Collagen remodeling is elevated in fibrotic hypersensitivity pneumonitis and may distinguish it from idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP) are two common causes of pulmonary fibrosis. Unlike IPF, fHP is caused by a persistent immune response to an antigen. Misclassification of fHP and IPF can lead to significant delays in antifibrotic treatment, particularly in cases where the eliciting antigen cannot be identified and removed. Extracellular matrix (ECM) and, particularly, collagen remodeling is a key feature of fibrosis. We characterized ECM remodeling in HP phenotypes by quantifying serological biomarkers of type III and VI collagen turnover in comparison to healthy controls. We then evaluated the potential of these biomarkers as tools to differentiate fHP from IPF in two separate independent cohorts. Biomarkers of type III and VI collagen formation (nordicPRO-C3™ and nordicPRO-C6™) and degradation (nordicC3M™ and nordicC6M™) were quantified cross-sectionally in serum from PFBIO-HP (NCT05549635, PFBIO-non-fHP; n = 25, PFBIO-fHP; n = 24) and healthy controls ( n = 20). Biomarkers were then compared between the HP phenotypes and IPF patients from PFBIO (NCT02755441, n = 46). Findings were validated in an independent cohort, (AUH-ILD, NCT05311345, AUH-IPF; n = 43, AUH-fHP; n = 21). Serum C3M and C6M were elevated compared to healthy in PFBIO-non-fHP (C3M 95% CI: 0.34–0.56, p < 0.0001 and C6M: 0.46–0.81, p = 0.001) and PFBIO-fHP (C3M: 0.31–0.51, p < 0.0001, C6M: 0.47–0.82, p = 0.001). Biomarker levels did not differ between fHP and non-fHP. Serum PRO-C3, PRO-C6 and C6M were elevated in PFBIO-IPF compared to PFBIO-fHP (PRO-C3: 0.68–0.99, p = 0.038, PRO-C6: 0.56–0.83, p = 0.0002, C6M: 0.47–0.76, p < 0.0001), whereas only PRO-C3 was significantly elevated in AUH-IPF compared to AUH-fHP (1.004–1.353, p = 0.044). Serological biomarkers of type III and VI collagen remodeling were significantly elevated in HP compared to healthy, regardless of fibrosis status, suggestive of an increased ECM remodeling in the disease. Furthermore, these biomarkers were elevated in IPF compared to fHP in a cohort of both diagnoses. Our findings suggest that type III and VI collagen remodeling biomarkers are reflective of active ECM turnover in HP and may also be used alongside existing criteria to differentiate between fHP and IPF in the clinic.