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.