Antihypertensive drugs and risk of COVID-19? – Authors' reply
Authors: Lei Fang, George Karakiulakis, Michael Roth
Journal: The Lancet Respiratory Medicine (2020)

We thank Joshua Brown, Kevin Lo and colleagues, and Christopher Tignanelli and colleagues for their responses to our Correspondence1Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; (published online March 11.)https://doi.org/10.1016/S2213-2600(20)30116-8Summary Full Text Full Text PDF Scopus (2084) Google Scholar, and we welcome the opportunity to reply. The fast-developing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported from Wuhan, China,2Zhu N Zhang D Wang W et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020; 382: 727-733Crossref PubMed Scopus (18588) Google Scholar and has spread globally. As of March 22, 2020, 307 297 people have been infected by SARS-CoV-2, with 13 049 deaths and 92 382 people recovered. Several reports have summarised the clinical and epidemiological features of COVID-19 and have shown specific comorbidities associated with increased risk of infection and developing into a severe or fatal case. Of 1099 infected patients, 173 had severe disease, in whom the most common comorbidities were hypertension (24%), diabetes (16%), coronary heart disease (6%), and cerebrovascular disease (2%).3Guan W Ni Z Hu Y et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; (published online Feb 28.)DOI:10.1056/NEJMoa2002032Crossref Google Scholar In a second cohort of 41 patients hospitalised with COVID-19,4Huang C Wang Y Li X et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-506Summary Full Text Full Text PDF PubMed Scopus (32861) Google Scholar diabetes (20%), hypertension (15%), and cardiovascular disease (15%) were frequent comorbidities. Among 191 patients hospitalised with COVID-19,5Zhou F Yu T Du R et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; (published online March 11.)https://doi.org/10.1016/S0140-6736(20)30566-3Summary Full Text Full Text PDF Scopus (18725) Google Scholar the most common comorbidities with significant effects on mortality were hypertension (30%; p=0·0008), diabetes (36%; p=0·0051), and coronary heart disease (15%; p=0·0001). In an analysis of 201 patients with COVID-19,6Wu C Chen X Cai Y et al.Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.JAMA Intern Med. 2020; (published online March 13.)DOI:10.1001/jamainternmed.2020.0994Crossref Scopus (5774) Google Scholar 84 (42%) patients developed acute respiratory distress syndrome, with hypertension (27%) and diabetes (19%) as the most common comorbidities. Hypertension, diabetes, and cardiovascular disease, which seem to be the most common comorbidities in patients with COVID-19, are typically treated with drugs that inhibit the renin–angiotensin system (RAS), including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). The long history of use and thorough investigation of these drugs means that efficacy and safety of RAS inhibitors is very well documented, not only for management of blood pressure but also for protection from disease-associated inflammation and organ remodelling.7Simoes ESAC Teixeira MM ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis.Pharmacol Res. 2016; 107: 154-162Crossref PubMed Scopus (192) Google Scholar The high proportion of patients with severe COVID-19 and these comorbidities suggests a causative link and led to our hypothesis,1Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; (published online March 11.)https://doi.org/10.1016/S2213-2600(20)30116-8Summary Full Text Full Text PDF Scopus (2084) Google Scholar, 8University of BaselIbuprofen and COVID-19.https://www.unibas.ch/en/News-Events/News/Uni-Research/Ibuprofen-and-COVID-19-Setting-the-record-straight.htmlDate: March 17, 2020Date accessed: March 23, 2020Google Scholar which has also been presented by others.9Zheng YY Ma YT Zhang JY Xie X COVID-19 and the cardiovascular system.Nat Rev Cardiol. 2020; (published online March 5.)DOI:10.1038/s41569-020-0360-5Crossref Scopus (2269) Google Scholar, 10Diaz JH Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19.J Travel Med. 2020; (published online March 18.)DOI:10.1093/jtm/taaa041Crossref Scopus (135) Google Scholar Based on the drugs most frequently given to patients to treat these comorbidities (ie, ACEIs and ARBs), we postulated whether these drugs might further increase risk for severe or fatal COVID-19.1Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; (published online March 11.)https://doi.org/10.1016/S2213-2600(20)30116-8Summary Full Text Full Text PDF Scopus (2084) Google Scholar This hypothesis is supported by the observation that organ-specific expression of angiotensin converting enzyme 2 (ACE2) correlates with the vulnerability to infection by SARS-CoV-2.11Zou X Chen K Zou J Han P Hao J Han Z Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.Front Med. 2020; (published online March 12.)DOI:10.1007/s11684-020-0754-0Crossref PubMed Scopus (1613) Google Scholar Our concern was initiated after investigating the molecular mechanism by which SARS-CoV-2 attaches to and infects cells. Both SARS-CoV-2 and severe acute respiratory syndrome coronavirus (SARS-CoV) bind to the host cell's membrane via ACE2,12Wan 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; 94: e00127-e00220Crossref PubMed Scopus (3161) Google Scholar which is specifically highly expressed by epithelial cells in oral mucosa.13Xu H Zhong L Deng J et al.High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.Int J Oral Sci. 2020; 12: 8Crossref PubMed Scopus (1850) Google Scholar ACE2 is a widely expressed protein in lung, intestine, kidney, and blood vessels, and on immunoreactive cells.11Zou X Chen K Zou J Han P Hao J Han Z Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection.Front Med. 2020; (published online March 12.)DOI:10.1007/s11684-020-0754-0Crossref PubMed Scopus (1613) Google Scholar Moreover, circulating amounts of ACE2 are increased in patients with hypertension or diabetes, and levels are further increased by different drugs, including ACEIs and ARBs.14Anguiano L Riera M Pascual J et al.Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease.Nephrol Dial Transplant. 2015; 30: 1176-1185Crossref PubMed Scopus (84) Google Scholar, 15Hristova M Stanilova S Miteva L Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy.Clin Exp Hypertens. 2019; 41: 662-669Crossref PubMed Scopus (14) Google Scholar It should also be emphasised that specific alleles control ACE2 expression, activity, and response to ACEIs.15Hristova M Stanilova S Miteva L Serum concentration of renin-angiotensin system components in association with ACE I/D polymorphism among hypertensive subjects in response to ACE inhibitor therapy.Clin Exp Hypertens. 2019; 41: 662-669Crossref PubMed Scopus (14) Google Scholar In addition to animal models, humans given ACEIs, ARBs, or both, had increased ACE2 levels on intestine luminal cells.16Vuille-dit-Bille RN Camargo SM Emmenegger L et al.Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors.Amino Acids. 2015; 47: 693-705Crossref PubMed Scopus (244) Google Scholar In this context, it should be noted that modification of glycosylation is essential for binding of SARS-CoV-2 spike protein. Inhibition of ACE2 glycosylation by either chloroquine, hydrochloroquine, or a serine protease inhibitor significantly reduces the infection of host cells by SARS-CoV and SARS-CoV-2 in vitro.17Hoffmann M Kleine-Weber H Schroeder S et al.SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; (published online March 5.)DOI:10.1016/j.cell.2020.02.052Summary Full Text Full Text PDF PubMed Scopus (13427) Google Scholar, 18Vincent MJ Bergeron E Benjannet S et al.Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.Virol J. 2005; 2: 69Crossref PubMed Scopus (1389) Google Scholar, 19Wang M Cao R Zhang L et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.Cell Res. 2020; 30: 269-271Crossref PubMed Scopus (4986) Google Scholar We are aware of the beneficial effects of ACEIs and ARBs protecting the heart and kidney for patients with hypertension and diabetes. An opposing hypothesis has suggested that upregulation of ACE2 expression or infusion of human recombinant ACE2 might protect against SARS-CoV-2 infections.20Gurwitz D Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.Drug Dev Res. 2020; (published online March 4.)DOI:10.1002/ddr.21656Crossref PubMed Scopus (610) Google Scholar, 21Fedson DS Opal SM Rordam OM Hiding in plain sight: an approach to treating patients with severe COVID-19 infection.mBio. 2020; 11: e00398-e00420Crossref PubMed Scopus (131) Google Scholar However, it has to be emphasised that the role of ACE2 in these protective effects are not well understood.12Wan 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; 94: e00127-e00220Crossref PubMed Scopus (3161) Google Scholar, 13Xu H Zhong L Deng J et al.High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa.Int J Oral Sci. 2020; 12: 8Crossref PubMed Scopus (1850) Google Scholar, 14Anguiano L Riera M Pascual J et al.Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease.Nephrol Dial Transplant. 2015; 30: 1176-1185Crossref PubMed Scopus (84) Google Scholar Furthermore, it should be noted that ACEIs have been reported to modify the adaptive immune response,22Bernstein KE Khan Z Giani JF Cao DY Bernstein EA Shen XZ Angiotensin-converting enzyme in innate and adaptive immunity.Nat Rev Nephrol. 2018; 14: 325-336Crossref PubMed Scopus (151) Google Scholar suggesting that long-term use of ACEIs might suppress the adaptive immune response, which is a key defence against viral infections. Similar effects on the adaptive immune response are known for most non-steroid anti-inflammatory drugs. These effects need to be addressed in an extended discussion and investigated with clinical trials in the context of the COVID-19 pandemic. Available published data indicate that ACE2 is a double-edged sword, particularly when considering patients with SARS-CoV-2 infection and comorbidities of hypertension, diabetes, and cardiovascular disease. The final answer as to whether drugs to treat these comorbidities (ie, ACEIs or ARBs) are more beneficial than harmful in this current pandemic is unclear, and all hypotheses should be investigated rather than being interpreted as evidence. This work is of special importance because coronaviruses in general have always been a part of the common influenza season and, in the future, new SARS-CoV will probably develop. The overinterpretation of our hypothesis should not lead to changing drugs for patients with hypertension or diabetes without first consulting with an expert clinician. Nevertheless, it is of utmost urgency for the scientific and medical community to work together to find evidence-based proof to address these concerns. Related links•The latest guidance from WHO on ibuprofen and COVID-19 (dated: 19.03.2020)•Statement from Prof Michael Roth on how to interpret the original letter •The latest guidance from WHO on ibuprofen and COVID-19 (dated: 19.03.2020)•Statement from Prof Michael Roth on how to interpret the original letter We declare no competing interests. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues1 were cerebrovascular diseases (22%) and diabetes (22%). Another study2 included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study,3 of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Full-Text PDF Antihypertensive drugs and risk of COVID-19?Lei Fang and colleagues1 extrapolated results from a molecular study of coronaviruses, which showed that this group of viruses uses angiotensin-converting enzyme 2 (ACE2) to target cells on the epithelium of the lungs, intestine, kidneys, and blood vessels.2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), would probably share these properties. Full-Text PDF Antihypertensive drugs and risk of COVID-19?Lei Fang and colleagues1 postulate that because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor to facilitate host cell entry,2,3 disease severity and mortality of coronavirus disease 2019 (COVID-19) might be increased in patients taking angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) during the COVID-19 pandemic, because the ACE2 receptor might be upregulated with use of ACEIs and ARBs. Full-Text PDF Antihypertensive drugs and risk of COVID-19?Lei Fang and colleagues1 suggest that clinicians should consider withholding angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) because of a potential increased risk of worse clinical outcomes in patients with coronavirus disease 2019 (COVID-19), and they suggest calcium channel blockers as an alternative. The hypothesis behind this suggestion is that the entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the ACE2 receptor and that ACEIs and ARBs have the potential to upregulate ACE2. Full-Text PDF