Residency · Residency · Respirology

Hypersensitivity Pneumonitis

Definition and Classification

Overview

Hypersensitivity pneumonitis is an immune-mediated inflammatory and/or fibrotic lung disease caused by the inhalation of organic antigens or low-molecular-weight chemicals in individuals who have become immunologically sensitized. The ATS/JRS/ALAT 2020 guideline introduced a simplified reclassification that divides HP into two categories, replacing the traditional acute, subacute, and chronic terminology. Non-fibrotic HP encompasses the inflammatory, potentially reversible forms of the disease previously categorized as acute and subacute HP. Fibrotic HP corresponds to the previously termed chronic HP, characterized by irreversible fibrosis that may be progressive and can closely mimic idiopathic pulmonary fibrosis.

Epidemiology

The true incidence of hypersensitivity pneumonitis remains uncertain due to underdiagnosis and the variability of antigen exposure across different geographic and occupational settings. Prevalence varies substantially by geography and occupation, with bird fancier's lung being the most common cause in urban settings and farmer's lung predominating in agricultural regions. Cigarette smoking is paradoxically protective against the development of HP through a mechanism thought to involve nicotine-mediated suppression of alveolar macrophage and lymphocyte function. However, smokers who do develop HP may experience worse fibrotic outcomes, a clinically important distinction.

Causative Antigens

Major Categories

The spectrum of antigens capable of causing hypersensitivity pneumonitis is remarkably broad. Avian proteins derived from feather bloom and droppings of birds including parakeets, pigeons, parrots, chickens, and goose down represent the most common cause in many clinical series. Microbial antigens include thermophilic actinomycetes, with Saccharopolyspora rectivirgula causing farmer's lung and Thermoactinomyces vulgaris implicated in various occupational settings, and Trichosporon cutaneum causing summer-type HP in Japan. Fungal antigens encompass Aspergillus, Penicillium, and Cladosporium species, with hot tub lung involving Mycobacterium avium as well as fungal organisms, and mold from water-damaged buildings representing an increasingly recognized cause. Chemical sensitizers such as isocyanates can produce diisocyanate HP in industrial workers, and epoxy resins are similarly implicated. Feather bedding, including duvet and pillow exposure causing so-called feather duvet lung, may present insidiously and is easily overlooked without specific inquiry. Additional causes include metalworking fluid-associated HP, mushroom worker's lung, cheese washer's lung, and sauna taker's lung.

Exposure Assessment

A detailed environmental and occupational history is the single most critical diagnostic step in evaluating suspected HP. Home inspection may be necessary to identify exposures not recognized by the patient, including visible mold, birds, humidifiers, hot tubs, feather bedding, and water damage. Specific IgG antibodies (precipitating antibodies) against suspected antigens can be measured, though sensitivity varies widely from 40-90%. A positive result confirms immunologic sensitization but does not prove disease causation, and a negative result does not exclude HP. Environmental cultures and air sampling through specialized occupational hygiene assessment may be required in complex cases.

<image>A visual catalog of common hypersensitivity pneumonitis antigens and their sources. Display a grid format with images and labels for: (1) Bird fancier's lung - pigeon, parakeet, feather duvet; (2) Farmer's lung - moldy hay with Saccharopolyspora rectivirgula; (3) Hot tub lung - contaminated hot tub/spa; (4) Humidifier lung - contaminated HVAC system; (5) Mushroom worker's lung - mushroom compost; (6) Chemical HP - industrial isocyanate spray painting. For each, show the antigen source, the offending organism/chemical, and typical exposure setting. Include a timeline showing typical latency from exposure to symptom onset for non-fibrotic (4-8 hours post-exposure) vs. fibrotic (insidious over months-years) presentations.</image>

Pathogenesis

Immunologic Mechanisms

The immunopathogenesis of HP involves both Type III (immune complex-mediated) and Type IV (cell-mediated) hypersensitivity responses. In acute and non-fibrotic HP, antigen-antibody complex formation activates the complement cascade, driving the inflammatory response. In chronic and fibrotic HP, T-cell mediated granulomatous inflammation predominates, with both CD8+ and CD4+ T cells participating through a Th1/Th17 cytokine profile characterized by IFN-gamma and IL-17 production. Non-caseating granulomas form but are typically less well-organized than those seen in sarcoidosis, with a characteristic airway-centered distribution. The transition from inflammatory to fibrotic HP involves activation of profibrotic pathways mediated by TGF-beta and PDGF, pathways that share substantial overlap with those driving IPF.

Genetic Susceptibility

Genetic factors influence susceptibility to HP development. HLA associations, particularly with HLA-DRB1 and HLA-DQB1 alleles, have been linked to increased disease risk. The MUC5B promoter variant, the same genetic variant associated with IPF, is also associated with fibrotic HP, suggesting shared fibrotic pathways between these conditions. Familial clustering of HP has been reported, further supporting a genetic contribution to disease susceptibility.

Clinical Presentation

Non-Fibrotic HP

Non-fibrotic HP may present with acute episodes occurring 4-8 hours after antigen exposure, characterized by fever, chills, cough, dyspnea, and malaise that resolve within 24-48 hours after removal from the exposure, often resembling recurrent pneumonia. A more insidious subacute presentation involves progressive cough and dyspnea developing over weeks to months with ongoing exposure, accompanied by weight loss and fatigue. Physical examination reveals inspiratory crackles and characteristic squeaks, but clubbing is typically absent. Pulmonary function testing demonstrates a restrictive pattern with reduced DLCO, and a mixed obstructive-restrictive pattern may be observed.

Fibrotic HP

Fibrotic HP presents insidiously over months to years with progressive dyspnea, cough, and fatigue. The clinical presentation may be identical to IPF, and the condition is frequently mistaken for IPF, making it the most commonly misdiagnosed condition in the IPF differential. Clubbing may be present in fibrotic HP. The exposure history may be remote or entirely unrecognized, a scenario termed cryptogenic fibrotic HP. The presence of a UIP-like pattern on HRCT confers the worst prognosis within the fibrotic HP spectrum.

Diagnosis

ATS/JRS/ALAT 2020 Diagnostic Approach

The 2020 guideline established a diagnostic confidence framework incorporating multiple factors. Diagnostic confidence levels include definite HP, probable HP, and possible HP, with higher confidence achieved when more diagnostic criteria are satisfied. The factors assessed include an identified exposure or positive specific IgG, an HRCT pattern typical for HP, BAL lymphocytosis, and histopathology consistent with HP.

HRCT Findings

HRCT findings differ between non-fibrotic and fibrotic HP. In non-fibrotic HP, the characteristic findings include ground glass opacity in a diffuse or mosaic pattern, centrilobular poorly defined nodules (a key diagnostic finding), mosaic attenuation reflecting air trapping on expiratory images, and an upper and mid-lung predominant or diffuse distribution. In fibrotic HP, the findings include reticulation and traction bronchiectasis with variable distribution that may involve the upper and mid-lung zones, be diffuse, or occasionally be basal predominant. The three-density pattern, characterized by the combination of ground glass opacity, normal lung, and mosaic attenuation within the same imaging section, is highly suggestive of HP. The classic triad of fibrotic changes, mosaic attenuation, and centrilobular nodules strongly suggests HP over IPF. Honeycombing may occur in fibrotic HP, further complicating differentiation from UIP/IPF.

Distinguishing Fibrotic HP from IPF on HRCT

Several imaging clues favor HP over IPF: upper and mid-lung involvement, mosaic attenuation, centrilobular nodules, and relative subpleural sparing in some cases. Conversely, strictly basal-predominant subpleural honeycombing without mosaic attenuation or air trapping favors IPF. Substantial overlap exists between these patterns, and MDD is critical for accurate diagnosis.

BAL

BAL lymphocytosis exceeding 20-30% supports the diagnosis of HP, though sensitivity is approximately 50-60% for fibrotic HP and higher for non-fibrotic HP. BAL lymphocytosis below 20% does not exclude HP, particularly fibrotic HP, where the inflammatory component may be less prominent. The CD4/CD8 ratio is typically below 1.0 in HP, reflecting CD8+ T cell predominance, but the ratio may vary and has limited discriminatory value in isolation. Elevated mast cells exceeding 1% may provide additional support for the diagnosis of HP.

Histopathology (When Biopsy Needed)

When biopsy is required, non-fibrotic HP demonstrates airway-centered lymphocytic interstitial inflammation, poorly formed non-caseating granulomas, peribronchiolar distribution of findings, and multinucleated giant cells. Fibrotic HP shows these same features superimposed on fibrosis, with bridging fibrosis between centrilobular and subpleural regions being a characteristic finding. UIP-like fibrosis may coexist within areas of HP. Differentiation from IPF is supported by the presence of granulomas, airway-centered inflammation, and peribronchiolar fibrosis. Transbronchial lung cryobiopsy (TBLC) is increasingly used and may demonstrate diagnostic features in 60-80% of cases.

<image>A diagnostic confidence matrix for hypersensitivity pneumonitis based on the ATS/JRS/ALAT 2020 guideline. Create a table with four diagnostic criteria as columns: (1) identified exposure or positive specific IgG, (2) HRCT typical for HP, (3) BAL lymphocytosis > 20-30%, (4) histopathology consistent with HP. Rows show combinations of these criteria present, with resulting diagnostic confidence levels (definite, probable, possible) color-coded green, yellow, orange. Show that definite HP requires HRCT + pathology + exposure identification, while probable requires fewer criteria. Include footnotes explaining that fibrotic HP requires at least HRCT evidence of fibrosis and that MDD is recommended at all levels.</image>

Management

Antigen Avoidance

Antigen avoidance is the most critical intervention and is potentially curative in non-fibrotic HP. Complete avoidance is preferred and may require removing birds from the home, replacing feather bedding, remediating mold, or changing occupation. Partial avoidance through respiratory protection or environmental controls may be insufficient to halt disease progression. In non-fibrotic HP, complete resolution is expected if the antigen is removed early in the disease course. In fibrotic HP, antigen removal may halt progression but will not reverse established fibrosis.

Pharmacotherapy - Non-Fibrotic HP

Mild cases of non-fibrotic HP may resolve with antigen avoidance alone. Moderate-to-severe cases typically require oral corticosteroids, with prednisone at 0.5 mg/kg/day to a maximum of 40-60 mg for 4-6 weeks followed by a gradual taper over 3-6 months. FVC and DLCO should be monitored during the taper, as relapse may necessitate prolonged low-dose corticosteroid therapy. Steroid-sparing agents, including mycophenolate mofetil at 1-1.5 g twice daily or azathioprine at 2 mg/kg/day, are employed for steroid-dependent patients.

Pharmacotherapy - Fibrotic HP

For fibrotic HP meeting progressive pulmonary fibrosis (PPF) criteria, antifibrotic therapy with nintedanib is supported by the INBUILD trial, which demonstrated a 57% relative reduction in FVC decline in the fibrotic HP subgroup. Pirfenidone, while lacking a dedicated HP trial, may be used off-label for fibrotic HP with a progressive phenotype. Immunosuppression with mycophenolate or azathioprine is commonly used to address the inflammatory component, though randomized controlled trial evidence is limited and retrospective data suggest benefit in stabilizing FVC. Combination antifibrotic and immunosuppressive therapy lacks trial data but is used empirically in clinical practice. Lung transplant referral should be pursued for progressive fibrotic HP unresponsive to medical therapy.

Prognosis

Prognostic Factors

The distinction between fibrotic and non-fibrotic HP carries the most significant prognostic implications, with fibrotic HP demonstrating a five-year survival of 70-85% compared to near-normal survival for non-fibrotic HP. Within fibrotic HP, a UIP-like pattern on HRCT confers the worst prognosis, approaching the survival seen in IPF. Ongoing antigen exposure accelerates decline and worsens outcomes. The absence of an identifiable antigen, termed cryptogenic fibrotic HP, is associated with worse outcomes, potentially reflecting ongoing unrecognized exposure. Short telomere length in fibrotic HP predicts worse outcomes, paralleling the role of telomere biology in IPF. MUC5B variant carriers with HP may have worse fibrotic outcomes.

Key Clinical Pearls

• Fibrotic HP is the most commonly misdiagnosed condition as IPF; always obtain a detailed exposure history including birds, molds, hot tubs, and feather bedding even when UIP pattern is present
• The three-density pattern on HRCT (ground glass + normal lung + mosaic attenuation) is highly suggestive of HP and helps differentiate from IPF
• BAL lymphocytosis > 20-30% supports HP, but normal BAL lymphocytes do NOT exclude fibrotic HP (sensitivity drops to ~50-60%)
• Smoking is protective against developing HP, but this should never be used to exclude the diagnosis in smokers
• Nintedanib is the only antifibrotic with RCT evidence in fibrotic HP (INBUILD trial); it should be considered for any fibrotic HP meeting PPF criteria despite antigen avoidance and immunosuppression

References

1. Raghu G, Remy-Jardin M, Ryerson CJ, 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, Wells AU, Cottin V, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381(18):1718-1727. (INBUILD)
3. Morisset J, Johannson KA, Jones KD, et al. Identification of Diagnostic Criteria for Chronic Hypersensitivity Pneumonitis. An International Modified Delphi Survey. Am J Respir Crit Care Med. 2018;197(8):1036-1044.
4. Vasakova M, Morell F, Walsh S, et al. Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management. Am J Respir Crit Care Med. 2017;196(6):680-689.
5. Fernandez Perez ER, Travis WD, Lynch DA, et al. Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report. Chest. 2021;160(2):e206-e232.

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