Discussion
We investigated the differential effects of using ACEI and ARB among
COVID-19 patients. The results showed a strong association between ARB
treatment and reduced rate of severe illness and ARDS. These findings
potentially indicate a protective role for the use of ARB in COVID-19.
These observations were not replicated when the use of ACEI was the
independent variable.
In our study, more than one-third of patients were on treatment with
ACEI/ARB. Not surprisingly, ARB was used in the majority (78.4%), as
Chinese patients’ compliance decreases with ACEI is
used13 primarily due to the higher incidence of
ACEI-induced cough in Asian population7. While we
showed a potential benefit from the use of ACEI/ARB on the rate of
severe illness and ARDS, the advantage was solely limited to the use of
ARB among COVID-19 patients.
Recently, Zhang et al. reported that ACEI/ARB utilization could be
associated with reduced mortality of COVID-19 patients who had a history
of hypertension5. As the majority of patients in Zhang
et al. study predominantly received ARB, the observed survival benefit
could be due to ARB rather than ACEI5. Li et al. found
the use of ACEI/ARB not to be associated with illness severity or
mortality14, suggesting the uncertainties related to
the effects of the use of ACEI and ARB on the outcome of COVID-19
patients.
SARS-CoV-2 uses the ACE2 receptor for entry into target
cells15. ACE2 is predominantly expressed by epithelial
cells of the lung, intestine, kidney, heart, and blood
vessels16. Animal studies have shown that expression
of ACE2 is increased by ACEI/ARB17. Thus, they may
facilitate infection with COVID-19. Treating COVID-19 patients with ACEI
and ARB leads to increased ACE2 receptors in the lung. However, enhanced
ACE2 activity as a result of the treatment with RAAS inhibitors showed
an essential effect in response to acute injury in animal
models18. In preclinical models of other viral
infections, the restoration of ACE2 by the administration of recombinant
ACE2 appeared to reverse devastating lung-injury
processes19. In experimental animal models, the
effects of ACEI and ARB on the ACE2 levels have been reported variably6,20,21. Our study indicated a different effect of the
use of ACEI or ARBs to COVID-19 patients but we couldn’t know the ACE2
true levels in patients induced by ACEI of ARBs.
Acute respiratory distress syndrome (ARDS) is a leading cause of death
in COVID-19 patients 2. In the present study, we
showed that treatment with ARB, but not ACEI, was associated with
reduced risk of severe illness and ARDS. The frequency of that while was
not statistically different, however, there was an impressive trend
towards ARB benefits. A previous study showed that the use of ACEI and
ARBs was associated with considerable discrepancies in ACE2 expression
in animal experiments6. Wang et al. recently showed
that the use of ARB was associated with an increased ACE2 protein by
approximately 2-fold folds in the heart of aorta-constricted
mice22. Furthermore, Lely et al. found no effect of
ACEI treatment on ACE2 protein expression in renal biopsy samples of
patients23. Contrary to Li et al
study14, our results showed that the use of ACEI/ARB
was associated with the severity or mortality of COVID-19 patients with
a history of hypertension. Further analysis indicated that the use of
ACEI vs. ARB was associated with a significantly different incidence of
ARDS and mortality (Figures 1A and 1D).
Our findings warrant confirmation in prospective studies with engagement
of larger sample sizes and
multiethnic populations. As ACE2 polymorphism is correlated with the
extent of ACE2 expression, patients from different races and ethnicities
may show the variable protective effect of these medications among
patients with COVID-19 and history of
hypertension24,25. This hypothesis, itself, warrants
further investigations. Also, future mechanistic studies in humans are
required to understand the unique interplay between SARS-CoV-2 infection
and the RAAS network leading to modifications in ACE2 levels.