Prognostic biomarkers for the development of progressive pulmonary fibrosis in hypersensitivity pneumonitis: a systematic review

Background In fibrotic hypersensitivity pneumonitis (fHP) an ongoing immune response triggers pulmonary inflammation and concurrent fibrotic pathways, leading to irreversible disease progression. Patients with the progressive pulmonary fibrosis (PPF) phenotype have a poor prognosis. Reliable identification of biomarkers to predict PPF could aid clinicians in determining disease prognosis and optimising patient care. We aimed to identify prognostic biomarkers for the PPF phenotype in fHP using existing literature. Methods We performed a systematic review (PROSPERO, CRD42024537599) and searched Medline, Embase and Scopus from inception to 10 April 2024. We included studies that evaluated the ability of biomarkers measured in blood or bronchoalveolar lavage fluid (BALF) to predict disease progression in adult patients with fHP. Study quality was assessed using the Quality Assessment of Prognostic Accuracy Studies tool. Results Of the 3027 articles initially identified, 31 met the inclusion criteria, encompassing a total of 3766 fHP patients. 65 biomarkers were identified; however, most were evaluated in only one (n=49) or two (n=6) studies. The most frequently evaluated biomarkers were BALF cellular composition, serum Krebs von den Lungen-6 and serum surfactant protein D levels. Survival was the most commonly assessed outcome, followed by disease progression and acute exacerbation. None of the biomarkers reliably predicted the prognosis. Conclusions A large number of biomarkers have been evaluated for their prognostic ability in fHP, but none of them appear to be consistently associated with the PPF phenotype. Heterogeneity across studies in terms of methods, disease definitions, outcomes and measurement time points complicates the identification of a marker with strong potential, and this situation should be improved in the clinical field.