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

Angiotensin-converting enzyme 2 (ACE2) and AXL are the main cell entry receptors for severe acute respiratory syndrome-coronavirus-2. Both receptors can be cleaved by the action of specific metalloproteases. Our study aims to evaluate the association between circulating ACE2 and AXL and its ligand, growth arrest-specific gene 6 (GAS6), with coronavirus disease 2019 (COVID-19) severity at first attendance to the emergency room.

We collected serum samples from two large cohorts of patients (study, n = 1652 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 the intensive care unit. We measured circulating ACE2 activity by an enzymatic assay and serum levels of sAXL and GAS6 by enzyme-linked immunoassay and we built a multivariate Cox model to predict COVID-19 severity.

Circulating 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 area under the curve of 0.81), which was validated in the external cohort (best sensitivity-specificity relation of 90.9-51.7% and area under the curve of 0.76).

Increased levels of ACE2 and GAS6 at admission are independently associated with COVID-19 severity, supporting its value as early biomarkers to predict worse disease outcome.