Circulating Biomarkers of Endothelial Dysfunction Associated With Ventilatory Ratio and Mortality in ARDS Resulting From SARS-CoV-2 Infection Treated With Antiinflammatory Therapies

Abstract

BackgroundThe association of plasma biomarkers and clinical outcomes in acute respiratory distress syndrome (ARDS) due to SARS-CoV-2 predate the evidence-based use of immunomodulators. Research QuestionWhich plasma biomarkers associate with clinical outcomes in ARDS patients with SARS-CoV-2 treated routinely with immunomodulators? Study Design and MethodsWe collected plasma from ARDS patients with SARS-CoV-2 within 24 hours of admission to the intensive care unit (ICU) between December 2020-March 2021 (n=69). We associated 16 total biomarkers of inflammation (e.g., IL-6), coagulation (e.g., D-dimer), epithelial injury (e.g., surfactant protein-D), and endothelial injury (e.g., angiopoietin-2) with the primary outcome of in-hospital mortality and secondary outcome of ventilatory ratio (at baseline and day 3). ResultsThirty patients (43.5%) died within 60 days. All patients received corticosteroids and 6% also received tocilizumab. Compared to survivors, non-survivors had a higher baseline modified SOFA score (8.5 [7-9] vs 7 [5-8]), p=0.004), lower PaO2/FiO2 (153 [118-182] vs 184 [142-247], p=0.04), and higher ventilatory ratio (2.0 [1.9-2.3] vs 1.5 [1.4-1.9], p<0.001). There was no difference in inflammatory, coagulation, or epithelial biomarkers between groups. Non-survivors had higher median NEDD9 (8.4 [7.0-11.2] vs 6.9 [5.5-8.0] ng/mL, p=0.0025), von Willebrand factor domain A2 (8.7 [7.9-9.7] vs 6.5 [5.7-8.7] ng/mL, p=0.007), angiopoietin-2 (9.0 [7.9-14.1] vs 7.0 [5.6-10.6] ng/mL, p=0.01), and syndecan-1 (15.9 [14.5-17.5] vs 12.6 [10.5-16.1] ng/mL, p=0.01). Only NEDD9 met the adjusted threshold for significance (p<0.003). Plasma NEDD9 associated with 60-day mortality (adjusted OR 9.7, 95% CI 1.6-60.4, p=0.015). Syndecan-1 correlated with both baseline (ρ=0.4, p=0.001) and day 3 ventilatory ratio (ρ=0.5, p<0.001). InterpretationBiomarkers of inflammation, coagulation, and epithelial injury were not associated with clinical outcomes in a small cohort of ARDS patients uniformly treated with immunomodulators. However, endothelial biomarkers, including plasma NEDD9, associated with 60-day mortality.