Circulating ACE2 Activity Predicts Mortality and Severity in COVID-19 Patients

Coronavirus disease 2019 (COVID-19) has been associated with significant morbidity and mortality worldwide in the last two years. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Angiotensin-converting enzyme 2 (ACE2) represents the main receptor for SARS-CoV-2 to enter endothelial cells. ACE2 mediates the infection of endothelial cells, which induces endothelial activation and damage resulting in substantial release of von Willebrand factor and enhanced levels of soluble E-selectin.


Medical Laboratorians at the University of Debrecen (Debrecen, Hungary) recruited for a retrospective clinical study, 176 consecutive COVID-19 patients older than 18 years of age from two medical centers. These subjects suffered from different degrees of acute respiratory distress at admission and were confirmed to be positive for COVID-19 disease by reverse transcription polymerase chain reaction (RT-qPCR) test of a nasopharyngeal swab.

Two-thirds of these patients had a positive hemoculture (e.g. Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, or Streptococcus pneumoniae), while the rest of individuals were culture-negative. All subjects had peripheral blood samples drawn at admission, and follow-up samples were also available before discharge or death in case of 106 subjects. The analysis of serum ACE2 activity was performed by a specific quenched fluorescent substrate (Peptide2, Chantilly, VA, USA). The cleavage of the quenched Mca-APK(Dnp) to liberate the fluorescent K(Dnp) was recorded using 340-nm excitation and 405-nm emission filters in a CLARIOstar microplate reader (BMG Labtech, Ortenberg, Germany).

Routinely available laboratory serum tests (i.e. CRP, PCT, IL-6, cTnT and ferritin) were determined by electro-chemiluminescent immunoassays on a Cobas e 411 analyzer, while enzyme activities (i.e. AST, ALT, LDH) and creatinine with urea levels were analyzed by kinetic colorimetric assays on a Cobas 8000 analyzer (Roche Diagnostics, Mannheim, Germany).

The investigators reported that initial 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) and non-COVID-19 sepsis patients (40.9 [21.4-65.7] mU/L) regardless of comorbidities. Further, there was a tendency for higher ACE2 activity in relation to increasing age regardless of disease severity. Circulating ACE2 activity correlated with inflammatory biomarkers and was further elevated during 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. Overall, non-survivors demonstrated significantly higher ACE2 activities (54.6 [IQR 37.3-94.7] mU/L) at hospital admission compared with survivors (35.6 [25.3-58.5] mU/L).

Miklós Fagyas, MD, PhD, an assistant professor and lead author of the study, said, “Serum ACE2 activity at hospital admission correlates with COVID-19 severity and predicts mortality, independently of the pulmonary function (Horowitz index). It appears that serum ACE2 is a non-specific biomarker in systemic inflammation, since it is also elevated in severe sepsis.” The study was published on November 25, 2021 in the International Journal of Infectious Diseases.

Related Links:
University of Debrecen
Peptide2
BMG Labtech
Roche Diagnostics