Fibroblast activity biomarkers are associated with mortality in severe COVID-19: a post-hoc analysis of a phase 2 clinical trial

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease characterised by systemic inflammation and lung tissue damage. In injured lungs, fibroblast activity increases in response to tissue insult and has been shown to be prognostic in fibrotic disease. This study investigated whether fibroblast activity is associated with mortality in severe COVID-19. METHOD: Severe COVID-19 patients were enrolled in the randomised, sequential, multicentre, placebo-controlled, double-blind study Otilimab in severe COVID-19-related disease (OSCAR; NCT04376684). In this post-hoc analysis, serum samples from 242 placebo-treated patients were analysed on days 1, 7, and 14, alongside serum from 20 healthy controls. Two serological biomarkers reflecting fibroblast activity, PRO-C3 and PRO-C6, were quantified using ELISAs. RESULTS: Patients who died or experienced respiratory failure had higher PRO-C3 and PRO-C6 serum levels on day 1 compared with healthy controls (p < 0.0001 and p = 0.053, respectively) and recovering patients (both p < 0.0001). Levels gradually increased over 14 days, with the sharpest increase seen at the last measured timepoint before death. High PRO-C3 and PRO-C6 levels on day 1 were associated with increased risk of mortality (hazard ratio [HR]: 2.93, 95% confidence interval [CI]: 1.6-5.4, p = 0.0006 and HR: 3.88, 95% CI: 1.96-7.70, p = 0.0001, respectively). CONCLUSION: Elevated PRO-C3 and PRO-C6 levels, and their increase shortly before death, were strongly associated with mortality in severe COVID-19. These findings highlight fibroblast activity as a key driver of poor outcomes and suggest that PRO-C3 and PRO-C6 could serve as early prognostic biomarkers to identify high-risk patients and guide future disease management strategies.