ACEi and ARB with COVID-19.

To The Editor

We thank the author for their comments on our article “ACE inhibitors and COVID‐19: We don't know yet” regarding the controversies for the use of angiotensin‐converting enzymes (ACE) inhibitors (ACEi) in novel coronavirus disease‐19 (COVID‐19) and whether it is beneficial or harmful. We explore the authors proposal for the use of angiotensin receptor antagonist (ARBs) vs the favorable ACEi due to the drugs ability to reduce all‐cause mortality, whereas ARBs do not. ARBs tend to be preferred for patients who have adverse reactions to ACE inhibitors.

Alongside ACEi, ARBs have been shown in studies that they may increase messenger RNA expression or protein levels of ACE2 in tissues. Similarly, to ACEi, these findings have been inconsistent with others showing no effect. In a longitudinal cohort study involving Japanese patients with hypertension, urinary ACE2 levels were higher among patients who received long‐term treatment with the ARB olmesartan than among untreated control patients, but that association was not observed with the ACE inhibitor enalapril or with other ARBs. Though clinical data is still lacking in whether increased ACE2 expression would in turn facilitate greater engagement and entry of severe acute respiratory syndrome coronavirus‐2 spike protein. The bradykinin‐chymase pathway, could potentially worsen the prognosis of COVID‐19. However, the impact and severity of this pathway varies. The prevalence of bradykinin‐related dry cough accounts for 1% in ACEi users, whereas bradykinin triggered angioedema has a prevalence of 0.7%. A differentiation between ARBS vs ACEi in COVID‐19 clinical studies would give us an idea of the relevance of the bradykinin‐chymase pathway in COVID‐19. A review article suggested the replacement of the renin‐angiotensin‐aldosterone system (RAAS) associated antihypertensives with drugs which are neutral concerning angiotensin II availability such as calcium channel blockers. Other antihypertensive classes such as ACE1 inhibitors and beta‐adrenergic blockers were also found to reduce plasma concentrations of angiotensin II. Although these drugs are not as favorable as the ACEi/ARB in the treatment of hypertension, they are neutral in terms of the controversies regarding the RAAS system and COVID‐19.

The possibility that the use of ARB/ACEi can cause benefit during the COVID‐19 pandemic is still likely. Evidence has a shown that there is reduction of proinflammatory marker alongside the use of ACEi, which, therefore, could lessen inflammation in COVID‐19 pneumonia, potentially reducing mortality. Another potential pathway is the conversion of angiotensin 1 to angiotensin 1‐9 and angiotensin 1‐7, which are known to have vasodilator and anti‐inflammatory properties. However, is still unclear whether the use of ACEi would directly or indirectly contribute to increase levels of these anti‐inflammatory molecules, therefore, more studies are required into this field to expand on our knowledge.