# Endothelial Biomarkers and Cytokine Profiles: Signatures of Mortality in Severe COVID-19

## TL;DR

The study identifies specific biomarkers and cytokine ratios that predict mortality in severe COVID-19 patients, highlighting the role of inflammation and endothelial dysfunction.

## Contribution

The study introduces novel biomarker combinations and ratios that improve mortality prediction in severe COVID-19.

## Key findings

- IL-1α and ADAMTS13 autoantibodies are independent predictors of mortality in severe COVID-19.
- The ADAMTS13 activity/autoantibody ratio and IL-6/IL-10 ratio are protective against mortality.
- A combined model of IL-1α, IL-8, IL-10, and ADAMTS13 autoantibodies yields high mortality prediction accuracy.

## Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in dysregulated inflammatory and coagulation pathways that drive immunothrombosis and contribute to adverse clinical outcomes. While individual cytokines and endothelial biomarkers have been associated with disease severity and mortality, the prognostic relevance of combined inflammatory and endothelial signatures remains incompletely characterised. To identify inflammatory cytokines and markers of endothelial activation associated with mortality in patients with severe COVID-19 requiring supplemental oxygen. This retrospective observational study included 73 consecutive adults admitted to a dedicated supplemental oxygen unit with severe COVID-19. Plasma concentrations of IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, von Willebrand factor (VWF) antigen and propeptide, ADAMTS13 antigen and activity, and ADAMTS13 autoantibodies were measured on admission using ELISA-based assays. Associations with mortality were assessed using non-parametric analyses, age-adjusted logistic regression, multivariable logistic regression, and receiver operating characteristic (ROC) curve analysis. Increasing age was independently associated with mortality. After adjustment for age, higher IL-1α concentrations were associated with increased odds of death, whereas a higher IL-6/IL-10 ratio was independently protective. In multivariable models, including non-ratio variables, ADAMTS13 autoantibody levels remained independently associated with mortality. In ratio-based multivariable analysis, both the ADAMTS13 activity/autoantibody ratio and the IL-6/IL-10 ratio were independently protective, while age was no longer significant. IL-10 and ADAMTS13 autoantibodies demonstrated moderate discriminative performance for mortality prediction (AUC ~0.70). A combined biomarker model incorporating IL-1α, IL-8, IL-10, and ADAMTS13 autoantibodies yielded very high predicted mortality probabilities. Our findings highlight IL-1α and ADAMTS13 autoantibodies as independent predictors of mortality in severe COVID-19, reflecting the interplay between inflammatory and endothelial pathways. Biomarker ratios capturing immune and endothelial balance—particularly the ADAMTS13 activity/autoantibody ratio—may enhance risk stratification and support integrated prognostic models.