Collagen- and elastin-derived biomarkers and acute severe exacerbations in COPD: a sub study of the CORTICO-COP trial

Extracellular matrix (ECM) turnover and neutrophil protease activity contribute to chronic obstructive pulmonary disease (COPD) pathobiology, but the prognostic value of circulating neoepitopes for acute exacerbations (AECOPD) is uncertain. In a prospective cohort from the CORTICO-COP trial, the biomarkers C5M and C6M (type V/VI collagen degradation), ELP-3 (proteinase 3-generated elastin fragment), and CPa9-HNE (neutrophil elastase-generated calprotectin fragment) were measured in plasma at hospital admission for AECOPD (exacerbation phase; n = 299) and at day-30 follow-up (stable phase; n = 200). The primary endpoint was time to a composite of readmission with AECOPD or all-cause mortality within 12 months; the secondary endpoint was all-cause mortality. Cox models were adjusted for age, sex, pack-years, Charlson Comorbidity Index, and randomization arm. Single-time-point levels were not associated with the composite endpoint or with mortality at exacerbation or at stable phase. In a post-hoc analysis of paired data, a larger decline in CPa9-HNE from admission to day-30 (lowest quartile of change) was associated with a shorter time to the composite endpoint (HR 1.88, 95% CI 1.18-3.01) but not with mortality. This exploratory signal suggests within-patient decline in plasma CPa9-HNE may mark early re-exacerbation risk, but this requires validation in independent cohorts.