Hypersensitivity Pneumonitis

Risk factors

• Avian antigens (parakeets, pigeons, down bedding) — bird fancier's lung
• Thermophilic actinomycetes in moldy hay or grain — farmer's lung
• Mycobacterium avium complex in hot tubs and indoor pools — hot tub lung
• Fungal contamination of HVAC systems, humidifiers, basements
• Occupational exposures: isocyanates (paint, polyurethane foam), metalworking fluids, wood dust
• Genetic predisposition: MHC class II polymorphisms, possible MUC5B variant

Pathophysiology

Repeated inhalation of small (<5 micrometer) antigens reaches the distal airways and alveoli. In susceptible hosts, a combined type III (immune complex) and type IV (T-cell mediated) hypersensitivity reaction produces bronchiolocentric lymphocytic inflammation, poorly formed non-necrotizing granulomas, and giant cells. Persistent exposure drives fibroblast activation and bronchiolocentric fibrosis indistinguishable from UIP in advanced cases.

Clinical presentation

Differential diagnosis

• Idiopathic pulmonary fibrosis (IPF) — Older smokers, basal/subpleural honeycombing, no exposure history, no upper-lobe or air-trapping predominance; biopsy shows UIP without bronchiolocentric inflammation
• Sarcoidosis — Bilateral hilar lymphadenopathy, perilymphatic micronodules, well-formed non-caseating granulomas, multisystem involvement (skin, eyes, heart)
• Non-specific interstitial pneumonia (NSIP) — Connective tissue disease association, symmetric ground-glass with subpleural sparing, lacks mosaic attenuation and air trapping
• Atypical or viral pneumonia — Acute fever and consolidation rather than recurrent ground-glass; resolves with treatment; lacks exposure pattern
• Eosinophilic pneumonia — Peripheral and BAL eosinophilia; reverse pulmonary edema pattern on chest imaging
• Connective tissue disease-associated ILD — Positive serologies (ANA, RF, anti-CCP, myositis panel), extrapulmonary features (arthritis, Raynaud, rash)
• Drug-induced pneumonitis — Temporal relation to amiodarone, methotrexate, nitrofurantoin, immune checkpoint inhibitors

Diagnostic workup

Diagnostic algorithm

flowchart TD
  A[Suspected HP<br/>exposure + Sx] --> B[HRCT inspiratory<br/>+ expiratory]
  B --> C{Pattern?}
  C -->|Centrilobular GGN<br/>+ mosaic + air trapping| D[Non-fibrotic HP]
  C -->|Reticulation + traction<br/>± honeycombing + mosaic| E[Fibrotic HP]
  C -->|Indeterminate| F[BAL ± biopsy<br/>MDD]
  D --> G[Antigen avoidance<br/>± prednisone taper]
  E --> H[Avoidance + MMF/AZA<br/>± nintedanib<br/>transplant referral]
  F --> I[Diagnostic confidence<br/>tier per ATS 2020]

Treatment

Complications

• Progression to pulmonary fibrosis with respiratory failure
• Pulmonary hypertension and right heart failure
• Increased risk of acute exacerbation similar to IPF
• Iatrogenic complications of chronic immunosuppression (opportunistic infection, steroid-induced metabolic disease)

PANCE pearls

• Always take a meticulous exposure history including hobbies, second homes, hot tubs, down comforters, and workplace.
• Positive serum precipitins indicate exposure, not disease — many exposed asymptomatic individuals are positive.
• Mosaic attenuation with lobular air trapping on expiratory CT is the imaging hallmark.
• Smoking paradoxically reduces the incidence of HP but worsens prognosis once disease is established.
• Fibrotic HP and IPF can be radiologically and histologically indistinguishable — multidisciplinary discussion is essential before committing to long-term therapy.

References

• ATS/JRS/ALAT 2020 — Diagnosis of Hypersensitivity Pneumonitis in Adults: An Official ATS/JRS/ALAT Clinical Practice Guideline (Raghu et al., AJRCCM 2020;202:e36-e69)
• CHEST 2021 — Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management (Costabel et al., CHEST 2020)
• INBUILD Trial — Flaherty KR et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. NEJM 2019;381:1718-1727