Follicular Bronchiolitis: Clinical Profile and Prognosis

Follicular bronchiolitis is a rare lung disorder marked by inflammation of the small airways, often linked to immune disturbances. It occurs in both children and adults, with widely varying clinical manifestations that make early recognition difficult. The condition is frequently associated with autoimmune diseases or immunodeficiency but can also develop without an identifiable cause. Due to its nonspecific symptoms and overlap with other respiratory conditions, accurate diagnosis requires thorough evaluation.

Pathological Features

Follicular bronchiolitis is defined by lymphoid hyperplasia centered around the bronchioles, forming well-defined lymphoid follicles with germinal centers. These follicles develop within the peribronchiolar interstitium and can extend into adjacent alveolar septa. The proliferation of lymphoid tissue may partially obstruct the small airways, contributing to airflow limitation and respiratory symptoms. Histopathological examination typically reveals dense B-cell-rich lymphoid aggregates, often accompanied by plasma cells and T lymphocytes, reflecting ongoing inflammation.

The structural changes extend beyond the bronchioles, sometimes affecting surrounding lung tissue. Reactive lymphoid follicles can narrow or even completely obstruct the bronchiolar lumen, a process exacerbated by peribronchiolar fibrosis. Unlike other small airway diseases, follicular bronchiolitis lacks significant neutrophilic infiltration or granuloma formation, distinguishing it from diffuse panbronchiolitis or hypersensitivity pneumonitis.

Histological severity varies, from mild peribronchiolar lymphoid aggregates to extensive lymphoid proliferation with structural distortion. Some cases show reactive epithelial changes, including bronchiolar metaplasia or mild goblet cell hyperplasia, which can contribute to mucus accumulation and airway narrowing. The presence of germinal centers indicates an active antigen-driven process that may persist and lead to progressive airway dysfunction.

Possible Immune Mechanisms

The immune dysfunction in follicular bronchiolitis is driven by an exaggerated lymphoid response involving B-cell proliferation and T-cell activation. The formation of organized lymphoid follicles suggests antigen-driven stimulation, potentially triggered by chronic infections, environmental exposures, or autoimmune conditions. Studies have identified an increased presence of CD20+ B lymphocytes in peribronchiolar follicles, indicating an ongoing humoral immune response. The surrounding interstitium also contains CD4+ and CD8+ T cells, contributing to persistent inflammation and airway changes.

Cytokine profiling highlights the role of inflammatory mediators in sustaining lymphoid hyperplasia. Elevated levels of interleukin-6 (IL-6) and B-cell activating factor (BAFF) promote B-cell survival and differentiation, facilitating autoantibody production. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) contribute to T-cell and macrophage recruitment, perpetuating chronic inflammation.

Antigen presentation plays a role, with dendritic cells and macrophages actively driving the immune response. Increased expression of major histocompatibility complex (MHC) class II molecules in biopsy samples suggests enhanced interactions between immune cells and potential autoantigens. Some cases show aberrant somatic hypermutation within germinal centers, raising the possibility of an abnormal or self-reactive B-cell response that worsens local inflammation.

Clinical Profile

Patients typically present with persistent cough, usually dry and non-productive, though some experience mild sputum production. Progressive exertional dyspnea is common, often worsening gradually. Wheezing may occur but is less pronounced than in asthma or chronic obstructive pulmonary disease. Some individuals report chest tightness or discomfort, though these symptoms are generally mild.

Pulmonary function tests often reveal a restrictive or mixed obstructive-restrictive pattern, with reduced forced expiratory volume in one second (FEV1) and a mildly decreased forced vital capacity (FVC). The diffusing capacity for carbon monoxide (DLCO) may be slightly impaired, reflecting subtle alveolar gas exchange alterations. Spirometry findings can be variable, with some patients showing near-normal lung function despite persistent symptoms, delaying diagnosis.

Disease progression varies. Some individuals remain stable for years, while others develop worsening airflow limitation and exertional hypoxia. Respiratory failure is rare but more likely in those with concurrent systemic diseases. Digital clubbing is uncommon but may appear in advanced cases, particularly with interstitial lung involvement. Fatigue and mild constitutional symptoms, such as low-grade fever or weight loss, may occur in some patients but are not defining features.

Diagnostic Evaluation

Diagnosing follicular bronchiolitis requires clinical assessment, pulmonary function testing, imaging studies, and histopathologic analysis. Given its nonspecific symptoms and overlap with other small airway diseases, early misdiagnosis is common. A thorough history is essential, especially in identifying associations with autoimmune disorders, immunodeficiencies, or chronic infections. Physical examination findings may be unremarkable, though some patients exhibit fine crackles or subtle airflow limitation.

Pulmonary function tests provide supportive evidence but are not definitive. Findings range from mild obstruction to a restrictive pattern, with some individuals displaying preserved lung volumes despite symptoms. Bronchoscopy with bronchoalveolar lavage may help exclude infectious or inflammatory conditions, though lavage fluid findings are often nonspecific. A surgical lung biopsy remains the gold standard for diagnosis, as transbronchial biopsies frequently yield insufficient tissue.

Radiological Characteristics

High-resolution computed tomography (HRCT) is the preferred imaging modality, revealing characteristic small airway abnormalities. The most common finding is a combination of centrilobular nodules and peribronchiolar thickening, reflecting lymphoid proliferation. These nodules, typically 2 to 10 mm in diameter, are often diffuse but more prominent in the lower lung zones. A mosaic attenuation pattern, indicative of air-trapping from partial bronchiolar obstruction, is best seen on expiratory imaging.

Mild bronchial wall thickening and tree-in-bud opacities may be present but are more typical of infectious bronchiolitis. Unlike constrictive bronchiolitis, which primarily manifests as air-trapping, follicular bronchiolitis often shows peribronchiolar ground-glass opacities, reflecting active inflammation. In advanced cases, subtle interstitial changes may develop, particularly in patients with underlying connective tissue diseases. While HRCT strongly suggests the diagnosis, histopathologic confirmation is usually required. The extent of radiologic abnormalities correlates with functional impairment, with more widespread involvement predicting worse outcomes.

Associated Systemic Conditions

Follicular bronchiolitis frequently coexists with systemic diseases, particularly those involving immune dysregulation. Rheumatoid arthritis is the most common association, with follicular bronchiolitis presenting as an isolated pulmonary manifestation or alongside interstitial lung disease. Sjögren’s syndrome is another notable association, with affected individuals often exhibiting concurrent lymphocytic infiltration of the salivary and lacrimal glands.

Immunodeficiency states, particularly common variable immunodeficiency (CVID), also predispose individuals to follicular bronchiolitis. Recurrent infections and persistent immune activation in CVID contribute to lymphoid hyperplasia and chronic airway inflammation, complicating diagnosis. Less commonly, follicular bronchiolitis has been reported in inflammatory bowel disease and chronic granulomatous disease, suggesting a broader spectrum of immune-mediated lung involvement. Recognizing these systemic associations is crucial for guiding management.

Differential Diagnosis

Distinguishing follicular bronchiolitis from other small airway diseases requires careful evaluation of clinical, radiologic, and histopathologic findings. Hypersensitivity pneumonitis also presents with centrilobular nodules and peribronchiolar inflammation but typically exhibits a more diffuse ground-glass pattern and a clear exposure history. Unlike follicular bronchiolitis, it often features poorly formed granulomas on biopsy.

Diffuse panbronchiolitis, more common in East Asian populations, is another consideration. It is characterized by chronic infection-related bronchiolar inflammation, often with neutrophilic infiltration and mucus plugging. Radiologically, it shows more prominent lower lobe involvement with extensive bronchiectasis, distinguishing it from follicular bronchiolitis. Constrictive bronchiolitis primarily presents with obliterative fibrosis and lacks the organized lymphoid follicles seen in follicular bronchiolitis. Definitive diagnosis often requires histopathologic confirmation.

Prognostic Indicators

The course of follicular bronchiolitis varies, with some patients experiencing stable disease while others develop progressive respiratory impairment. Prognostic assessment relies on functional, radiologic, and histopathologic parameters. Declining FEV1 or worsening DLCO on pulmonary function tests suggests progression. Serial spirometry helps track changes, particularly in patients with coexisting systemic conditions.

Radiologic findings provide additional prognostic insight, with more extensive peribronchiolar involvement correlating with greater functional decline. Patients with widespread centrilobular nodules and mosaic attenuation are more likely to have persistent airflow limitation. Histopathologic severity, particularly the degree of lymphoid follicle proliferation and associated fibrosis, further informs prognosis. In cases with significant fibrosis, irreversible airway obstruction is more likely. While some individuals respond to immunomodulatory therapy, others may require long-term respiratory support. Identifying early indicators of progression is essential for guiding treatment and optimizing outcomes.