Introduction: Coronavirus disease 2019 (COVID-19) can cause viral pneumonia resulting in serious respiratory illness. It was one of the leading global causes of death in 2020/21 and is associated with systemic inflammation, pulmonary fibrosis, and changes to the lung?s collagens. Tools to identify high-risk patients are highly sought.

Aims: This study aims to investigate if collagen biomarkers reflecting fibrogenesis are related to outcome in patients with severe COVID-19.

Methods: Serum was collected from patients enrolled in the Otilimab in Severe COVID-19 Related Disease (OSCAR) trial (NCT04376684). Collagen biomarkers were assessed in serum from 102 placebo treated patients from days 1, 7, and 14 using ELISAs measuring type III and VI collagen formation (PRO-C3 and PRO-C6) as part of a post hoc analysis. The cohort was divided into patients with a fatal outcome (dead at day 60) and patients in recovery (free of respiratory failure at day 28 and alive at day 60).

Results: At day 1, serum PRO-C3 was elevated in patients with a fatal outcome vs those who recovered (p=0.025). PRO-C3 levels increased over time (46.4-117.3 ng/mL) contrary to those who recovered (27.0-37.3 ng/mL, p<0.0001). PRO-C6 increased over time in the fatal outcome group (15.9-31.6 ng/mL) as opposed to the recovery group (p<0.0001) who had increased levels at day 14 compared to day 1 (18.3 vs 14.6 ng/mL, p=0.01).

Conclusion: Elevated serum levels of PRO-C3 at day 1 and increasing levels of PRO-C3 and PRO-C6 over time were related to mortality in patients with severe COVID-19. These markers may reflect a subgroup of patients who could benefit from anti-fibrotic treatment.