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The Proceedings of the American Thoracic Society 3:41-47 (2006)
© 2006 The American Thoracic Society

Bronchiolitis

The Pathologist's Perspective

Daniel W. Visscher and Jeffrey L. Myers

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; and Department of Pathology, University of Michigan, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Daniel W. Visscher, M.D., Division of Anatomic Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: visscher.daniel{at}mayo.edu

ABSTRACT

The term "bronchiolitis" refers to a broad morphologic spectrum of inflammatory events that are centered on small conducting airways. Bronchiolitis may be an isolated pathologic finding, although it is often a secondary consequence of diseases affecting other parts of the conducting apparatus or pulmonary acinus. Divergent causes of bronchiolitis may have similar microscopic findings. Hence, a pathologic diagnosis is nonspecific and not clinically meaningful unless placed in the context of relevant clinical and radiographic findings. Etiologically, most cases of bronchiolitis are infectious in nature or related to smoking. Increasingly, other causes of bronchiolitis have been recognized, including collagen vascular disease, idiopathic inflammatory bowel disease, or toxins/drugs. Many cases are idiopathic. Histologically, most examples of bronchiolitis demonstrate acute inflammation, usually corresponding to viral infection. Other well-defined histologic categories of bronchiolitis include bronchiolitis obliterans, in which there is fibroblast proliferation within airspaces, and follicular bronchiolitis, corresponding to lymphoid hyperplasia with formation of germinal centers. In recent years, several new forms of bronchiolitis have been recognized, including constrictive bronchiolitis, diffuse panbronchiolitis, and airway-centered fibrosis. This article highlights the clinical and pathologic features of these more recently described entities.

Key Words: bronchiolitis • lung pathology • pulmonary infection

DEFINITION AND CLASSIFICATION

The term "bronchiolitis" has been historically confusing to clinicians and pathologists alike. Bronchiolitis is inconsistently applied as both a descriptive and a formal diagnostic term in part because bronchiolitis comprises a heterogeneous group of etiologically, clinically, and pathologically disparate lesions (1). In addition, many of these conditions are complicated by pathologic changes in proximal bronchi and/or more distal alveolar lung tissues (2). In a purely histologic context, this diversity of lesions translates into a broad morphologic spectrum of inflammatory events centered on noncartilagenous airways generally measuring less than 2 mm in diameter.

Bronchioles represent the proximal extent of the pulmonary acinus and as such correspond to the central portion of the secondary pulmonary lobule. For that reason, primary lesions of the small airways are centrilobular in distribution and situated away from connective tissue septa. Bronchioles are sometimes histologically inconspicuous and easily obscured by airway-centered inflammatory infiltrates. The patchy, centrilobular distribution of bronchiolitis in histologic sections is helpful in separating bronchiolitis from other forms of diffuse lung disease. Bronchioles are lined by a simple columnar epithelium that contains both ciliated and nonciliated secretory (Clara) cells. Peribronchiolar interstitium is sparse but contains a layer of smooth muscle, without submucosal glands. More proximal terminal bronchioles are lined by a continuous columnar epithelium and give rise to respiratory bronchioles, which are partially alveolated (Figure 1).


Figure 1
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  		Figure 1. Normal bronchiole with surrounding alveolated parenchyma.

 
Microscopic patterns of bronchiolitis are diverse and can be broadly separated into acute and chronic categories (Figure 2) (3). Acute lesions are sometimes characterized by epithelial necrosis. Chronic bronchiolitis is typically accompanied by variable degrees of intralumenal or peribronchiolar fibrosis ranging from proliferation of fibroblasts and myofibroblasts to collagen scarring. Reparative or reactive hyperplasia of Clara cells and/or smooth muscle often accompanies fibrosis in various forms of chronic bronchiolitis.


Figure 2
Figure 2
Figure 2
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  		Figure 2. (A) Acute bronchiolitis secondary to infection with intraluminal inflammatory exudates. (B) Bronchiolitis in a patient with idiopathic inflammatory bowel disease. (C) Chronic bronchiolitis with mural mononuclear inflammatory cell infiltrates.

 
A pathologic diagnosis of bronchiolitis is meaningless in any individual patient until and unless it is linked to the clinical and radiologic context. Although the problematic nature of bronchiolitis derives partly from the diversity and complexity of associated histologic findings, as noted above, two other important factors must be recognized. First, the various clinical syndromes that present clinically as bronchiolitis are characterized by overlapping histopathologic findings. Hence, a pathologic diagnosis of bronchiolitis is etiologically nonspecific. Second, the presence of bronchiolitis in a biopsy specimen may represent a primary condition or merely a secondary phenomenon in some other primary pathologic process (e.g., bronchiectasis).

Table 1 lists the syndromes that are most often included under the generic heading of "bronchiolitis." This table refers mostly to conditions that are believed to be primary and not diseases in which bronchiolitis complicates other lesions. Functionally, these conditions usually present with airflow limitation, although restrictive defects may also occur in diseases morphologically centered on small airways (4). Moreover, the categories are not mutually exclusive. Constrictive bronchiolitis, for example, may develop as a consequence of acute infectious bronchiolitis.


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  		TABLE 1. SYNDROMES INCLUDED UNDER THE GENERIC HEADING OF "BRONCHIOLITIS"

 
ACUTE BRONCHIOLITIS

This term is most often used clinically to describe an illness of infancy characterized by onset of wheezing with concomitant signs of respiratory viral infection, including low-grade fever and cough, which may persist for weeks. Severe cases, especially in adults, may be accompanied by radiographic abnormalities, typically having a bilateral alveolar pattern. Respiratory syncytial virus is the etiologic agent in the majority of pediatric age patients but other viruses (adenovirus, influenza, parainfluenza) and nonviral pathogens (Mycoplasma) can cause a similar syndrome. In many cases, particularly adults, a microbial agent is never identified.

Primary acute bronchiolitis is not invariably infectious. It is also caused by/associated with asthma or aspiration and may develop as a component of multisystem organ involvement in connective tissue diseases or inflammatory bowel disease. Acute bronchiolitis, in a pathologic sense, often accompanies bronchiectasis, a condition defined histologically by dilation, inflammation, and persistent infection (usually bacterial) of large airways.

Due to its clinically self-limited course, acute viral bronchiolitis is rarely encountered in biopsy material. Pathologic studies of infectious bronchiolitis have shown intense neutrophilic and mononuclear infiltration (5, 6). Necrosis of bronchiolar epithelium occurs in severe cases. By definition, there is no fibroblast proliferation or collagen deposition. In rare cases, though, healing of viral bronchiolitis can lead to fibrous obliteration of small airways, resulting in chronic airflow limitation (7). At least some of these patients are believed to evolve to the histologic finding of constrictive bronchiolitis, which is characterized by a number of causes and clinical associations (see later).

PRIMARY SMALL AIRWAY DISEASE

Hogg and colleagues coined the term "small airway disease" over 30 yr ago in reference to the inflammatory changes present in the peripheral airways of patients, primarily smokers with chronic obstructive pulmonary disease, having moderate to severe airflow limitation (8). Histologically, small airway disease is incompletely defined but believed to be characterized by mononuclear infiltrates involving distal bronchioles, a relatively nonspecific finding. There is no predictable correlation, moreover, between the degree of cellular infiltrate and the severity of airway dysfunction.

Macklem and colleagues subsequently applied the term small airway disease to an idiopathic syndrome of chronic airflow obstruction in patients without evidence of underlying emphysema or chronic bronchitis (9). The pathologic findings in their patients consisted of peribronchiolar mononuclear infiltrates with varying degrees of concentric fibrosis. The fibrosis was dense, without marked cellularity, and resulted in mural thickening of terminal and respiratory bronchioles. It should be noted that these microscopic findings are also etiologically nonspecific. As several of their patients were discovered to have bronchiectasis at autopsy, some have concluded that the bronchiolar abnormalities may have been secondary to proximal large airway disease.

These historical observations highlight one of the key principles regarding histologic diagnosis and classification of bronchiolitis: the pathology of small airway disease is incompletely defined microscopically despite its occurrence in specific clinical settings (10). It has been noted that the pathologic findings in examples of small airway disease overlap significantly with constrictive bronchiolitis (see later). Hence, the precise relationship between these categories remains ill defined.

The concept of small airways disease is histologically distinct from respiratory bronchiolitis, although both may be observed in smokers. The latter was defined pathologically as the presence of excess numbers of pigmented macrophages within distal airways, not associated with significant inflammation, fibroblast activity, or collagen deposition (Figure 3). It is nearly always seen as an incidental marker of cigarette smoking and is not considered a functionally significant lesion except in an uncommon subset of patients who develop a syndrome of mild restrictive lung disease termed "respiratory bronchiolitis interstitial lung disease."


Figure 3
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  		Figure 3. Respiratory bronchiolitis with increased numbers of pigmented alveolar macrophages.

 
CONSTRICTIVE (OBLITERATIVE) BRONCHIOLITIS

The term "constrictive bronchiolitis" was first used to describe lesions characterized by submucosal and peribronchiolar fibrosis, without accompanying fibroblastic proliferation (Figure 4) (10). Inflammatory cell infiltrates are present, but variable in composition. These are more prominent early in the disease process, when bronchioles may also exhibit ectasia and/or mucus trapping. A combination of neutrophils and mononuclear cells is common, with the former more often present in the lumens of affected bronchioles (11, 12). Histologically, constrictive bronchiolitis is often patchy and focal, making histologic diagnosis difficult for inexperienced observers or in small samples. Advanced cases may be especially inconspicuous because of lack of active inflammation and disappearance of bronchioles. In such cases, elastic stains may be useful in identification of affected structures. The pathologic changes in constrictive bronchiolitis are considered to be irreversible.


Figure 4
Figure 4
Figure 4
Figure 4
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  		Figure 4. (A) Constrictive bronchiolitis with mural fibroblast activity and collagen deposition. (B) Constrictive bronchiolitis in a patient with rheumatoid arthritis. (C) Constrictive bronchiolitis, late stage, with "disappearance" of bronchioles (elastic stain). (D) Bronchiolitis obliterans organizing pneumonia, low magnification, showing filling of airspaces by plugs of granulation tissue.

 
Clinically, patients having constrictive bronchiolitis in biopsy specimens usually complain of breathlessness and have functionally significant airflow limitation (13, 14). This reflects the effect of concentric narrowing of bronchiolar lumens and eventually luminal obliteration. The disease is chronic and slowly progressive, although it may be characterized by intermittent episodes of acute bronchiolitis.

Constrictive bronchiolitis is a rare lesion that, in at least some cases, follows as a sequela of acute bronchiolitis (7). In biopsy series, however, it has been described primarily in patients with underlying connective tissue disease, mostly long-standing rheumatoid arthritis. Table 2 lists other syndromes that have been associated with constrictive bronchiolitis.


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  		TABLE 2. CLINICAL SYNDROMES ASSOCIATED WITH CONSTRICTIVE BRONCHIOLITIS

 
Chest roentgenograms in cases of constrictive bronchiolitis are often normal or show only hyperinflation. Computed tomography scans, however, can be extremely helpful by showing a characteristic "mosaic attenuation" pattern (15–17). This finding is typically accentuated in expiratory views. The disease course is typically progressive and often leads to respiratory failure. Prognosis may be better in cases not associated with connective tissue disease (18).

Constrictive bronchiolitis differs from bronchiolitis obliterans (a.k.a. bronchiolitis obliterans organizing pneumonia, or simply, organizing pneumonia) in several notable ways, both conceptually and histologically, although both are etiologically nonspecific (19–21). First, in contrast to the minimally cellular picture and dense collagen seen with constrictive bronchiolitis, bronchiolitis obliterans is characterized microscopically by a very cellular appearance, with active fibroblast proliferation, always with pale-staining, immature collagen. Second, the disease process in bronchiolitis obliterans develops and remains confined within airspace lumens, whereas the collagen deposition is extrinsic in constrictive bronchiolitis. Third, in contrast to the diffuse and progressive nature of constrictive bronchiolitis, bronchiolitis obliterans is often localized to one lobe and consistently resolves with therapy. Finally, constrictive bronchiolitis is an uncommonly encountered lesion compared with the relatively frequent finding of bronchiolitis obliterans in biopsy specimens.

DIFFUSE PANBRONCHIOLITIS

This lesion has been reported almost exclusively in Japanese men, mostly in their fourth and fifth decades of life (Figure 5) (22–26). Although most accept diffuse panbronchiolitis as a discrete, unique syndrome, pathologic findings overlap considerably with idiopathic bronchiectasis, constrictive bronchiolitis, and rheumatoid arthritis–associated bronchiolitis (27–29). This disease presents insidiously, with signs and symptoms of progressive airway obstruction. Most patients, about 75%, also have chronic sinusitis, suggesting (together with the presence of bronchiectasis) that there may be an underlying abnormality of ciliary function. Histologic findings resembling diffuse panbronchiolitis have also been reported in patients with ulcerative colitis (30), allergic angiitis and granulomatosis, adult T-cell leukemia, and non-Hodgkin lymphoma.


Figure 5
Figure 5
Figure 5
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  		Figure 5. (A) Diffuse panbronchiolitis at low magnification. (B) Diffuse panbronchiolitis, higher magnification, showing unit lesion with foam cells and lymphoid hyperplasia. (C) Follicular bronchiolitis, showing prominent lymphoid infiltrates with germinal centers.

 
In addition to progressive airways obstruction, patients with diffuse panbronchiolitis develop episodic bacterial infection, often with Pseudomonas aeruginosa (31). Approximately 30% of patients succumb to the disease within 10 yr of presentation, usually as a result of progressive airflow limitation and hypoxemia (32). Low-dose erythromycin has shown efficacy in some cases (33).

The unit pathologic lesion of diffuse panbronchiolitis consists of the triad of exquisitely bronchiolocentric inflammation, lymphoid hyperplasia, and accumulation of interstitial foam cells (34–36). Similar findings may accompany bronchiectasis and cystic fibrosis, but the triad has been observed in less than 10% of chronic bronchitis, hypersensitivity pneumonia, follicular bronchiolitis, idiopathic constrictive bronchiolitis, or bronchiolitis obliterans cases (37–39). Nevertheless, the presence of any histologic overlap, however limited, serves to emphasize that a diagnosis of bronchiolitis is meaningless in the absence of correlation with clinical and radiographic findings (37–39).

The presence of lymphoid hyperplasia in diffuse panbronchiolitis raises the pathologic differential diagnosis of follicular bronchiolitis, which occurs in the setting of systemic connective tissue diseases, "allergic" conditions, and immunodeficient states. Follicular bronchiolitis may also demonstrate secondary pathology because of airway obstruction. However, it is characterized by more prominent (even confluent) and bronchocentric lymphoid follicles; these have well-defined germinal centers, without the foam cell accumulations that are characteristic of diffuse panbronchiolitis.

CHRONIC BRONCHIOLITIS WITH FIBROSIS (AIRWAY-CENTERED INTERSTITIAL FIBROSIS)

This microscopically distinctive pattern of bronchiolocentric injury has been referred to by a variety of terms, including centrilobular fibrosis, idiopathic bronchiolocentric interstitial pneumonia, airway-centered interstitial fibrosis, and peribronchiolar metaplasia (Figure 6). Regardless of the synonym one prefers, all of these terms refer to overlapping manifestations of chronic airway-centered injury that is distinctly different from the peripheral pattern of fibrosis observed in usual interstitial pneumonia. Unlike other forms of bronchiolitis, fibrosis is accompanied by prominent epithelial hyperplasia involving adjacent alveolar septa, producing a characteristic low-magnification picture. Goblet cell metaplasia, squamous metaplasia, and necrosis have also been described.


Figure 6
Figure 6
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  		Figure 6. (A) Airway-centered interstitial fibrosis. (B) Airway-centered interstitial fibrosis, higher magnification, showing prominent epithelial hyperplasia.

 
Table 3 summarizes data from four studies that have reported clinical findings in patients having various degrees of airway-centered fibrosis with associated epithelial hyperplasia. Most patients are women who present in their fifth to sixth decade of life with chronic nonproductive cough. Some patients have restrictive lung disease. Although imaging studies are variable, a combination of peribronchovascular ground glass opacities with traction bronchiectasis and thickening of bronchial walls is characteristic of those with more advanced peribronchiolar fibrosis. The heterogeneity of clinical findings implies that chronic bronchiolitis with fibrosis may not represent a discrete clinicopathologic syndrome. De Carvalho and colleagues have suggested that at least some of these patients have chronic aspiration (40). Churg and coworkers, on the other hand, identified environmental exposures in a subset of patients, suggesting that toxic or hypersensitivity reactions may contribute in some (41).


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  		TABLE 3. SUMMARY OF STUDIES REPORTING AIRWAY-CENTERED INTERSTITIAL FIBROSIS AND RELATED FORMS OF CHRONIC BRONCHIOLITIS

 
Progressive disease has occurred in patients with more advanced airway-centered interstitial fibrosis, including death from respiratory failure in as many as 37% of those with follow-up. This contrasts with the uniformly good prognosis reported by Fukuoka and associates, suggesting that the degree of peribronchiolar fibrosis may be key in separating prognostically distinct groups (42).

CONCLUSIONS

Bronchiolitis is pathologically defined as any inflammatory process that involves air-conducting passages measuring less than 2 mm in diameter. Clinical and pathologic manifestations of bronchiolitis are diverse. Depending on the nature of the underlying disease, it may be acute or chronic and present with obstructive or restrictive physiology. Bronchiolitis often represents one component in a constellation of histologic findings related to diseases of more proximal airways (e.g., bronchiectasis) or alveolated parenchyma (e.g., pneumonia). As an isolated microscopic finding, it is etiologically nonspecific and must be interpreted in the context of clinical presentation and radiographic features. In other words, clinically distinct disease processes may exhibit histologically overlapping patterns of bronchiolitis.

Despite morphologically nonspecific findings in many cases, certain forms of bronchiolitis are histologically distinctive; these tend to occur in characteristic clinical settings. Examples include lesions such as constrictive bronchiolitis and diffuse panbronchilitis. However, even these microscopic patterns must be correlated with clinical and radiographic features to have diagnostic significance.

FOOTNOTES

Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form December 2, 2005; accepted in final form December 15, 2005)

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