RAAS treatments in Covid-19
The role of ACE2 in COVID-19 and the protective role of ACE2 in different organs has recently been reviewed. Clinical trial and retrospective data pertaining to RAAS treatments during COVID-19 are beginning to surface. In one retrospective study looking at ARB use in COVID-19 patients, ongoing use of these medications compared to other hypertensive treatments, was associated with lower risk of all-cause mortality compared with ACEI/ARB non-users (adjusted HR 0.30; 95% CI, 0.12-0.70; P=0.01). (14) Another study also confirmed a lower risk of mortality (relative risk 0.65, 95% CI 0.45-0.94, P= 0.02). (15)
Statin drugs, which prevent ART-mediated activation of Nox and reduce oxidative stress, recently showed a lower crude 28-day mortality (IRR 0.78; 95% CI, 0.61-0.996; p=0.046) in COVID-19. (16) Equally, dexamethasone showed a reduced risk of 28-day mortality (age-adjusted ratio 0.83; 95% CI 0.743-0.92; P<0.00). (17)
Although ARBs are not being used as de-novo treatment during COVID-19, current recommendations and consensus is to continue established treatment. There is little discussion of either statin drugs or MR blockers in COVID-19. As with ARBs, discontinuing these RAAS-modifying medications should not be taken lightly in view of the acute RAAS stress experienced during this illness.
Confirming the “Covid Syndrome” hyperaldosterone hypothesis would require the measurement of renin/aldosterone levels and their correlation with serum cytokine levels and disease severity and outcomes. Cytokine levels, particularly IL-6, have been shown to predict outcome. Electrolyte and blood pressure levels are unlikely to directly correlate with aldosterone levels due to many confounding variables and influences. Elevated aldosterone levels with low/normal renin could result from ACE2-depletion/Ang II-mediated stimulation.
This hypothesis advocates for the use of a cocktail of medications that counter the acute loss of ACE2 during “Covid Syndrome” by blocking the downstream effects of acutely increased Ang II activity. These medications would include dexamethasone, ARBs and MRBs such as spironolactone and eplerenone. (18) Supportive treatment with a statin drug could also be included, but may not add much benefit in combination with the aforementioned drugs. (16) All of these medications are readily available worldwide and have established safety and efficacy records when used, including in combination, in patients with severe RAAS-mediated disease. (19,20) Patients who recover from severe illness often experience severe fibrosis of the lungs, heart and kidneys. Blocking RAAS until complete resolution of the cytokine storm is achieved may reduce these debilitating long-term effects.
Acknowledgements: No funding was sought or provided for preparation of the current work.
The author would like to thank Ngoc Nguyen for her assistance with preparation of the summary schematic (Figure 1).
Declaration of Interests: Dr. Henry currently has a patent application pending for the use of mineralocorticoid receptor (MR) blockers for the treatment of COVID 19.