Plasma ACE2 levels predict outcome of COVID-19 in hospitalized
patients
Authors: Kragstrup Tue W. , Søgaard Singh Helene , Grundberg Ida , Nielsen Ane Langkilde-Lauesen , Rivellese Felice , Mehta Arnav , Goldberg Marcia B. , Filbin Michael , Qvist Per , Bibby Bo Martin 
Published: March 2021

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.

Key Points

Question
Can plasma levels of the receptor for severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2), angiotensin converting enzyme 2
(ACE2), predict outcome of coronavirus disease of 2019
(COVID-19).

Findings
In this study of 306 COVID-19 positive patients, high baseline levels of
ACE2 in plasma from COVID-19 patients were associated with worse outcome
measured by the World Health Organization (WHO) COVID-19 outcomes
scale.

Meaning
Measuring ACE2 is potentially valuable in predicting COVID-19 outcomes
and link COVID-19 disease and the risk factors hypertension, pre-existing
heart disease and pre-existing kidney disease.