminal polyps) has been reported, possibly representing indirect histologic changes. (316-332,336)





Bronchiolitis Interstitial Pneumonitis

Bronchiolitis interstitial pneumonitis was described recently by Mark and Ruangchira-urai. (337) Histologically, bronchiolitis interstitial pneumonitis reportedly shows regional and occasionally widespread organizing pneumonia with associated alveolar inflammation and alveolar fibrosis in most cases. Many cases contained bronchiolar scarring and mucus plugging, and some cases showed purulent bronchiolitis. Differential diagnosis includes usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, and constrictive bronchiolitis, as well as the also recently described diagnoses of airway-centered interstitial pneumonia and idiopathic bronchiolocentric interstitial pneumonia. Whether bronchiolitis interstitial pneumonitis is ultimately classified as an individual, specific form of interstitial lung disease remains to be determined, and further studies of cases with these histologic features will help better characterize these patients.


Small airways diseases include a wide variety of diseases of which the pathologist must consider. Although uncommon conditions such as diffuse idiopathic neuroendocrine cell hyperplasia and diffuse panbronchiolitis have histologic features that allow for relatively specific diagnoses, and although some conditions such as mineral dust-associated small airways disease, RBILD, granulomatous bronchiolitis, eosinophilic bronchiolitis, and fol licular bronchiolitis have histologic features that may be diagnostic in the appropriate clinical and radiologic setting, most cellular and fibrotic changes found in small airways disease are nonspecific. These nonspecific small airways findings are found in a variety of both primary small airways diseases and diseases that affect the small airways secondarily, such as hypersensitivity pneumonitis, asthma, chronic obstructive pulmonary disease, and Wegener granulomatosis. Diseases and conditions that are not considered primarily pulmonary, such as collagen vascular diseases, bone marrow transplantation, and inflammatory bowel disease, must also be considered in patients with significant histologic changes in the small airways. More recently described entities such as airway-centered interstitial fibrosis and bronchiolocentric interstitial pneumonia must be further studied to determine whether these cases represent separate, independent diagnostic entities or whether they represent uncommon presentations of recognized entities such as hypersensitivity pneumonitis.


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* References 39, 42-49, 52, 55, 61, 63, 64, 66.

([dagger]) References 39, 42, 43, 47, 52, 54-56, 62, 64, 66.

([double dagger]) References 42-44, 47, 52, 53, 55, 56, 59, 60, 73-79.

([section]) References 116-118, 120-126, 131-133.

** References 29, 122, 123, 125, 126, 136-138.

([dagger])(dagger) References 122, 125, 126, 131, 139-142.

([double dagger])([double dagger]) References 29, 39, 156-178, 180, 181, 184-186.

([section])([section]) References 29, 39, 156-177, 179-181, 185, 187, 188.

*** References 11, 15, 29, 39, 67, 71, 84, 189-203.

([dagger])([dagger])([dagger]) References 29, 39, 67, 71, 189, 190, 192-194, 204, 205.

([double dagger])([double dagger])([double dagger]) References 14, 29, 38, 39, 206-220.

([section])([section])([section]) References 14, 206-208, 210, 212, 222-224.

**** References 29, 39, 67, 234, 236, 237, 239, 241, 244, 248, 250- 252, 254-257.

([dagger])([dagger])([dagger])([dagger]) References 29, 39, 196, 197, 201, 244, 258-296.

([double dagger])([double dagger])([double dagger])([double dagger]) References 29, 39, 196, 197, 201, 244, 261, 263, 265, 267, 268, 271, 273, 274, 279-281, 283, 284, 286-296.

Timothy Craig Allen, MD, JD

Accepted for publication September 8, 2009.

From the Department of Pathology, The University of Texas Health Science Center at Tyler.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Timothy Craig Allen, MD, JD, Department of Pathology, The University of Texas Health Science Center at Tyler, 11937 Highway 271, Tyler, TX 75708-3154 (e-mail:
Table 1. Classification of Small Airways Disease, 1993 (a)

Acute (infectious) bronchiolitis
Bronchiolitis obliterans-organizing pneumonia; cryptogenic
  organizing pneumonia
Constrictive (obliterative) bronchiolitis; bronchiolitis obliterans
Adult bronchiolitis
Respiratory (smoker's) bronchiolitis-associated interstitial lung
Mineral dust airways disease
Follicular bronchiolitis
Diffuse panbronchiolitis

(a) Data were derived from Myers and Colby. (23)

Table 2. Classification of Small Airways Disease, 2006 (a)

Cellular bronchiolitis
Constrictive bronchiolitis obliterans
Nonspecific chronic bronchiolitis
Respiratory (smoker's) bronchiolitis
Follicular bronchiolitis
Diffuse panbronchiolitis

(a) Data were derived from Katzenstein. (27)

Table 3. Classification of Small Airways Disease, 2008 (a)

Cellular bronchiolitis
  Acute bronchiolitis
  Acute and chronic bronchiolitis
  Chronic bronchiolitis, with or without fibrosis
Subtypes of cellular bronchiolitis
  Follicular bronchiolitis
  Diffuse panbronchiolitis
Bronchiolitis obliterans with intraluminal polyps
Constrictive bronchiolitis
Respiratory bronchiolitis
Mineral dust-associated airway disease
Peribronchiolar metaplasia
Bronchiolocentric nodules
Asthmatic-type changes
Chronic bronchitis/emphysema-associated small airways

(a) Data were derived from Cagle et al. (39)

Table 4. Potential Etiologies of Acute Bronchiolitis (a)

Viral infection
Bacterial infection
Acute exposure to fumes and toxins
Local changes of acute bronchopneumonia
Wegener granulomatosis (rarely)

(a) Data were derived from Cagle et al. (39)

Table 5. Potential Etiologies of Acute and
Chronic Bronchiolitis (a)

Viral infection
Bacterial infection
Mycoplasma infection
Hypersensitivity pneumonitis
Respiratory bronchiolitis
Aspiration pneumonia
Pulmonary involvement with collagen vascular disease
Posttransplantation, graft-versus-host disease
Wegener granulomatosis
Bronchocentric granulomatosis
Diffuse panbronchiolitis
Inhalation of fumes and toxins
Inflammatory bowel disease-related small airways disease

(a) Data were derived from Cagle et al. (39)

Table 6. Potential Etiologies of Chronic Bronchiolitis (a)

Collagen vascular disease
Posttransplantation graft-versus-host disease
Inflammatory bowel disease-related small airways disease
Hypersensitivity pneumonitis
Pulmonary Langerhans cell histiocytosis
Aspiration pneumonia
Diffuse panbronchiolitis
Distal to bronchiectasis
Lymphoproliferative disorders
Local inflammatory reaction such as with middle lobe syndrome
Chronic obstructive pulmonary disease

(a) Data were derived from Cagle et al.39

Table 7. Potential Etiologies of Bronchiolar Necrosis (a)

Viral infections
  Herpes virus
Bronchocentric fungal infections
Bacterial infections
Bronchocentric granulomatosis
Exposure to fumes and toxins
Wegener granulomatosis

(a) Data were derived from Cagle et al. (39)

Table 8. Potential Etiologies of
Granulomatous Bronchiolitis (a)

Fungal infections
Mycobacterial infections, including atypical mycobacterial
Hypersensitivity pneumonitis
Aspiration pneumonia
Bronchocentric granulomatosis
Crohn disease
Wegener granulomatosis
Hard metal disease

(a) Data were derived from Cagle et al. (39)

Table 9. Potential Etiologies of Organizing
Pneumonia With Intraluminal Polyps (a)

Diffuse alveolar damage, organizing
Aspiration pneumonia, organizing
Resolving infections
Postobstruction organization
Hypersensitivity pneumonitis
Organization after exposure to fumes and toxins
Collagen vascular disease
Acute lung transplant rejection
Drug reactions
  Secondary to bone marrow transplantation or other organ
Reaction to radiation therapy or chemotherapy
Chronic eosinophilic pneumonia
Secondary reaction with chronic bronchiolitis
Reparative process adjacent to abscess, necrotic tumor, infarct, etc
Secondary to a hematologic disorder
Inflammatory bowel disease-related small airways disease
Wegener granulomatosis

(a) Data were derived from Cagle et al. (39)

Table 10. Potential Etiologies of
Constrictive Bronchiolitis (a)

Post lung transplantation
Post bone marrow transplantation
Healed infection, especially adenovirus infection
Drug reactions
Healed injury from exposure to fumes and toxins
Collagen vascular disease, especially rheumatoid arthritis
As a component or complication of:
  Cellular bronchiolitis
  Chronic bronchitis
  Cystic fibrosis
  DIPNECH or carcinoid tumorlets
Inflammatory bowel disease-associated small airways disease

Abbreviation: DIPNECH, diffuse idiopathic neuroendocrine cell

(a) Data derived from Cagle et al. (39)
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