Global prevalence of identified causative antigens and geographic variation in antigen distribution among patients with hypersensitivity pneumonitis: protocol for a systematic review and meta-analysis

Abstract Background Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease triggered by inhalation of a causative antigen. Antigen identification is central to management because antigen removal is the cornerstone of treatment and is independently associated with improved transplant-free survival. Nevertheless, the antigen remains unidentified in an estimated 30 to 60% of cases, with substantial variation reported across geographic regions, clinical settings, and diagnostic eras. No systematic review has pooled the proportion of HP patients with identified versus unidentified antigens globally, nor quantified the distribution of antigen categories across regions. The proposed review will address that gap. Methods We will search MEDLINE (via PubMed), Embase, Scopus, and Web of Science from inception to April 2026, with no language restriction, supplemented by grey-literature sources and by backward and forward citation tracking. Eligible studies will be observational in design—cohort studies, cross-sectional studies, registries, or case series with at least ten participants—reporting antigen identification status or antigen category distribution in adult patients (aged 18 years or older) with a confirmed or probable diagnosis of HP. Two reviewers will independently screen records in Rayyan and extract data in duplicate. Risk of bias will be assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Prevalence Studies. Proportion meta-analysis will use a random-effects DerSimonian–Laird model after Freeman–Tukey double arcsine transformation. Pre-specified subgroup analyses will examine geographic region (WHO classification), HP subtype (fibrotic versus non-fibrotic), diagnostic era (pre- versus post-2020 ATS/JRS/ALAT guideline), source population (clinically defined versus exposure-defined or occupational cohorts), and study setting. Heterogeneity will be summarised using the between-study variance (τ 2 ), a 95% prediction interval, and the observed range of study proportions; the I 2 statistic will be reported but interpreted with caution, given its known limitations in proportion meta-analyses. Publication bias will be assessed by funnel plot and Egger’s test where at least ten studies contribute. The overall certainty of evidence will be rated using the GRADE approach. Reporting will follow PRISMA 2020; this protocol adheres to PRISMA-P 2015. Discussion The review will provide what is, to our knowledge, the first set of pooled quantitative estimates of antigen identification rates and antigen category distribution in HP globally, stratified by geographic region, HP subtype, and diagnostic era. The findings are intended to inform regionally tailored exposure-assessment questionnaires, to guide the prioritisation of serum specific-IgG testing panels, and to establish evidence-based benchmarks against which newly diagnosed HP cohorts can be compared. Systematic review registration This protocol was registered on PROSPERO prior to commencement of database searches (CRD420261371922).