Hypersensitivity pneumonitis

Background

  • Hypersensitivity pneumonitis (HP), formerly known as extrinsic allergic alveolitis, is an immune-mediated interstitial lung disease caused by an exaggerated inflammatory response to repeated inhalation of a sensitizing antigen in a susceptible host.[1] More than 300 causative antigens have been identified.[2] The disease exists on a spectrum from acute self-limiting inflammation to irreversible pulmonary fibrosis indistinguishable from idiopathic pulmonary fibrosis (IPF).
  • Antigen avoidance is the cornerstone of management[3] — the ED physician's most important role is to consider the diagnosis, obtain a thorough exposure history, and initiate appropriate workup.
  • Combination of type III (immune complex) and type IV (delayed-type/cell-mediated) hypersensitivity reactions[3]
  • Inflammation is bronchiolocentric — centered on the small airways due to the inhalational route of injury[3]
  • Pathologic hallmark: poorly formed, non-caseating granulomas with lymphocytic infiltration around bronchioles (distinct from sarcoidosis, which has well-formed granulomas along the bronchovascular bundle)[3]
  • Cigarette smoking is paradoxically protective — nicotine inhibits macrophage activation and lymphocyte proliferation; however, smokers who do develop HP tend to have more fibrotic disease[3]
  • Genetic susceptibility through MHC class II (HLA-DR and HLA-DQ) polymorphisms[3]
  • Incidence: ~1–2 per 100,000 person-years; accounts for 1.5–12% of all interstitial lung diseases[4]
  • Current classification (ATS/JRS/ALAT 2020): Two phenotypes replace the older acute/subacute/chronic terminology[1]
    • Non-fibrotic HP: Inflammatory, often reversible with antigen avoidance ± corticosteroids
    • Fibrotic HP: Established fibrosis present on imaging or biopsy; worse prognosis; may progress to end-stage lung disease
  • Common exposures and eponyms:
    • Farmer's lung — thermophilic Actinomycetes (Saccharopolyspora rectivirgula) in moldy hay, grain, straw; the prototype of HP[3]
    • Bird fancier's lung (pigeon breeder's disease) — avian proteins in droppings, feathers, serum; most common form of HP worldwide (66–68% of all cases); 5-year mortality ~30% (worse prognosis than farmer's lung due to persistent domestic antigen exposure)[5]
    • Hot tub lung — Mycobacterium avium complex (MAC) in aerosolized warm water; may represent true infection vs. HP (debated)[5]
    • Humidifier lung — Thermoactinomyces, Cladosporium in contaminated HVAC systems, humidifiers
    • Chemical worker's lung — isocyanates (toluene diisocyanate, MDI), zinc, nickel; low-molecular-weight haptens that form antigenic complexes with host proteins[4]
    • Others: Mushroom worker's lung, maple bark disease, malt worker's lung (Aspergillus clavatus), saxophone lung (Candida/Ulocladium in mouthpieces), metalworking fluid HP, cheese worker's lung
    • Feather bedding HP — indirect bird antigen exposure from down pillows and duvets; easily missed on history[3]
  • Farming, bird contact, and water contamination account for ~75% of cases[4]

Clinical Features

Acute/non-fibrotic HP (high-dose, intermittent exposure):

  • Symptoms begin 4–8 hours after antigen exposure (key historical clue)[3]
  • Fever, chills, malaise, myalgias, dry cough, dyspnea — often misdiagnosed as flu-like illness or pneumonia
  • Symptoms typically resolve within 1–2 days of avoiding exposure[3]
  • Recurrent stereotyped episodes temporally linked to a specific environment are highly suggestive
  • Exam: fever, tachypnea, bibasal fine inspiratory crackles; wheeze is uncommon[6]
  • Severe acute HP can cause life-threatening respiratory failure with cyanosis and respiratory distress at rest[6]

Chronic/fibrotic HP (low-dose, prolonged exposure):

  • Insidious onset of progressive dyspnea, chronic dry cough, fatigue, weight loss[3]
  • Often no history of acute episodes — the intermittent febrile response may be absent
  • No clear temporal link to exposure (antigen exposure may be continuous and low-level)
  • Exam: tachypnea, inspiratory crackles (particularly bibasal), clubbing in up to 50% of chronic cases[7]
  • Late findings: cyanosis, signs of pulmonary hypertension and right heart failure
  • May be clinically and radiologically indistinguishable from IPF[1]

Key history questions for the ED:

  • Occupation (farming, bird handling, factory work, metalworking, brewing, woodworking)
  • Hobbies (bird keeping, pigeon racing, hot tub use, gardening/composting)
  • Home environment (feather bedding/pillows, visible mold, water damage, humidifiers, HVAC maintenance, pet birds, indoor hot tub)
  • Timing of symptoms relative to specific environments — do symptoms improve on weekends, vacations, or hospitalizations?
  • New exposures (recently acquired birds, new home, new workplace, CPAP/BiPAP equipment)

Differential Diagnosis

Acute HP differential:

  • Pneumonia (community-acquired — the most common initial misdiagnosis)
  • Influenza and other viral respiratory infections
  • Organic dust toxic syndrome (ODTS) — the critical ED differential; occurs after heavy organic dust exposure with identical flu-like symptoms; differs from HP because: (1) CXR is normal (no infiltrates), (2) severe hypoxemia does not occur, (3) no prior sensitization required (can occur on first exposure), (4) no long-term sequelae; ODTS is 30–50 times more common than farmer's lung[8]
  • Metal fume fever (zinc, copper exposure — similar flu-like presentation hours after exposure)
  • Inhalation fever (self-limited; no CXR infiltrates; no sequelae)[5]
  • Silo filler's disease (nitrogen dioxide exposure — distinct toxicant, different mechanism)
  • Pulmonary embolism

Chronic HP differential:

  • Idiopathic pulmonary fibrosis (UIP pattern; basal predominant; no exposure history; no granulomas; no air trapping)
  • Sarcoidosis (well-formed granulomas; hilar lymphadenopathy prominent on CXR; non-caseating but along bronchovascular bundle, not bronchiolocentric)[3]
  • Non-specific interstitial pneumonia (NSIP)
  • Cryptogenic organizing pneumonia (COP/BOOP)
  • Bronchiolitis obliterans
  • Connective tissue disease–associated ILD
  • Drug-induced pneumonitis (methotrexate, amiodarone, nitrofurantoin, bleomycin)
  • Tuberculosis (caseating granulomas; positive AFB)
  • Lymphocytic interstitial pneumonia (LIP)
  • Allergic bronchopulmonary aspergillosis (ABPA)

Acute dyspnea

Emergent

Non-Emergent


Pulmonary Fibrosis

Cough

Acute (< 3 wks)

Chronic (> 8 wks)

Evaluation

Workup

Laboratory (ED):

  • CBC: leukocytosis with left shift and neutrophilia in acute HP; eosinophilia is NOT typical (its presence suggests ABPA, eosinophilic pneumonia, or parasitic disease)
  • CRP/ESR: elevated in acute HP
  • Basic metabolic panel, lactate
  • ABG/VBG: hypoxemia; may show widened A-a gradient; severe acute HP can cause significant respiratory failure
  • Procalcitonin: may help differentiate from bacterial pneumonia (often low in HP, elevated in bacterial infection)
  • Serum-specific IgG antibodies (precipitins): NOT an ED test, but understand their limitations — positive results reflect exposure/sensitization, not necessarily disease (~40% of pigeon breeders have positive IgG without clinical HP); false negatives are common because the offending antigen may not be in the test panel[9]

Imaging:

Chest X-ray:

  • Acute HP: diffuse bilateral reticulonodular or ground-glass infiltrates; may be normal in mild disease[5]
  • Chronic HP: reticulonodular pattern, fibrotic changes, volume loss (upper/mid-zone predominance may help distinguish from IPF)
  • ODTS: CXR is normal — this is the key imaging distinction from acute HP[8]

High-resolution CT (HRCT) — the key imaging study:

Non-fibrotic HP:

  • Profuse ground-glass centrilobular nodules — often described as "fluffy" or "rosette" pattern; essentially diagnostic in the appropriate clinical context[9]
  • Diffuse ground-glass opacities
  • Air trapping on expiratory images (mosaic attenuation)
  • Upper/mid-lung predominance (unlike IPF which is basal-predominant)

Fibrotic HP:

  • Reticular pattern, traction bronchiectasis, honeycombing (but honeycombing is usually minimal and not basal-predominant unlike IPF)
  • Three-density pattern (previously called "head cheese sign"): coexisting areas of ground-glass opacity, normal lung, and air trapping (low attenuation) — highly suggestive of fibrotic HP over IPF[1]
  • Air trapping on expiratory CT in ≥3 lobes bilaterally is inconsistent with IPF and favors HP[9]
  • Upper/mid-zone fibrosis (vs. basal in UIP/IPF)
  • Centrilobular nodules may still be visible (~50% of cases)[9]
  • Mild mediastinal lymphadenopathy may occur (usually <15 mm, 1–2 nodes)[9]

Pulmonary function tests (not performed in ED, but understand the pattern):

  • Classically restrictive pattern (reduced FVC, reduced TLC) with reduced DLCO[3]
  • May also show obstructive or mixed pattern (especially with air trapping component)
  • Reduced DLCO is common in both fibrotic and non-fibrotic HP

Bronchoalveolar lavage (BAL) (outpatient/inpatient — not ED):

  • Lymphocytosis (often >50%) with low CD4:CD8 ratio supports HP[3]
  • Helps distinguish from sarcoidosis (normal cell count, high CD4:CD8) and IPF (neutrophilia, not lymphocytosis)
  • Lymphocytosis may be absent in chronic/fibrotic HP[3]

Diagnosis

  • No single test is diagnostic — HP requires integration of clinical history, exposure assessment, imaging, and sometimes BAL and/or biopsy through multidisciplinary discussion (MDD)[1]
  • The 2020 ATS/JRS/ALAT guideline provides a diagnostic confidence framework combining: (1) identified exposure, (2) characteristic HRCT pattern, (3) BAL lymphocytosis, and (4) histopathology when needed[1]
  • In the ED, focus on:
    • (1) Recognizing the clinical pattern — recurrent flu-like illness temporally linked to specific environments, or progressive ILD with exposure history
    • (2) Obtaining a thorough exposure history (occupation, hobbies, home environment, pets, bedding, hot tubs, HVAC)
    • (3) Ordering HRCT (or at minimum CXR) and basic labs
    • (4) Communicating suspicion to the admitting team or arranging outpatient pulmonology referral
  • Surgical lung biopsy is reserved for cases where confident diagnosis cannot be reached after clinical evaluation, imaging, and BAL[1]
  • Transbronchial cryobiopsy is increasingly used as a less invasive alternative with reasonable yield[1]

Management

1. Antigen avoidance — the single most important intervention[3]

  • Identify and eliminate the causative exposure
  • Occupational: workplace modification, personal protective equipment (N95 mask), job change if necessary
  • Domestic: remove birds, replace feather bedding, remediate mold/water damage, clean or replace HVAC systems and humidifiers, maintain hot tubs properly
  • Nonfibrotic HP is often fully reversible if antigen exposure is eliminated early[3]

2. Corticosteroids — hasten recovery but do not change long-term prognosis if exposure continues[3]

  • Acute HP: Prednisone 0.5–1 mg/kg/day for 1–2 weeks, then taper[10]
  • Subacute/chronic HP: Prednisone 0.5–1 mg/kg/day for 4–8 weeks, then gradual taper to maintenance ~10 mg/day or off, guided by clinical response and PFTs[10]
  • Note: No randomized controlled trials demonstrate long-term benefit of corticosteroids in HP; they improve short-term lung function but without antigen avoidance, disease will recur[3]
  • Mild acute HP may resolve spontaneously with antigen avoidance alone — corticosteroids are not always required

3. ED management of acute presentation:

  • Supplemental O2 to maintain SpO2 >92%
  • Corticosteroids if moderate-to-severe respiratory impairment (methylprednisolone IV or prednisone PO)
  • Consider empiric antibiotics pending workup if pneumonia cannot be excluded (HP and infection are often indistinguishable early)
  • Do NOT dismiss recurrent "flu-like illness" in a farmer, bird keeper, or hot tub user — ask about exposure history and symptom timing

4. Outpatient management (coordinate with pulmonology):

  • Steroid-sparing immunosuppression for chronic HP with ongoing inflammation: mycophenolate mofetil or azathioprine[11]
  • Antifibrotic therapy for progressive fibrotic HP (progressive pulmonary fibrosis phenotype): nintedanib (INBUILD trial) slows FVC decline; pirfenidone is an alternative[4]
  • PCP prophylaxis should be considered for patients on dual immunosuppression or >20 mg prednisone chronically[12]
  • Pulmonary rehabilitation, supplemental O2 as needed
  • Lung transplantation for end-stage fibrotic HP refractory to all therapy

Disposition

  • Admit:
    • Respiratory failure or significant hypoxemia (new O2 requirement)
    • Severe acute HP with high fever, tachypnea, and respiratory distress
    • Diagnostic uncertainty — cannot exclude pneumonia, pulmonary embolism, or other life-threatening cause
    • Known HP with acute exacerbation not responding to initial treatment
    • Chronic HP with acute deterioration in functional status
  • Discharge with close follow-up:
    • Mild acute HP with adequate oxygenation, improving on corticosteroids, and identifiable antigen source that can be immediately avoided
    • Suspected HP with stable vital signs and adequate oxygenation — arrange:
      • HRCT if not performed in ED
      • Outpatient pulmonology referral within 1–2 weeks
      • Outpatient PFTs
    • Specific discharge counseling:
      • Identify and avoid the exposure — this is the most important instruction
      • Return for worsening dyspnea, fever, or inability to maintain oral intake
      • Do not return to the implicated environment (barn, bird room, workplace, hot tub) until seen by pulmonology
      • Begin prednisone taper if prescribed, with PCP follow-up for monitoring

See Also

External Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 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. ↑ Hypersensitivity Pneumonitis. American Lung Association.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 Hypersensitivity Pneumonitis. StatPearls. NCBI Bookshelf. Updated July 2023.
  4. ↑ 4.0 4.1 4.2 4.3 Hypersensitivity Pneumonitis. Merck Manual Professional Edition. Updated 2025.
  5. ↑ 5.0 5.1 5.2 5.3 Hypersensitivity Pneumonitis. Medscape/eMedicine. Updated 2024.
  6. ↑ 6.0 6.1 Extrinsic Allergic Alveolitis. Patient.info. Updated August 2024.
  7. ↑ Hypersensitivity pneumonitis. Wikipedia. Updated September 2025.
  8. ↑ 8.0 8.1 Von Essen SG, et al. Organic dust toxic syndrome: an acute febrile reaction to organic dust exposure distinct from hypersensitivity pneumonitis. Clin Toxicol. 1990;28(4):389-420.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Hypersensitivity Pneumonitis (HP). EMCrit/IBCC. Updated August 2025.
  10. ↑ 10.0 10.1 Hypersensitivity Pneumonitis Treatment. Medscape/eMedicine. Updated 2024.
  11. ↑ Costabel U, et al. Diagnosis, course and management of hypersensitivity pneumonitis. Eur Respir Rev. 2022;31(163):210169.
  12. ↑ Salisbury ML, et al. Diagnosis and treatment of fibrotic hypersensitivity pneumonia. Am J Respir Crit Care Med. 2017;196(6):690-699.
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