Intended for healthcare professionals

Rapid response to:


Preventing a covid-19 pandemic

BMJ 2020; 368 doi: (Published 28 February 2020) Cite this as: BMJ 2020;368:m810

Read our latest coverage of the Coronavirus outbreak

Rapid Response:

ACE-inhibitors may facilitate COVID-19 related respiratory distress syndrome beside increasing the risk of infection

Dear Editor

I have read with great interest the recent correspondence on CODIV-19 mode of transmission, which involves the angiotensin-converting enzyme 2 (ACE2) receptor similar to the infection mechanism of SARS-CoV (1). In addition, Hoffman et al. recently demonstrated that the importance of serine protease TMPRSS2 for spike protein priming (2). Concerns have been raised about the use of ACE inhibitors and angiotensin receptor blockers to increase the risk of infection due to the ability of these drugs, used to treat arterial hypertension and heart disease, in inducing the expression of ACE2 (3). In the absence of epidemiological evidence, these treatments should be not suspended especially in patients that need association therapies for severe hypertension or heart failure unless the specialist decides to adjust the therapeutic schedule according to the specific needs of the patient.

Nonetheless, there are also considerations to bare in mind beyond infection. Serine proteases, such as plasma and tissue kallikrein, release kinins which are vasoactive pro-inflammatory peptides implicated in respiratory distress syndrome, and ACE2 inhibitors may exacerbate the symptoms by preventing ACE2 activity in cleaving and degrading kinins. Moreover, carriers of specific variants of the ACE2 gene could be susceptible to a stronger interaction between ACE2 and the S-protein (4) but also more prone to develop the respiratory distress syndrome (5). This provides a rationale to treatment at different level. Protease inhibitors blocking TMPRSS2 with camostat mesylate (2), kallikrein with aprotinin (6), and kinins by available receptor antagonists could provide an opportunity not only to reduce the risk of infection but also to improve the outcome of patients with respiratory distress syndrome. We have previously shown that aprotinin infusion is safe in patients with arterial hypertension (6).

Measurements of kinin and other peptides that are substrate for ACE2 cleavage in bronchoalveolar lavage fluid may help to identify subjects that could take major benefit from the above treatments. Likewise, genotyping for the ACE I/D and the AGT (-6)A/G polymorphisms may be useful to predict the risk of mortality. These assessments may prove difficult in a critical situation like the one the emergency units are experiencing now. Patients who experienced cough or allergic reaction to ACE inhibitors may ask advise regarding the opportunity to withdraw ACE inhibitors treatment if particularly exposed to the risk of infection.

With best regards

Paolo Madeddu


1. Zhou, P., Yang, X., Wang, X. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).

2. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Mar 4. pii: S0092-8674(20)30229-4. doi: 10.1016/j.cell.2020.02.052.

3. Sommerstein R. Preventing a covid-19 pandemic. BMJ 2020; 368 doi: (Published 28 February 2020) BMJ 2020;368:m810

4. Yanan Cao, Lin Li, Zhimin Feng, Shengqing Wan, Peide Huang, Xiaohui Sun, Fang Wen, Xuanlin Huang, Guang Ning & Weiqing Wang. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery volume 6, Article number: 11 (2020)

5. AM. Adamzik, U. Frey, S. Sixt, L. Knemeyer, M. Beiderlinden, J. Peters, W. Siffert. ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS. European Respiratory Journal 2007 29: 482-488; DOI: 10.1183/09031936.00046106

6. Madeddu P, Oppes M, Soro A, Dessi'-Fulgheri P, Glorioso N, Bandiera F, Manunta P, Rubattu S, Rappelli A. The effects of aprotinin, a kallikrein inhibitor, on renin release and urinary sodium excretion in mild essential hypertensives. J Hypertens. 1987 Oct;5(5):581-6. PMID: 2448367

Competing interests: No competing interests

12 March 2020
Paolo Madeddu
Medical full professor
University of Bristol, UK
Upper Maudlin Street, Bristol, UK