What are the hallmark diagnostic criteria for Hypersensitivity Pneumonitis (HP)?

Hallmark Diagnostic Criteria for Hypersensitivity Pneumonitis

The diagnosis of hypersensitivity pneumonitis requires integration of three primary domains: (1) identification of exposure to an inciting antigen, (2) characteristic high-resolution CT imaging patterns, and (3) BAL lymphocytosis ≥30% or compatible histopathological findings. 1, 2

The Three-Domain Diagnostic Framework

Domain 1: Exposure Identification

• A thorough environmental and occupational exposure history is essential and should focus on household, occupational, and recreational exposures to known HP antigens (birds, mold, hot tubs, farming exposures). 1, 2
• The exposure history should be comprehensive and tailored to geographic region, as up to 60% of patients may not have an identifiable antigen despite thorough investigation. 3
• Serum antigen-specific IgG testing may help identify putative exposures when history is unclear, but positive results only indicate exposure, not disease. 1, 2 The sensitivity ranges from 25-96% and specificity from 60-100%, with significant heterogeneity limiting reliability. 1

Domain 2: High-Resolution CT Imaging Patterns

For Nonfibrotic (Acute/Subacute) HP:

• Profuse centrilobular nodules of ground-glass attenuation 2, 4
• Inspiratory mosaic attenuation with air-trapping on expiratory images 2, 4, 5
• Ground-glass opacities 4, 5
• The combination of mosaic pattern with ground-glass opacification and centrilobular nodules is particularly suggestive of HP. 5

For Fibrotic (Chronic) HP:

• Coarse reticulation with minimal honeycombing 4
• Evidence of small airway disease with air-trapping 3
• Architectural distortion and fibrotic changes 4, 3

Domain 3: BAL Lymphocytosis or Histopathology

BAL Findings:

• BAL lymphocytosis ≥30% is the recommended threshold for supporting the diagnosis of HP. 1, 2, 3
• BAL should be performed before considering more invasive procedures and is particularly useful in nonfibrotic HP. 3

Histopathological Criteria for Nonfibrotic HP (all three features required):

1. Cellular interstitial pneumonia with bronchiolocentric (airway-centered) distribution, cellular NSIP-like pattern, and lymphocyte-predominant inflammation 1, 4
2. Cellular bronchiolitis that is lymphocyte-predominant (lymphocytes > plasma cells) 1
3. Poorly formed nonnecrotizing granulomas consisting of loose clusters of epithelioid cells and/or multinucleated giant cells, situated in peribronchiolar interstitium or terminal air spaces 1, 4

Histopathological Criteria for Fibrotic HP:

• Chronic fibrosing interstitial pneumonia with architectural distortion and fibroblast foci 1, 4
• Airway-centered fibrosis with or without peribronchiolar metaplasia 1, 4
• May show NSIP or UIP-like patterns, requiring careful examination for HP-specific features 1, 4

Diagnostic Confidence Levels

High-Confidence Diagnosis (80-90% confidence):

• All three domains are present: identified exposure + typical HRCT pattern + BAL lymphocytosis ≥30% or compatible histopathology. 1, 2

Moderate-to-Low Confidence:

• When the diagnostic triad is incomplete, additional testing such as transbronchial biopsy or surgical lung biopsy may be required. 2
• Multidisciplinary discussion is essential when diagnostic confidence is not high after initial testing. 1, 2

Critical Pitfalls to Avoid

• Do not rely solely on lack of clinical improvement with antigen avoidance to rule out HP, as measurable improvement may only occur in nonfibrotic HP. 1
• Fibrotic HP is frequently misdiagnosed as idiopathic pulmonary fibrosis due to overlapping features and occasional UIP-like histopathologic patterns. 1, 4
• Absence of an identifiable exposure does not rule out HP, as the inciting antigen remains unidentified in up to 60% of cases. 4, 3
• Isolated histopathological findings such as nonnecrotizing granulomas alone are not specific enough for HP diagnosis and can be seen in other ILDs. 1
• Serum precipitins have limited diagnostic utility with high false-positive and false-negative rates; 60% of patients with positive precipitins reported no exposure, while 32% with negative precipitins had identifiable exposure. 1

When to Pursue Lung Biopsy

• Consider transbronchial biopsy or surgical lung biopsy only when all other diagnostic testing has not yielded a diagnosis and after multidisciplinary discussion. 1, 3
• The harm from invasive procedures must be weighed against potentially useful information, particularly in suspected nonfibrotic or advanced fibrotic HP cases. 1
• Biopsy findings require multidisciplinary reconciliation with clinical and radiological information due to potential interobserver variation and sampling error. 1