Circulating ACE2 activity predicts mortality and disease severity in hospitalized COVID-19 patients

Miklós Fagyas,Zsolt Fejes,Renáta Sütő,Zsuzsanna Nagy,Borbála Székely,Marianna Pócsi,Gergely Ivády,Edina Bíró,Gabriella Bekő,Attila Nagy,György Kerekes,Zoltán Szentkereszty,Zoltán Papp,Attila Tóth,János Kappelmayer,Béla Nagy

doi:10.1016/j.ijid.2021.11.028

Miklós Fagyas, Zsolt Fejes + Show 14 more

Open Access

https://doi.org/10.1016/j.ijid.2021.11.028

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Abstract

ObjectivesAngiotensin-converting enzyme 2 (ACE2) represents the primary receptor for SARS-CoV-2 to enter endothelial cells. Here we investigated circulating ACE2 activity to predict the severity and mortality of COVID-19. MethodsSerum ACE2 activity was measured in COVID-19 (110 critically ill and 66 severely ill subjects at hospital admission and 106 follow-up samples) and in 32 non-COVID-19 severe sepsis patients. Associations between ACE2, inflammation-dependent biomarkers, pre-existing comorbidities, and clinical outcomes were studied. ResultsInitial ACE2 activity was significantly higher in critically ill COVID-19 patients (54.4 [36.7-90.8] mU/L) than in severe COVID-19 (34.5 [25.2-48.7] mU/L; P<0.0001) and non-COVID-19 sepsis patients (40.9 [21.4-65.7] mU/L; P=0.0260) regardless of comorbidities. Circulating ACE2 activity correlated with inflammatory biomarkers and was further elevated during the hospital stay in critically ill patients. Based on ROC-curve analysis and logistic regression test, baseline ACE2 independently indicated the severity of COVID-19 with an AUC value of 0.701 (95% CI [0.621-0.781], P<0.0001). Furthermore, non-survivors showed higher serum ACE2 activity vs. survivors at hospital admission (P<0.0001). Finally, high ACE2 activity (≥45.4 mU/L) predicted a higher risk (65 vs. 37%) for 30-day mortality (Log-Rank P<0.0001). ConclusionsSerum ACE2 activity correlates with COVID-19 severity and predicts mortality.

Highlights

Coronavirus disease 2019 (COVID-19) has been associated with significant morbidity and mortality worldwide in the last 1.5 years
Patients were divided into two severity subgroups: 110 individuals were considered as ‘critically ill’ patients; another 66 patients presenting with moderate symptoms were enrolled into the ‘severe’ cohort based on the Sequential Organ Failure Assessment (SOFA) scores determined by the clinicians and the requirement for respiratory support during hospitalization
We studied the correlation between circulating Angiotensin-converting enzyme 2 (ACE2) activity and the levels of routinely available laboratory tests suggesting a link between the elevated expression of ACE2 and systemic inflammation causing cardiac, liver, and kidney disorders in COVID-19

Summary

Introduction

Coronavirus disease 2019 (COVID-19) has been associated with significant morbidity and mortality worldwide in the last 1.5 years. This disease is caused by severe acute respiratory syndrome coro-. Navirus 2 (SARS-CoV-2) infection and represents a mild course in the majority of cases; about one-fifth of the patients develop severe clinical complications, such as acute respiratory distress syndrome (ARDS), systemic hyperinflammatory response and death (Huang et al 2020, Martincic et al 2020). There are several risk factors for fatal infection, e.g., increasing age, male sex, smoking, history of hypertension, heart, lung, and kidney disorders (Zhou et al 2020; Kaur et al 2021).

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