Background: Hypersensitivity pneumonitis (HP) is a heterogeneous interstitial lung disease (ILD) that may be difficult to confidently diagnose. Recently, the 2020 ATS/JRS/ALAT HP diagnostic guidelines were published, yet data validating their performance in real-life settings are scarce.

Aims and Objectives: To assess the diagnostic performance of the HP guidelines compared to multi-disciplinary discussion (MDD) diagnosis.

Methods: Consecutive ILD patients that underwent diagnostic bronchoscopy between 2017 and 2021 in three large medical centers were included. All patients had an MDD diagnosis. Four diagnostic factors (antigen exposure history, chest CT pattern, bronchoalveolar lavage (BAL) lymphocyte count, and histology results) were used to assign guideline-based HP diagnostic confidence level. A sensitivity analysis was performed, with MDD diagnosis as the reference standard.

Results: Overall, 213 ILD patients were included, 45 (21%) with an MDD diagnosis of HP (26 fibrotic, 19 non-fibrotic). The guidelines? moderate (?70%) confidence threshold had the optimal performance with 73% sensitivity, 89% specificity, and a J-index of 0.62. The area under the receiver operating characteristic curve (AUC) for a correct guideline-based diagnosis was 0.86. The guidelines had better performance for non-fibrotic than fibrotic HP (AUC 0.92 vs. 0.82). All diagnostic factors, except BAL lymphocytes, were independent predictors for MDD diagnosis of HP in multivariate regression analysis.

Conclusions: The 2020 ATS/JRS/ALAT HP guidelines exhibited good diagnostic performance compared to MDD diagnosis in real-life settings, with the moderate confidence threshold being the optimal.