Findings from our systematic review and meta-analysis suggest that prior use of ACEIs or ARBs is not associated with a higher risk of COVID-19. Our pooled effect estimates are precise with narrow confidence intervals which argues against the possibility of underpowered findings. Our results are in support of the recent recommendations of cardiac societies not to discontinue ACEI or ARB in patients who have indications for their use because of COVID-19 concerns11,12.
The hypothesis that the use of ACEIs or ARBs is associated with a higher risk of COVID-19 emerged based on two facts from multiple previous studies. First, the observations that ACEIs or ARBs upregulate the expression of ACE2. Second, the high prevalence of comorbidities such as hypertension, diabetes, and ischemic heart disease among COVID-19 patients where these drugs are commonly used. However, this hypothesis is an oversimplification of a very complex interaction of multiple signaling pathways involved in SARS-COV-2 infection and COVID-19 disease.
Several possible explanations can be offered for the possible lack of association between ACE2 expression and the risk of COVID-19. Increased ACE2 protein expression does not necessarily mean increased number of ACE2 molecules on the cell membrane since the ACE2 cell membrane density is determined not only by the gene expression and protein production but also by the rate of ACE2 shedding from the cell membrane. It is well established that ACE2 is cleaved at the cell membrane by the metalloprotease ADAM17 generating soluble ACE2 that is released into the circulation. ADAM17 expression and activity can alter ACE2 shedding and consequently may affect cell membrane ACE2 density24.
Another possible explanation would be that even if ACEIs or ARBs increase the risk of SARS-CoV-2 infection, it is conceivable that many of these cases are mild or asymptomatic and therefore not tested and go undiagnosed. This is due to the fact that ACEIs and ARBs seem to exert protective effect against severe COVID-19 through modulation of inflammatory and immune responses. ACEIs and ARBs have been shown to influence several signaling pathways involved in inflammation and the regulation of immune responses, which include nuclear factor Kappa-B, mitogen activated protein kinases and Roh/ROCK pathway. These effects result in reduction in inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, inhibition of dendritic cell maturation and Th1 and Th17 cell polarization responses , and suppression of Rho/ROCK pathway25-27. Additionally, in one study, losartan inhibited dendritic cell maturation and Th1 and Th17 cell polarization responses26. These inflammatory and immune modulating effects of ACEIs and ARBs may have clinical relevance in the context of COVID-19 disease.
Moreover, ACE2 is a well-known cardioprotective protein as it mediates vasodilatory, anti-fibrotic, immune modulating, anti-inflammatory, and anti-proliferative effects. These effects are realized through conversion of angiotensin-II to angiotensin-(1-7) peptide and angiotensin I to angiotensin-(1-9) peptide which leads to reduction in angiotensin II levels. In addition, angiotensin-(1-7) peptide activates Mas receptor through which it exerts its cardiovascular protective effects28. Interestingly, Angiotensin II is pro-inflammatory and has been shown to play a significant role in the pathogenesis of acute lung injury/adult respiratory distress syndrome (ARDS) in several animal models including SARS-CoV-1. Conversely administration of ARBs and ACE2 were protective in animal model studies 29. It was intriguing that it has been reported recently that COVID-19 patients exhibit high levels of angiotensin II and was associated with higher viral load and lung injury30. Hence, up-regulation of ACE2 expression by ACEIs and ARBs may have lung protective effects against SARS-CoV-2 triggered acute lung injury. In a recent systematic review and meta-analysis, we observed that use of ACEIs/ARBs is associated with a decreased risk of death or critical outcome among SARS-CoV-2 infected patients31.
We observed a high degree of heterogeneity for the pooled effect estimate of the ARB use and COVID-19 due to the study by Yan et al. The study by Yan et al. from China reported lower effect estimates as compared to the other identified studies and this could be related to residual confounding or an underlying biological explanation. The OR for ARB use in the study by Yan et al. was only adjusted for age, sex and BMI and therefore, could have been affected by residual confounding. On the other hand, it has been shown in a, Chinese population that rs12692386 G promotor polymorphism was associated with higher ADMA17 expression32.Moreover, several ACE2 polymorphisms have been reported in different populations including the Chinese. These polymorphisms have been shown to be associated with HTN, DM and CVD as well as with ACE2 activity, and serum ACE2 and angiotensin-(1-7) peptide levels33.It remains to be determined whether increased circulating ACE2 levels are due to increased shedding or due to both increased shedding and expression. Notwithstanding, these differences in regulatory processes of ACE2 may modify membrane ACE2 density and theoretically, could influence susceptibility to SARS-CoV-2 infection. Lastly, SARS-CoV-2 needs not only ACE2 but it is also dependent on the serine protease TMPRSS2 and it has been demonstrated that inhibition of TMRSS2 blocks SARS-CoV-2 cell entry 34. Thus, factors regulating TMRSS2 expression or its enzymatic activity would modulate SARS-CoV-2 infectivity. For example, TMPRSS2 expression is regulated by androgens and has been reported in a recent study that men treated with antiandrogenic therapy were less susceptible to CoV-2 infection35. Accordingly, population differences in testosterone levels, androgen receptor function and it’s downstream signaling pathway could affect TMPRSS2 levels and hence susceptibility to SARS-CoV-2 infection.
Our systematic review has several strengths. First, the hypothesis that treatment with ACEI or ARB increases ACE2 expression by several folds and therefore increases the risk of COVID-19 can only be feasibly tested using an observational study design similar to studies included in our meta-analysis. It is not conceivable to randomize patients for years of ACEI or ARB use vs. control groups to see if they are at a higher risk for COVID-19. Second, we included all published studies including pre-prints. Third, we pooled only adjusted effect estimates to decrease the chance of confounding effect. Fourth, the pooled effect estimates were very precise. Nevertheless, inferences from our meta-analysis could be weakened by limitations inherent to the meta-analysis and the individual studies. Given the observational design of included studies and retrospective data collection, the possibility that the observed association between ACEI/ARB use and COVID -19 was affected by bias or confounding should be considered. For example, comorbidities and severity of illness are known confounders that are associated with ACEI/ARB intake and mortality and the healthy user effect could theoretically explain a potential role for ACEI/ARB in infection outcome. However, the opposite could also be the case where the sicker patients have more exposure to ACEI/ARB because patients with hypertension and cardiovascular risk factors have higher risk for COVID. Although we have pooled effect estimates from regression models that adjusted for possible confounders including age, comorbidities and medications—although the models were not uniform— residual confounding cannot be fully excluded. Finally, the presence of publication bias is very unlikely during this pandemic, where to date (May 15,2020) 3477 articles about COVID-19 were published on pre-print servers (2790 medRxiv, 687 bioRxiv).
Despite the recommendations of major cardiac societies advising patients and physicians not to discontinue ACEI or ARB because of fear of COVID-19, recent data from at least one large cohort of 5700 patients with COVID-19 admitted to 12 hospitals in New York between March 1, 2020, and April 4, 2020, have shown otherwise. In this cohort, of the patients who were taking an ACEI or ARB prior to hospitalization, only (48.1%) continued taking an ACEI while in the hospital and (50.1%) continued taking an ARB while in the hospital36.