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Preventing a covid-19 pandemic

BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m810 (Published 28 February 2020) Cite this as: BMJ 2020;368:m810

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Re: Preventing a covid-19 pandemic

Dear Editor

I read with quite some excitement the original article and the related responses.

R. Sommerstein’s and M.Phadke’s letters indeed led to some questioning among emergency physicians and internists.

Angiotensin-converting enzymes (ACE) 1 and 2 are key factors in the renin-angiotensin system (RAS) and act as a counterbalance. (1, 2). Angiotensin (AT) 2, resulting from the enzymatic cleavage of AT1 from ACE1, via activating AT2-type 1 receptors, and besides its actions on the RAS system, plays a role as bronchoconstrictive, pro-inflammatory and proliferative actor (via different signaling pathways implicating NFkB, Toll 4, free radicals and others), resulting in inflammatory lung injuries. AT 1-7, resulting from the cleavage of AT2 by ACE2 has opposite actions, namely anti-inflammatory and anti-proliferative. (1, 2) ACE2 is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. It is increased / upregulated in patients treated chronically with AT2-type 1 receptor blockers (1, 3, 4). ACE2 is also increased by ibuprofen and ACE inhibitors (5). SARS-CoV-2 uses ACE2 for target cell entry by fixing on it via its viral spike glycoprotein (1, 2, 6). Hence stems the idea that ACE2 stimulating drugs would increase the risk of developing severe and fatal COVID-19. (1)

However, SARS-CoV-2 downregulates ACE2 (4) after binding and internalisation, hence diminishing the formation of AT 1-7 (and 1-9), thereby diminishing AT 1-7’s action as an anti-inflammatory and anti-proliferative actor, leading to inflammatory lung injury, and increasing AT2 (4), thus favoring its action on AT2-type 1 receptors with subsequent proliferation, apoptosis and inflammation of pulmonary cells, bronchoconstriction and increased pulmonary vascular permeability. By blocking these receptors via losartan or an analogous compound, we diminish proliferation, inflammation and apoptosis in pneumocytes together with upregulating ACE2 due to excess in AT2 (shift), and favour again the formation of AT 1-7. (7)

Angiotensin receptor 1 inhibitors could be used as a novel therapy in SARS-CoV-2 Covid 19 pneumonia. (7) But instead of preventing viral entry into target cell, as suggested by Phadke and al., it would be through its anti-inflammatory actions on lung tissue.

1. Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci. 2004 Jun;25(6):291-4.
2. Rella M, Rushworth CA, Guy JL, Turner AJ, Langer T, Jackson RM. Structure-based pharmacophore design and virtual screening for novel angiotensin converting enzyme 2 inhibitors. J Chem Inf Model. 2006 Mar-Apr;46(2):708-16.
3. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virology 2020; published online Jan 29. DOI:10.1128/JVI.00127-20.
4. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020 Mar 4. doi: 10.1002/ddr.21656. [Epub ahead of print]
5. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11. pii: S2213-2600(20)30116-8. doi: 10.1016/S2213-2600(20)30116-8. [Epub ahead of print]
6. Wan Y#, Shang J#, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020 Mar 17;94(7). pii: e00127-20. doi: 10.1128/JVI.00127-20. Print 2020 Mar 17.
7. Sun ML, Yang JM, Sun YP, Su GH. [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):219-222. doi: 10.3760/cma.j.issn.1001-0939.2020.03.016.

Competing interests: No competing interests

19 March 2020
David Michely
Resident in internal and emergency medicine
Hôpital Neuchâtelois, Switzerland
rue de la Maladière, 2000 Neuchâtel, Switzerland