Diagnostic accuracy of serological tests and biomarkers for hypersensitivity pneumonitis: A systematic review

Hypersensitivity pneumonitis (HP) represents a significant diagnostic challenge in interstitial lung disease, where serological testing plays a crucial yet often misinterpreted role.

To systematically evaluate the diagnostic accuracy of antigen-specific antibody tests (ImmunoCAP, ELISA, precipitin assays) and serum biomarkers (KL-6, SAA) for HP, stratified by disease subtype, testing methodology, and disease stage.

Following PRISMA guidelines, we systematically searched PubMed, Embase, and Cochrane databases through October 2025. Two independent reviewers assessed antigen specific antibody testing (ImmunoCAP, ELISA, precipitin assays) and serum biomarkers (KL-6, SAA) using modified QUADAS-2 and GRADE frameworks.

Fifteen studies with 2194 participants revealed substantial heterogeneity in test performance. For bird related HP, ImmunoCAP bird specific IgG demonstrated optimal accuracy (sensitivity 68% to 100%, specificity 72% to 100%). ELISA outperformed traditional immunodiffusion (100% versus 80% sensitivity). Farmer's lung testing showed moderate performance (sensitivity 70% to 82%, specificity 75% to 94%), while Aspergillus fumigatus testing yielded lower accuracy (sensitivity 65% to 80%, specificity 60% to 70%). Diagnostic accuracy declined substantially from acute to fibrotic HP across all testing modalities. KL-6 demonstrated prognostic value but limited diagnostic specificity (sensitivity 68% to 82%, specificity 72% to 75%). GRADE assessment indicated low to moderate evidence quality.

Serological testing provides moderate diagnostic accuracy for HP with substantial variation by disease subtype, methodology, and stage. These tests should complement comprehensive multidisciplinary discussion. Positive results require clinical and radiological correlation while negative results cannot exclude HP, particularly in chronic fibrotic disease.