Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension?

to the editor: Coronavirus disease (COVID-19) is an emerging pandemic. Clinical manifestations of COVID-19 range from asymptomatic to acute respiratory distress syndrome (ARDS) (6, 11, 12, 20, 23).

Preliminary data on COVID-19 suggest hypertension to be correlated with worse outcomes (23.2%) compared with that of other metabolic disorders. This observation has been postulated to be correlated with use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) rather than hypertension. This alleged correlation has been disseminated among medical communities and media and has encouraged physicians to withdraw use of these drugs from COVID-19 patients.

The potential harm from inappropriate discontinuation of ACEIs/ARBs has led to communication (1, 5) recommending against withdrawal. Two recent reports (17, 18) have stated there are insufficient data to support speculations on the consequences of ACEIs/ARBs use in COVID-19.

The hypothesized rationale for the possible (but controversial) correlation between ACEIs and ARBs and progression to ARDS in COVID-19 is based on reports that the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a strong interaction with the angiotensin-converting enzyme-2 receptor (ACE-2R) (7, 10, 13, 22). Hence, an increase in expression of ACE-2Rs attached to cell surfaces in lung endothelia could amplify the capacity of SARS-CoV-2 to enter pulmonary cells. The only study to evaluate ACEI use for long periods demonstrated an increase in levels of angiotensin 1–7 (an indirect marker of ACE-2 action in the lung), which better reflects typical chronic use of ACEIs/ARBs (14).

Although attached ACE-2 may allow SARS-CoV-2 to enter cells, its free circulating forms may inactivate SARS-CoV-2 by stopping coupling to membrane ACE-2Rs and consequent entry into pulmonary endothelial cells (1, 10, 21). Recombinant human soluble ACE-2 has been proposed to protect against ARDS and death in COVID-19 (2, 21). Soluble ACE-2 is commercially unavailable, unaffordable, produced at insufficient scales, and lacks definitive data (4).

The circulating plasma level of ACE-2 may be insufficient to protect membrane-attached ACE-2Rs from coupling with SARS-CoV-2 (2), but, under particular conditions (e.g., soluble ACE-2), the protective actions of ACE-2 may become relevant. In addition to soluble ACE-2, potassium-sparing diuretics [another class of antihypertensive drug that also acts in the renin–angiotensin–aldosterone system (RAAS)] and its main representative, spironolactone, have been reported to increase ACE-2 expression in plasma by 3- to-5-fold (2, 9, 19), in contrast with the possibly unaffected plasma ACE-2 activity when using ACEIs/ARBs (2, 4, 8, 21)

Spironolactone could, theoretically, reduce ACE-2 expression on lung-cell surfaces, because, unlike ACEIs/ARBs, it does not act in the pulmonary RAAS. Although renin levels are enhanced when using ACEIs, ARBs, or potassium-sparing diuretics, the difference between the sites of blockade of renin effects may lead to a contrary metabolic microenvironment in the RAAS in the lungs (3, 15, 16).

Hence, switching ACEIs/ARBs for spironolactone could address the above-mentioned concerns, because spironolactone can prevent the effects of ACEI/ARB withdrawal (2), which has not been considered previously (6–9). Furthermore, despite the outstanding quality of studies by Vaduganathan and colleagues (18) and South and coworkers (17), the differentiation between circulating and cell-surface levels of ACE-2 in those reports was blurred, which hampers accurate mechanistic analysis.

The benefits of spironolactone, its extensively validated safety/risk profile, and its ability to substitute for ACEIs/ARBs appropriately would allow this switch without major ethical concerns in selected patients.

With regard to the difference in ACE-2 activity in plasma and cell surfaces, use of ACEIs/ARBs could be a risk factor, but this is speculative and dependent on more robust data. Use of spironolactone may address issues of withdrawal of ACEIs/ARBs and simultaneously rebalance plasma and cell-membrane levels of ACE-2.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

F.A.C. drafted manuscript; edited and revised manuscript; approved final version of manuscript.