Plasma ACE2 activity is increased in patients recovered from SARS-CoV-2 infection: Implications for the prolonged consequences of COVID-19

ABSTRACT

Objective: COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), utilises the catalytic site of membrane-bound angiotensin converting enzyme 2 (ACE2) for cell entry. It is thought that endocytosis of ACE2 results in a decrease in membrane bound ACE2 expression, and disruption of the local tissue renin angiotensin system protection. In this study, we hypothesised that SARS-CoV-2 infection would be associated with shedding of ACE2 leading to increased plasma ACE2 activity. Design and method: Australians aged >18 years (n=66) who had recovered from SARS-CoV-2 infection (positive result by PCR testing) and uninfected controls (n=70) were recruited. Serial samples were available in 23 recovered SARS-CoV-2 patients. Plasma ACE2 activity was measured using a fluorescent substrate-based assay and levels were compared using the Mann-Whitney or Kruskal-Wallis test. Serial ACE2 activity were analysed using the Friedman test for repeated measures. Post-hoc analysis was performed with a Bonferroni correction. Two-tailed P-values <0.05 were considered significant. Results: Controls and SARS-CoV-2 recovered patients were matched for age (mean±SD, 54±11 vs. 53±14 years, p=0.47) and gender (53% vs. 59% male, p=0.49). There were no significant differences (p>0.05) in the proportion of hypertension, obesity, diabetes, cardiovascular disease, or use of anti hypertensive, lipid lowering, and anti-platelet medications between the controls and SARSCoV-2 patients. Plasma ACE2 activity at median 35 days post-infection [interquartile range 30-38 days] was 97-fold higher in SARS-CoV-2 patients compared to controls (5.8 [2-11.3] vs. 0.06 [0.02-2.2] pmol/min/ml, p<0.0001). Plasma ACE2 activity was significantly different across disease severity (p=0.033), with severe COVID-19 associated with higher ACE2 activity compared to mild disease (11.2 [8.3-23.2] vs. 5.4 [1.8-9.0] pmol/min/ml, p=0.027). Men recovered from SARS-CoV-2 had higher ACE2 levels compared to women (9.2 [5.8-15.3] vs. 2.1 [0.2-5.1] pmol/min/ml, p<0.0001). In 23 patients who had serial blood samples at 63 [56-65] and 114 [111-125] days post infection, median ACE2 activity remained persistently elevated with no differences between time-points (p>0.05). Conclusions: Plasma ACE2 activity is elevated after SARS-CoV-2 infection and remains elevated post-infection. Our findings indicate the need for ongoing investigation to determine if ACE2 levels identify people at risk of prolonged illness following COVID-19.