The Interplay Between the Immune System, the Renin-Angiotensin-Aldosterone System (RAAS), and RAAS Inhibitors May Modulate the Outcome of COVID-19: A Systematic Review

Abstract

Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), numerous research has been undertaken to delineate the various effects of the virus which manifests in many ways all over the body. The association between the SARS-CoV-2 invasion mechanism and the renin-angiotensin-aldosterone system (RAAS) receptors, created many debates about the possible consequences of using RAAS-modulating drugs including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) during the pandemic. Many clinical studies were conducted to assess the outcomes of coronavirus disease 2019 (COVID-19) in patients who use ACEi/ARBs following the arguments claiming to discontinue these drugs as a precautionary measure. Although several studies mainly analyzed the outcomes of the disease, this review aimed to compare specific blood markers in both groups of COVID-19 patients to gain better insight into the interaction of ACEi/ARBs with different body functions during the infection. Several databases were searched using a combination of keywords followed by screening and data extraction. Only 28 studies met our inclusion criteria, the majority of which showed no significant difference between the inflammation markers of COVID-19 patients who used or did not use ACEi/ARBs. Interestingly, 6 studies reported lower inflammatory markers in COVID-19 patients who used ACEi/ARBs, and 6 studies reported better outcomes among the same group. We therefore concluded that the use of ACEi/ARBs may not lead to worse prognosis of COVID-19 and may even play a protective role against the hyperinflammatory response associated with COVID-19.

Keywords: Angiotensin-converting enzyme inhibitors; COVID-19; angiotensin receptor blockers; coronavirus; renin angiotensin aldosterone system.

Figure 1

PRISMA flow diagram illustrating the study selection protocol.

Figure 2

Summary of the blood marker and outcome results in the 28 included studies. Each pie chart illustrates the percentage and number of studies that reported no significant difference, significantly higher, or significantly lower blood marker/outcome in the ACEi/ARBs group compared with the control group. The significantly different proportions in patients with underlying comorbidities between the 2 groups in the studies that reported significantly different levels of markers/outcomes are reported next to each sector. The use of RAAS inhibitors did not increase the levels of inflammatory, cardiac, or liver markers in any of the studies. Lower inflammation markers in the ACEi/ARBs group were reported by 6 studies,, , , , , 1 of which reported higher proportions of the ACEi/ARBs group with comorbid CHD. Higher levels of coagulation, kidney,, ^, and cell damage markers were reported in the ACEi/ARBs group in 5 studies. However, in all these studies, the ACEi/ARBs group had higher proportions of patients with comorbidities. Lower levels of coagulation,, cardiac,, kidney, and cell damage, markers were reported in the ACEi/ARBs group in 6 studies. Higher proportions of the ACEi/ARBs group had comorbid CHD and diabetes in 2 of the 6 studies. Only 2 studies reported that the control group had higher proportions of patients with chronic kidney disease (CKD) and older age. The ACEi/ARBs group had significantly higher mortality rate in 2 studies,, which could be attributed to the higher proportions of patients with hypertension (HTN) and coronary artery disease (CAD). Interestingly, 6 studies, , , , , reported lower mortality in the ACEi/ARBs group, who had significantly higher proportions of patients with underlying HTN/CAD⁴¹ and coronary heart disease (CHD) in 2 studies.