Residency · Residency · Allergy Immunology

Hypersensitivity Pneumonitis

Overview

Hypersensitivity pneumonitis (HP), formerly known as extrinsic allergic alveolitis, is an immune-mediated interstitial lung disease caused by the inhalation of organic antigens or low-molecular-weight chemicals in susceptible individuals. The condition results from a combined Type III (immune complex) and Type IV (T cell-mediated) hypersensitivity response directed against the inhaled antigen. The current classification, established by the 2020 ATS/JRS/ALAT guideline, divides HP into two categories based on the presence or absence of fibrosis: non-fibrotic (inflammatory) HP, which is generally reversible with antigen avoidance, and fibrotic HP, which carries a significantly worse prognosis. Among exposed individuals, only 5 to 15% develop HP, indicating that host susceptibility factors, including genetic predisposition and regulatory immune mechanisms, play a critical role in determining who progresses from sensitization to disease.

Classification (ATS/JRS/ALAT 2020)

Comparison of Non-Fibrotic vs Fibrotic HP

Non-Fibrotic HP (Formerly Acute/Subacute)

Non-fibrotic HP is characterized by inflammatory disease without evidence of fibrosis on HRCT or histological examination. The imaging hallmarks are ground-glass opacities, mosaic attenuation reflecting air trapping, and centrilobular nodules. This form of HP is generally reversible with identification and avoidance of the offending antigen, and the prognosis is favorable, with a five-year mortality rate of less than 5%. The inflammatory nature of this subtype reflects the predominance of cellular immune responses in the lung parenchyma without the establishment of permanent structural remodeling.

Fibrotic HP (Formerly Chronic)

Fibrotic HP is defined by the presence of established fibrosis on HRCT -- manifesting as reticulation, traction bronchiectasis, or honeycombing -- or on histopathologic examination. This form may develop insidiously over months to years in the setting of chronic low-level antigen exposure that may go unrecognized. In advanced cases, the imaging appearance may become indistinguishable from idiopathic pulmonary fibrosis (IPF), presenting a significant diagnostic challenge. The prognosis of fibrotic HP is substantially worse than its non-fibrotic counterpart, with a five-year mortality of 20 to 50% and a median survival of 7 to 9 years after diagnosis.

Etiology - Common Antigens and Exposures

Common Antigens and Associated HP Syndromes

Microbial Antigens

The most recognized microbial causes of HP include thermophilic actinomycetes, particularly Saccharopolyspora rectivirgula, which is responsible for farmer's lung in individuals exposed to moldy hay. Bird fancier's lung, caused by exposure to avian proteins found in feather bloom and droppings from pigeons, parakeets, doves, and chickens, is the most common form of HP in many developed countries. Hot tub lung results from Mycobacterium avium complex growing in the warm, aerosolized water of hot tubs and spas. Humidifier lung and air conditioner lung arise from thermophilic actinomycetes and fungi contaminating climate control systems. Mushroom worker's lung is caused by thermophilic actinomycetes present in mushroom compost.

Chemical Antigens

Chemical exposures represent an important category of HP etiologies. Isocyanates, including toluene diisocyanate (TDI) and methylene diphenyl diisocyanate (MDI), are encountered in spray painting and foam manufacturing and can cause both occupational asthma and HP. Beryllium exposure in aerospace and electronics industries causes chronic beryllium disease (berylliosis), a granulomatous lung disease that requires the beryllium lymphocyte proliferation test (BeLPT) for diagnosis. Metalworking fluids contaminated with mycobacteria represent another occupational source.

Other Exposures

Indoor mold exposure from Aspergillus, Penicillium, and Cladosporium species in water-damaged buildings is an increasingly recognized cause of HP. Down feather bedding represents an occult source of bird antigen exposure that is easily overlooked during the exposure history. Less common etiologies include suberosis from cork dust (Penicillium glabrum), bagassosis from sugarcane processing (thermophilic actinomycetes), and maple bark disease from Cryptostroma corticale.

Pathophysiology

Immune Mechanisms

The pathogenesis of HP involves a combined immune response triggered by repeated antigen inhalation in genetically susceptible individuals. The Type III hypersensitivity component involves the formation of IgG immune complexes within the alveolar walls, leading to complement activation and neutrophil recruitment. The Type IV component consists of a CD4-positive and CD8-positive T cell-mediated granulomatous response, with CD8-positive T cells typically predominating in bronchoalveolar lavage fluid. Genetic susceptibility varies by antigen but is linked to specific HLA-DRB1 subtypes.

A critical conceptual point is that HP is not an IgE-mediated (Type I) hypersensitivity reaction, despite the potentially misleading name "hypersensitivity." The pathogenic mechanisms are fundamentally different from those of allergic asthma or allergic rhinitis. Dysfunction of regulatory T cells may contribute to the loss of tolerance observed in individuals who develop HP, as the majority of exposed individuals achieve immunologic tolerance and never develop clinical disease.

Histopathology

The histopathologic findings of HP are characterized by a classic triad. The first feature is chronic bronchiolocentric interstitial inflammation rich in lymphocytes and plasma cells, reflecting the T cell-driven immune response centered on the small airways. The second is the presence of non-necrotizing granulomas that are characteristically small, poorly formed, and distributed in a peribronchiolar pattern. This distribution and morphology are important distinguishing features from sarcoidosis, in which granulomas are well-formed, compact, and distributed along lymphatic routes. The third feature is either an organizing pneumonia pattern or fibrosis, depending on the stage and chronicity of the disease. Giant cells containing Schaumann bodies or asteroid bodies may be present but are nonspecific findings. In fibrotic HP, a pattern resembling usual interstitial pneumonia (UIP) may be observed, though upper-lobe predominance may help distinguish it from IPF.

<image>A side-by-side comparison of non-fibrotic versus fibrotic hypersensitivity pneumonitis on HRCT imaging and histopathology. Left side (Non-fibrotic HP): HRCT axial slice showing diffuse ground-glass opacities, mosaic attenuation pattern (alternating areas of different density suggesting air trapping), and scattered centrilobular nodules in upper and mid zones. Below: histopathology showing lymphocytic bronchiolitis, peribronchiolar non-necrotizing granuloma (small and poorly formed), and organizing pneumonia pattern with Masson bodies. Right side (Fibrotic HP): HRCT showing reticulation, traction bronchiectasis, and early honeycombing with upper-to-mid zone predominance; mosaic attenuation still visible (key distinguishing feature from IPF). Below: histopathology showing dense fibrosis, peribronchiolar granulomas amidst fibrosis, and architectural distortion. Center comparison panel noting key differentiating features between fibrotic HP and IPF on CT: mosaic attenuation and upper-lobe predominance favor fibrotic HP over IPF.</image>

Diagnosis

Clinical Assessment

The exposure history is the single most critical element in the diagnostic evaluation of HP. A detailed and systematic occupational, hobby, home, and environmental history must be obtained from every patient in whom HP is suspected. Specific inquiries should address exposure to birds (including down bedding and jackets, which represent occult avian antigen sources), farming activities, hot tub use, indoor mold or water damage, and occupational exposures. The temporal relationship between symptoms and exposure is an important diagnostic clue: symptoms that improve when the patient is away from the exposure source -- during weekends, vacations, or job changes -- strongly support the diagnosis.

The symptom profile differs between non-fibrotic and fibrotic HP. Non-fibrotic HP typically presents with acute episodes of fever, chills, cough, and dyspnea occurring 4 to 12 hours after exposure and resolving within 24 to 48 hours of avoidance. Fibrotic HP presents more insidiously with progressive dyspnea on exertion, dry cough, and weight loss, and may lack a clear temporal relationship to exposure, making diagnosis more challenging. Physical examination reveals fine inspiratory crackles and occasionally inspiratory squeaks; digital clubbing, when present, indicates fibrotic HP and portends a worse prognosis.

Laboratory

Serum precipitins, representing antigen-specific IgG antibodies directed against suspected causal antigens, indicate sensitization and exposure but do not confirm disease. Many exposed individuals who never develop HP have positive precipitins, limiting the specificity of this test. Conversely, negative precipitins do not exclude HP, as the available antigen panels are incomplete and the sensitivity ranges from approximately 50 to 90%. ImmunoCap-based specific IgG assays offer improved sensitivity compared to traditional Ouchterlony immunodiffusion methods. The complete blood count may show leukocytosis during acute episodes but notably does not demonstrate eosinophilia, which helps distinguish HP from eosinophilic pneumonia. KL-6 (Krebs von den Lungen-6) may be elevated in HP and other interstitial lung diseases but is a nonspecific marker.

Pulmonary Function Testing

Pulmonary function testing in non-fibrotic HP typically reveals a restrictive pattern with reduced forced vital capacity (FVC) and total lung capacity (TLC), or a mixed pattern, accompanied by a reduced diffusing capacity for carbon monoxide (DLCO). Fibrotic HP demonstrates a restrictive pattern with reduced DLCO, and may include an obstructive component reflecting associated bronchiolitis. Air trapping can be detected on body plethysmography as an elevated residual volume to total lung capacity ratio. Exercise desaturation is a sensitive early finding that may precede abnormalities on resting pulmonary function testing.

HRCT Findings

High-resolution CT is the imaging cornerstone of HP diagnosis. In non-fibrotic HP, the characteristic findings include ground-glass opacities, mosaic attenuation (the three-density sign), centrilobular nodules with upper and mid-zone predominance, and air trapping best demonstrated on expiratory images. In fibrotic HP, these inflammatory features coexist with signs of fibrosis including reticulation, traction bronchiectasis, and honeycombing. Two features are particularly useful in distinguishing fibrotic HP from IPF: the upper and mid-zone predominance of fibrosis in HP (versus the basal predominance typical of IPF) and the presence of mosaic attenuation, which is a hallmark of HP and is uncommon in IPF. The three-density sign, in which ground-glass opacity, normal lung, and hyperlucent areas (trapped air) coexist, is considered pathognomonic for HP.

Bronchoalveolar Lavage (BAL)

BAL in HP characteristically demonstrates marked lymphocytosis, typically exceeding 20 to 40% and often surpassing 50% in non-fibrotic HP, with values occasionally reaching 80% or higher. The CD4/CD8 ratio is typically low (below 1), reflecting a CD8-positive T cell predominance, though this finding is variable and not sufficiently reliable for independent diagnostic use. BAL lymphocytosis exceeding 20 to 30% supports the diagnosis of HP in the appropriate clinical context. Acute episodes may show associated neutrophilia, and mixed cellularity patterns are possible.

Multidisciplinary Discussion (MDD)

The ATS guideline strongly recommends multidisciplinary discussion involving a pulmonologist, radiologist, and pathologist for the diagnosis of HP. This collaborative approach assigns diagnostic confidence levels of definite, probable, or possible HP. When non-invasive assessment is inconclusive, tissue biopsy via surgical lung biopsy or transbronchial cryobiopsy should be considered to establish or exclude the diagnosis.

Treatment

Antigen Avoidance

Antigen avoidance is the cornerstone of HP management and the single most important therapeutic intervention. Identification and complete elimination of the exposure source is the primary goal. However, achieving complete avoidance is often challenging in practice. Occupational exposures may necessitate a job change, and patients with bird fancier's lung face the emotional burden of rehoming beloved pets. When complete avoidance is impossible, respiratory protection with N95 masks provides partial but imperfect protection. Environmental remediation measures include professional mold remediation for water-damaged homes, removal of feather bedding and down products, and use of HEPA air filtration systems.

Pharmacotherapy

For non-fibrotic HP, antigen avoidance alone is often sufficient, and corticosteroids are reserved for patients with persistent or severe symptoms. When indicated, prednisone at 0.5 mg/kg/day for four to six weeks followed by a taper over three to six months is the standard regimen. Serial pulmonary function testing and imaging are used to monitor the treatment response.

Fibrotic HP requires a more aggressive and multifaceted approach. Corticosteroids may stabilize or slow disease progression but are generally less effective than in non-fibrotic HP. Mycophenolate mofetil has emerged as the most commonly used steroid-sparing immunosuppressive agent based on retrospective evidence, with azathioprine serving as an alternative. For patients with progressive fibrosing disease despite immunosuppression, antifibrotic therapy represents an important advance. Nintedanib received approval for progressive fibrosing interstitial lung diseases, including fibrotic HP, based on the INBUILD trial. This landmark study demonstrated that nintedanib significantly reduced the annual rate of FVC decline, with a loss of 80.8 mL per year in the treatment group compared to 187.8 mL per year in the placebo group, representing an approximately 50% reduction in lung function decline. Pirfenidone, approved for IPF, is used off-label in some cases of fibrotic HP, though data are more limited. Lung transplantation should be considered for patients with end-stage fibrotic HP unresponsive to medical therapy.

<image>A treatment algorithm for hypersensitivity pneumonitis. Starting point: "Confirmed HP diagnosis via MDD." First branch: "Fibrotic or non-fibrotic?" Non-fibrotic branch: Step 1 - Antigen avoidance (detailed checklist of common sources to address). Step 2 - If persistent symptoms/PFT decline: oral corticosteroids (prednisone 0.5mg/kg, 4-6 week course, 3-6 month taper). Step 3 - Monitor PFTs q3-6 months; if stable, continue avoidance alone. Fibrotic branch: Step 1 - Antigen avoidance. Step 2 - Immunosuppression (corticosteroids +/- mycophenolate or azathioprine). Step 3 - If progressive despite immunosuppression (FVC decline >5% per year): add antifibrotic (nintedanib based on INBUILD trial). Step 4 - If continued progression: lung transplant evaluation. Monitoring panel: PFTs every 3-6 months, HRCT annually or with clinical change, 6-minute walk test.</image>

Key Clinical Pearls

• HP is NOT IgE-mediated; it is driven by Type III (immune complex) and Type IV (T cell-mediated) hypersensitivity
• The most important diagnostic step is a thorough exposure history: ask about birds (including down bedding), farming, hot tubs, indoor mold, and occupation
• Serum precipitins (specific IgG) indicate sensitization/exposure, NOT disease; many exposed individuals are precipitin-positive without HP
• BAL lymphocytosis >20-40% supports HP diagnosis; typically CD8+ T cell predominant (low CD4/CD8 ratio)
• Mosaic attenuation and centrilobular nodules on HRCT with upper/mid-zone predominance distinguish HP from IPF
• Antigen avoidance is the cornerstone of treatment; non-fibrotic HP is largely reversible with avoidance
• Nintedanib (INBUILD trial) is approved for progressive fibrosing ILDs including fibrotic HP; reduces FVC decline by ~50%
• Hot tub lung (M. avium complex HP) requires both antigen avoidance AND antimycobacterial therapy in some cases

References

1. Raghu G, et al. Diagnosis of hypersensitivity pneumonitis in adults: an official ATS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2020;202(3):e36-e69.
2. Flaherty KR, et al. Nintedanib in progressive fibrosing interstitial lung diseases (INBUILD). N Engl J Med. 2019;381(18):1718-1727.
3. Selman M, et al. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am J Respir Crit Care Med. 2012;186(4):314-324.
4. Vasakova M, et al. Hypersensitivity pneumonitis: perspectives in diagnosis and management. Am J Respir Crit Care Med. 2017;196(6):680-689.
5. Morisset J, et al. Use of mycophenolate mofetil or azathioprine for the management of chronic hypersensitivity pneumonitis. Chest. 2017;151(3):619-625.

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