Increased circulating ACE2 and GAS6 are independent predictors of COVID-19 severity

ObjectivesACE2 and AXL are the main cell entry receptors for SARS-COV-2.Both receptors can be cleaved by the action of specific metalloproteases.Our study aims to evaluate the association between circulating ACE2, AXL and its ligand GAS6 with COVID-19 severity at first attendance to the emergency room. MethodsWe collected serum samples from two large cohorts of patients (study n=1,652, and external validation, n=468) who were diagnosed of COVID-19 during 2020-2021.Data from all included patients were used to classify the patients' COVID-19 disease severity, defined as death or admission to intensive care unit.We measured ACE2 activity by an enzymatic assay and levels of sAXL and GAS6 by ELISA and we built a multivariate Cox model to predict COVID-19 severity. ResultsCirculating ACE2 activity and GAS6 levels were significantly increased in severe COVID-19.Moreover, both biomarkers were independently associated with COVID-19 severity in a multivariate Cox proportional hazards model.Our model showed high capacity to predict COVID-19 severity (best sensitivity-specificity relation of 82.1%-65.8%and AUC of 0.81) which was validated in the external cohort (best sensitivity-specificity relation of 90.9% -51.7% and AUC of 0.76). ConclusionIncreased levels ofACE2 and GAS6 at admission are independently associated with COVID-19 severity supporting its value as early biomarkers to predict worse disease outcome.