Treatment of patients with hypertension who are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type 1 receptor blockers (ARBs) may improve clinical outcomes, according to study results published in Emerging Microbes and Infections.1
The case fatality rate in patients with SARS-CoV-2 was found to be greater in patients with cardiovascular disease (10.5%) and hypertension (6.0%) compared with that in the general population (2.3%).2 The renin-angiotensin system (RAS) regulates blood pressure via the ACE/Angiotensin (Ang) II/ Ang type 1 receptor (AT1R) and the ACE2/Ang 1 to 7/Mas receptor signaling pathways. It is believed that ACEIs and ARBs inhibit and modulate the former and latter pathways, respectively.
SARS-CoV-2 enters cells by binding to ACE2 which is expressed at the surface of cells that include type 2 alveolar epithelial cells in the lungs.3 The level of Ang II was found to be higher in patients with vs without coronavirus disease 2019 (COVID-19).4
Two opposite hypotheses have been proposed for the effects of RAS inhibition with ACEIs or ARBs on the lungs (harmful vs beneficial effects).5 In the “harmful effect” hypothesis, RAS inhibition upregulates ACE2 expression at the cell surface, thus promoting SARS-CoV-2 entry. In the “beneficial effect” hypothesis, RAS inhibition reduces the production of Ang II, which would otherwise, upon SARS-CoV-2 binding, activate AT1R, driving inflammation and fibrosis in the lung.
Researchers sought to examine the effect of RAS inhibition in patients infected with SARS-CoV-2.1 They retrospectively examined the clinical data of 417 patients who were treated at the Shenzhen Third People’s Hospital, Guangdong Province, China, for confirmed COVID-19 between January 11, 2020, and February 23, 2020.
COVID-19 severity and treatment course were determined according to the National Health Commission of the People’s Republic of China guidelines. In this cohort, 51 patients had hypertension (12.23%) classified as Grades 1, 2, or 3, according to the European Society of Hypertension 2018 guidelines. Of the 51 patients with hypertension, 42 patients were treated with antihypertensive drugs (ACEI/ARB, n=17; other antihypertensive drugs, n=25) for >1 year (90%) and were maintained in the study (median age, 64.5 years; 57.1% men). Comorbidities in this cohort included coronary heart disease and type 2 diabetes (29.41% and 32% taking ACEI/ARB and non-ACEI/ARB, respectively). Hypertension grades, signs/symptoms, and baseline characteristics examined were comparable in the ACEI/ARB and non-ACEI/ARB groups.
The median number of days from symptom onset to hospital admission and discharge were 2.0 and 16.5, respectively in the non-ACEI/ARB group, and 3.0 and 20.0, respectively in the ACEI/ARB group. The median heart rates were 90.5 bpm and 80.0 bpm in the non-ACEI/ARB and ACEI/ARB groups, respectively, and the median respiratory rate was 20.0 in both groups.
There was a greater percentage of patients treated with non-ACEI/ARB vs ACEI/ARB categorized as exhibiting a severe case of COVID-19 during hospitalization (48% vs 23.5%, respectively; 1 vs 0 death, respectively).
Levels of C-reactive protein and lactate dehydrogenase, as well as counts of white blood cells, neutrophils, and platelets were comparable between the 2 groups, and absolute numbers of CD3+ and CD8+ (but not CD4+) T-cells were higher in the ACEI/ARB vs non-ACEI/ARB group (P =.02 and P =.01, respectively). Levels of interleukin-6 (IL-6) had a lower, nonsignificant trend in the ACEI/ARB group, and the peak viral load was lower in the ACEI/ARB vs non-ACEI/ARB group during hospitalization (P =.03), but not at hospital admission.
“[W]e found that ACEI/ARB therapy attenuated the inflammatory response, potentially through the inhibition of IL-6 levels, which is consistent with the findings that ACEI and ARB therapy alleviated [lipopolysaccharide]-induced pneumonic injury,6” noted the study authors. “This study also suggests that ACEI/ARB therapy had a beneficial effect on the immune system by avoiding peripheral T cell depletion…[W]e hypothesize that RAS inhibitors do not directly inhibit viral replication; rather, they play an indirect antiviral role by regulating immune function and inhibiting inflammatory responses.”
The investigators concluded, “Taken together, this is the first clinical evidence demonstrating that RAS inhibitors improve the clinical outcomes of [patients with] COVID-19 with hypertension, suggesting that these patients could benefit from the persistent or preferential usage of ACEI/ARB for antihypertensive treatment.”
- Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757-760.
- Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a Report of 72 314 cases from the Chinese Center for disease control and Prevention. JAMA. 2020;323(13):1239-1242.
- Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor [published online March 5, 2020]. Cell. doi:10.1016/j.cell.2020.02.052 2020
- Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374.
- South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic [published online April 3, 2020]. Nat Rev Nephrol. 2020. doi:10.1038/s41581-020-0279-4
- Ye R, Liu Z. ACE2 exhibits protective effects against LPS-induced acute lung injury in mice by inhibiting the LPS-TLR4 pathway. Exp Mol Pathol. 2020;113:104350. doi:10.1016/j.yexmp.2019.104350