Plasma ACE2 levels predict outcome of COVID-19 in hospitalized patients

Abstract

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) enabling entrance of the virus into cells and causing the infection termed coronavirus disease of 2019 (COVID-19). COVID-19 is a disease with a very broad spectrum of clinical manifestations, ranging from asymptomatic and subclinical infection to severe hyperinflammatory syndrome and death. Methods This study used data from a large longitudinal study of 306 COVID-19 positive patients and 78 COVID-19 negative patients (MGH Emergency Department COVID-19 Cohort with Olink Proteomics). Comprehensive clinical data were collected on this cohort, including 28-day outcomes classified according to the World Health Organization (WHO) COVID-19 outcomes scale. The samples were run on the Olink Explore 1536 platform which includes measurement of the ACE2 protein. Findings High baseline levels of ACE2 in plasma from COVID-19 patients were associated with worse WHOmax category at 28 days with OR=0.56, 95%-CI: 0.44-0.71 (P < 0.0001). This association was significant in regression models with correction for baseline characteristics, pre-existing medical conditions, and laboratory test results. High levels of ACE2 in plasma from COVID-19 patients were also significantly associated with worse WHO category at the time of blood sampling at both day 0, day 3, and day 7 (P = 0.0004, P < 0.0001, and P < 0.0001, respectively). The levels of ACE2 in plasma from COVID-19 patients with hypertension were significantly higher compared to patients without hypertension (P = 0.0045). The plasma ACE2 levels were also significantly higher in COVID-19 patients with pre-existing heart conditions and kidney disease compared with patients without these pre-existing conditions (P = 0.0363 and P = 0.0303, respectively). There was no difference in plasma ACE2 levels comparing patients with or without pre-existing lung disease, diabetes, or immunosuppressive conditions (P = 0.953, P = 0.291, and P = 0.237, respectively). The associations between high plasma levels of ACE2 and worse WHOmax category during 28 days were more pronounced in COVID-19 positive patients compared with COVID-19 negative patients but the difference was not significant in the two-way ANOVA analysis. Interpretation This study suggests that measuring ACE2 is potentially valuable in predicting COVID-19 outcomes. Further, ACE2 levels could be a link between severe COVID-19 disease and its risk factors, namely hypertension, pre-existing heart disease and pre-existing kidney disease. The design of the data analysis using the Olink platform does not allow assessment of quantitative differences. However, previous studies have described a positive correlation between plasma ACE2 and ACE1 activity. This is interesting because ACE1 (serum ACE) analysis is a standardized test in most hospital laboratories. Therefore, our study encourages quantitative investigations of both plasma ACE 1 and 2 in COVID-19.

Lock, Stock and Barrel: Role of Renin-Angiotensin-Aldosterone System in Coronavirus Disease 2019

“…Thus, several authors hypothesize that a down-modulation of ACE2 tissue activity-due to its shedding or internalization into the cells along with the virus-and the subsequent ACE/ACE2 imbalance could substantially contribute to the genesis of the hyperinflammatory state seen in COVID-19 [47,48]. However, it was demonstrated that sACE2 retains not only the capability of binding the virus, forming circulating sACE2-spike protein complexes, but also its enzymatic activity [45,52,53], and that in COVID-19 patients circulating ACE2 activity is actually increased, correlates positively with disease severity and remain elevated even after disease resolution [53,[118][119][120][121].…”

HMGB1, NLRP3, IL-6 and ACE2 Levels Are Elevated in COVID-19 with Headache: A Window to the Infection-Related Headache Mechanism

“…Soluble ACE2 on the other side could re ect the cleavage of membrane-bound ACE2 by the SARS-CoV-2 entry and lysis of ACE2expressing cells. High levels of plasma ACE2 was proposed to indicate poor outcome in critically ill patients (19,20). The moderately affected disease process was different in our patients, in whom elevated ACE2 levels were seen in association with good outcomes without any ARDS, serious complication or mortality.…”

“…Compared to COVID − 19 patients without headache, serum levels of HMGB1, NLRP3, IL-6, angiotensin II, and ACE2 were signi cantly higher in COVID- 19 COVID-19 patients with headache and pulmonary in ltration (n = 31) had signi cantly higher serum levels of HMGB1, IL-6, D-dimer (Table-2). NLRP3 was correlated with headache duration (w = 0.69) and hospital stay (w = 0.63) in COVID-19 patients with headache (Fig.…”

Which ones, when and why should renin-angiotensin system inhibitors work against COVID-19?

“…A confirmation that SARS-CoVs can induced an ACE2 hyperactivity comes from recent reports showing an increase of systemic ACE2 activity in COVID-19 patients and in accordance to disease severity ( Nagy et al, 2021 ; Patel et al, 2021 ; Reindl-Schwaighofer et al, 2021 ). Similarly, high circulating levels of sACE2 were significantly associated with worse or longer COVID-19 outcome in hospitalized patients ( Kragstrup et al, 2021 ; Lundström et al, 2021 ; Reindl-Schwaighofer et al, 2021 ). Notably, in healthy individuals circulating ACE2 activity is usually undetectable ( Lew et al, 2008 ), instead pre-existing high levels of circulating ACE2 protein/activity are typical of patients with comorbidities (e.g.…”

“…Notably, in healthy individuals circulating ACE2 activity is usually undetectable ( Lew et al, 2008 ), instead pre-existing high levels of circulating ACE2 protein/activity are typical of patients with comorbidities (e.g. male sex, age, cardiopathies, hypertension, diabetes) associated to severe COVID-19 (Anguiano et al, 2015; Epelman et al, 2009 ; Kornilov et al, 2020 ; Kragstrup et al, 2021 ; Narula et al, 2020 ; Ortiz-Pérez et al, 2013 ; Ramchand et al, 2018 ; Sama et al, 2020 ; Soro-Paavonen et al, 2012 ; Úri et al, 2014 , 2016 ; Wallentin et al, 2020 ; Walters et al, 2017 ), suggesting that an elevated baseline activity of ACE2 in circulation would predispose to severe COVID-19 because SARS-CoV infections would further increase ACE2 systemic activity. Altogether this evidence strongly supports the hypothesis that the main and initial cause of COVID-19 would be an excessive activity of circulating ACE2 zinc-metalloprotease, initially triggered by SARS-CoV infection ( Zamai, 2020a , 2021 ).…”