Immune-mediated interstitial lung disease triggered by inhaled organic antigens, classified as non-fibrotic or fibrotic.
Also known as: HP, extrinsic allergic alveolitis, farmer's lung, bird fancier's lung, hot tub lung
Overview
An immunologically mediated diffuse parenchymal lung disease provoked by repeated inhalation of a variety of organic and chemical antigens in susceptible individuals. The 2020 ATS/JRS/ALAT clinical practice guideline replaced the older acute/subacute/chronic framework with two phenotypes: non-fibrotic HP and fibrotic HP.
Epidemiology
Prevalence varies by exposure setting; estimated 1-3% of patients evaluated for ILD. No clear sex predominance. Non-smokers carry higher risk than smokers (smoking appears to dampen alveolar antigen response).
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Question 1PulmonaryMedium
A 50-year-old woman reports progressive exertional dyspnea over several months. For the past 3 years she has run a cool-mist humidifier in her bedroom every night and rarely cleans its reservoir. High-resolution CT of the chest shows bilateral ground-glass opacities with upper- and mid-lung predominance. Serum precipitins to microbial antigens cultured from the humidifier reservoir are positive. Video-assisted thoracoscopic lung biopsy demonstrates non-necrotizing granulomas with a lymphocytic alveolitis. Which of the following is the most likely diagnosis?
AChronic beryllium disease
BHypersensitivity pneumonitis
CPulmonary sarcoidosis
DCryptogenic organizing pneumonia
EIdiopathic pulmonary fibrosis
Reveal answer & full explanation
Correct answer: B — Hypersensitivity pneumonitis
AChronic beryllium disease
BHypersensitivity pneumonitis✓
CPulmonary sarcoidosis
DCryptogenic organizing pneumonia
EIdiopathic pulmonary fibrosis
Why hypersensitivity pneumonitis is correct
An identifiable inhaled antigen (a contaminated humidifier, 'humidifier lung') with positive serum precipitins, lymphocytic alveolitis, and non-necrotizing granulomas is diagnostic of hypersensitivity pneumonitis.
Bronchoalveolar lavage classically shows lymphocytosis with a low CD4:CD8 ratio.
Upper- and mid-lung predominance fits hypersensitivity pneumonitis and helps separate it from the lower-lobe fibrosis of idiopathic pulmonary fibrosis.
Antigen avoidance (removing or replacing the humidifier) is the cornerstone of management, with corticosteroids for non-fibrotic disease with significant symptoms or impairment.
Why the others are wrong
Pulmonary sarcoidosis — Also produces non-caseating granulomas, but it is not tied to a specific inhaled antigen and shows a high (not low) BAL CD4:CD8 ratio; the humidifier exposure and positive precipitins point away from it (confused-with-granulomatous-disease).
Cryptogenic organizing pneumonia — Produces organizing pneumonia with patchy consolidation, no granulomas, and is not antigen-driven (buzzword-matching on ground-glass opacities).
Idiopathic pulmonary fibrosis — Causes lower-lobe honeycombing with a UIP pattern and no granulomas or antigen exposure; the granulomas and exposure here exclude it (premature closure on the most common ILD).
Chronic beryllium disease — mimics sarcoidosis with non-necrotizing granulomas and a lymphocytic alveolitis after an inhaled exposure, but it requires beryllium exposure (usually occupational, as in aerospace, electronics, or metalworking), and diagnosis rests on beryllium sensitization shown by a beryllium lymphocyte proliferation test plus granulomas on biopsy; precipitins to humidifier microbial antigens point to an organic antigen (confused-with-occupational-granulomatous-disease).
Question 2PulmonaryMedium
A 42-year-old farmer presents with 6 hours of fever, dyspnea, dry cough, and malaise after cleaning a moldy hay barn. CXR shows diffuse ground-glass infiltrates. He has had similar episodes in the past that resolved within days of leaving the farm. Which is the most likely diagnosis?
AOccupational asthma
BAcute hypersensitivity pneumonitis
CCommunity-acquired pneumonia
DSarcoidosis stage I
EAcute eosinophilic pneumonia
Reveal answer & full explanation
Correct answer: B — Acute hypersensitivity pneumonitis
AOccupational asthma
BAcute hypersensitivity pneumonitis✓
CCommunity-acquired pneumonia
DSarcoidosis stage I
EAcute eosinophilic pneumonia
Why Acute hypersensitivity pneumonitis is correct
Hypersensitivity pneumonitis (HP) is a Type III/IV immune-mediated reaction to inhaled organic antigens
Farmer's lung is caused by thermophilic actinomycetes in moldy hay
Acute HP develops 4–8 hours after antigen exposure with flu-like symptoms and resolves with avoidance — matching this patient's recurrent episodic pattern
Why the others are wrong
Sarcoidosis stage I — sarcoidosis would show bilateral hilar lymphadenopathy (BHL) on CXR
Acute eosinophilic pneumonia — eosinophilic pneumonia has marked peripheral eosinophilia
Community-acquired pneumonia — CAP does not have the episodic antigen-exposure pattern or the rapid resolution with avoidance
Occupational asthma — work-related symptoms that remit away from the exposure fit occupational asthma, but it is an airway disease causing wheezing and variable airflow obstruction, not fever, malaise, and diffuse ground-glass infiltrates on CXR
Additional high-yield points
Chronic HP shows fibrosis with mid-to-upper lobe predominance, mosaic attenuation, and centrilobular nodules on high-resolution CT (HRCT)
Bronchoalveolar lavage (BAL) shows lymphocytosis (>50%), often with low CD4:CD8
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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
Symptoms
Non-fibrotic HP: cough, dyspnea, low-grade fever, malaise, and chest tightness developing 4-12 hours after antigen exposure; recurrent flares with re-exposure
Fibrotic HP: insidious progressive exertional dyspnea and dry cough over months to years; weight loss; may mimic IPF
Symptom improvement during weekends or vacations away from the antigen is a classic clue
2020 ATS/JRS/ALAT guideline integrates exposure identification, HRCT pattern, BAL lymphocytosis, and (when needed) lung biopsy into a confidence-level diagnosis (definite, high, moderate, low). Multidisciplinary discussion is recommended for cases without an identifiable exposure or with discordant features.
Labs
Serum-specific IgG (precipitins) against suspected antigens — supports exposure but is not diagnostic on its own (many asymptomatic exposed persons are positive)
CBC (mild leukocytosis acutely), CMP, ESR/CRP
Connective tissue disease serologies to exclude CTD-ILD
BAL: lymphocytosis typically >30% with CD4:CD8 ratio often <1 (supportive but variable)
Imaging
HRCT chest is the cornerstone imaging study (inspiratory and expiratory views)
Non-fibrotic HP: diffuse centrilobular ground-glass nodules, mosaic attenuation, lobular air trapping on expiratory imaging — the 'three-density' or 'headcheese' sign is suggestive
Fibrotic HP: reticulation, traction bronchiectasis, and honeycombing with upper- and mid-lobe predominance and superimposed mosaic attenuation
PFTs: restrictive pattern with reduced DLCO; obstructive or mixed patterns also occur due to bronchiolar involvement
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]
Diagnostic and management pathway for hypersensitivity pneumonitis based on HRCT phenotype.
Treatment
First-line
Antigen avoidance is the single most important intervention — environmental remediation, removal of birds, HVAC inspection, occupational reassignment
Supplemental oxygen for resting or exertional hypoxemia
Pulmonary rehabilitation for symptomatic and fibrotic disease
Vaccinations: influenza annually, pneumococcal (PCV20 or PCV15 followed by PPSV23), COVID-19, RSV per current adult schedule
Non-fibrotic HP with significant symptoms or impairment
Systemic corticosteroids: prednisone 0.5 mg/kg/day (max ~60 mg) for 1-2 weeks, then taper over 4-6 weeks based on response
Reassess imaging and PFTs after antigen removal before considering long-term immunosuppression
Fibrotic HP
Antigen avoidance plus consideration of immunosuppression
Steroid-sparing agents: mycophenolate mofetil or azathioprine for progressive disease
Antifibrotic therapy with nintedanib for progressive pulmonary fibrosis phenotype (INBUILD trial demonstrated reduced FVC decline)
Early lung transplant referral (ISHLT 2021): FVC <80% or DLCO <40% predicted, supplemental oxygen need, or progression despite therapy
Second-line / adjunct
Rituximab has been used in refractory fibrotic HP at experienced centers
Treat comorbid GERD, sleep-disordered breathing, and pulmonary hypertension
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 — Fernández Pérez ER, Travis WD, Lynch DA, et al. Diagnosis and Evaluation of Hypersensitivity Pneumonitis: CHEST Guideline and Expert Panel Report. Chest 2021;160(2):e97-e156
INBUILD Trial — Flaherty KR et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. NEJM 2019;381:1718-1727
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