Angiotensin converting enzyme inhibitors and angiotensin receptor blockers in an outbreak of SARS-CoV-2

In COVID-19, hypertension, diabetes mellitus, coronary artery disease, and immunosuppression are comorbid conditions most often associated with poor prognosis. Angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers are widely used in the treatment of these diseases. Therefore, scientists turned their attention to these drugs and brought up the question of whether angiotensin converting enzyme inhibitors and angiotensin receptor blockers may be drugs that adversely affect prognosis in SARS-CoV-2 infection. The authors generally discussed the role of these drugs in SARS-CoV-2 infection through the same mechanisms. We also investigated the effects of these drugs on the immune system.

Currently, there is no definitive treatment method or vaccine available for COVID-19, which is rapidly spreading worldwide. Recently published data of patients are similar to each other. Especially advanced age is associated with poor prognosis. Hypertension, diabetes mellitus, coronary artery disease and immunosuppression are comorbid conditions which are most commonly associated with poor prognosis. Angiotensin converting enzyme inhibitors (ACEI) and/or angiotensin receptor blockers (ARB) are widely used in the treatment of these diseases. Interestingly, those with chronic lung disease come after patients with above mentioned conditions [1-7]. Therefore, scientists turned their attention to these drugs and brought up the question of whether ACEIs and ARBs may be drugs that adversely affect prognosis in SARS-CoV-2 infection.

ACEIs and ARBs increase the expression of angiotensin converting enzyme 2 (ACE2) [8,9]. SARS-CoV-2 has four main structural proteins, one of which is the spike (S) protein that binds to the angiotensin converting enzyme 2 (ACE2) receptor and mediates subsequent fusion between the envelope and host cell membranes to aid viral entry into the host cell [10,11]. SARS-CoV-2 attaches to ACE2 receptors through the spike protein and invades tissues [12]. Based on this mechanism, some authors have argued that ACEI and/or ARB should not be used as they would enhance SARS-CoV-2 invasion, or some authors have reported their hesitation about the use of these drugs [1,6,13,14]. However, the fact that lung ACE2 expression is higher in young people, ACE2 expression decreases with age, and this decrease is more pronounced in men [15], do not support the hypotheses of these authors. This is because data on COVID-19 show that mortality rates are almost 0% in children and lower in women compared to men [2].

ACE2 is an important modulator of the renin-angiotensin system (RAS), which lowers Angiotensin II (Ang II) levels and increases production of Angiotensin 1-7 [Ang [1-7,16]. ACE inhibitors and ARBs exhibit lung-protective effects through providing ACE2-mediated increase in Ang [1-7]. Due to this mechanism, some authors have argued that ACEIs and ARBs would be beneficial or at least not be harmful in SARS-CoV-2 pneumonia. These authors have also argued that the virus reduced ACE2 levels after binding to ACE2, thereby inhibiting the protective effect of ACE2 in the lungs [17-20]. However, studies have shown that hypertensive patients who are hospitalized due to COVID-19 have a high rate of mortality [2,6]. This does not support the idea that ACEIs/ARBs protect the lungs by ACE2 upregulation.

Consequently, although both the hypothesis of authors who find ACEIs/ARBs harmful on the grounds that they enhance the virus invasion by ACE2 upregulation, and of authors who argue that ACEIs/ARBs protect patients from pneumonia on the grounds that they would increase production of Ang [1-7], by ACE2 upregulation are rational, neither hypothesis is supported by actual patient data. Therefore, we thought it was necessary to view ACEIs and ARBs from a wider framework.

One of the most interesting features of angioconverting enzyme (ACE) is its role in the immune response in addition to its role of regulating blood pressure [21]. Immune responses dependent on CD4+ T lymphocyte are critically important for mediating autoimmune diseases and controlling pathogen infection. MHC class II antigen processing pathway produces the cell surface MHC class II peptide complexes required for CD4+ T cell responses. Antibody production by B cells requires the aid of CD4 + T cells [22]. Major histocompatibility complex (MHC) molecules are cell surface molecules that present antigens to T cells and activate them and determine the direction of the T cell mediated immune response [23]. The newly synthesized MHC class II molecules combine with the invariant chain (Ii) in the endoplasmic reticulum [24]. Angiotensin converting enzyme (ACE) is a carboxyl peptidase [25], that is expressed by antigen-presenting cells (APC). ACE is a type I ectoenzyme associated with the cell membrane, but functionally active ACE is also found in the endoplasmic reticulum where ACE is involved in MHC class I antigen processing [26,27]. ACE is expressed with many different tissues, including APCs [28-30]. Zhao T, et al. showed in their study that ACE has a physiological role in the processing of peptides for MHC class II presentation via analysis of ACE null (knockout), normal type and ACE overexpressing (ACE10) mice and antigenpresenting cells derived from these mice. They demonstrated that the effectiveness of presenting MHC class II epitopes from ovalbumin and chicken egg lysosome was significantly affected by cellular ACE levels and that mice overexpressing ACE in myeloid cells had a much stronger CD4+ T cell and antibody response when immunized with ovalbumin. In the same study, mice overexpressing ACE were exposed to an ACE inhibitor, lisinopril and it has been observed that their previous capability to produce antibodies was completely eliminated [31]. Both in vitro and in vivo studies have consistently shown that ACE affects the peripheral activation of CD4+ T cells by APCs [32,33]. Harmer D, et al. have showed in their study that ACE expression was upregulated when APCs were stimulated by IFN-y or Listeria monocytogenes [27]. Khan Z, et al. have found in mouse experiments that overexpression of ACE in monocytes and macrophages regulates the immune responses of these cells and have shown that ACE inhibitors are detrimental to neutrophil function. However, they have demonstrated that ACEIs significantly reduced the bactericidal capacity of neutrophils after at least 7 days of use, rather than acute administration. They have also emphasized that individuals using ACEI may be susceptible to infections [34]. In another study, a higher incidence of urinary tract infections has been found in individuals taking ACE inhibitors [35].

Based on these mechanisms, we can easily say that ACEIs or ARBs disrupt the mechanism of antibody production in SARS-CoV-2 infection and contribute to the continuation of virus replication. We argue that the use of ACEIs/ARBs in patients with already impaired CD4/CD8 ratio due to aging may cause SARS-CoV-2 infection to be more fatal in these patients.

The immune system has been confirmed to play a vital role in the defense against SARS-CoV and MERS infections. In the acute phase of SARS-CoV infection, rapid reduction of lymphocytes in the peripheral blood has been observed, mainly T lymphocytes, and both CD4+ and CD8+ T lymphocytes.Lymphocyte loss occurred before abnormal changes appeared on the chest radiography [36-41]. In a study, it has been shown that T cell response before and during influenza infection and influenza-specific CD4+ T cells are associated with disease protection against influenza threat in humans [42]. Lymphocytes are also significantly decreased in severe type COVID -19 patients [43]. In our clinical observations, we found that severely ill patients had severe lymphopenia..

A low or inverted CD4/CD8 ratio is an immune risk phenotype and is associated with altered immune function, immune aging, and chronic inflammation in populations both infected and not infected with Human Immunodeficiency Virus-1 (HIV-1) [44]. The features of age-related inflammation are very similar to the inflammatory changes that occur during HIV-1 infection [45]. The prevalence of an inverted CD4/CD8 ratio increases with age. Inverse proportion is observed in 8% of the age group of 20-59 years, and in 16% of the age group of 60-94 years. Women of all age groups are less likely to have an inverse proportion than men [46]. Mouse models also emphasize the importance of age and estrogen on the CD4/CD8 ratio, because lower rates have been reported in mice after both natural menopause and ovariectomy [47]. This information gives us an explanation of why older patients compared to younger patients and men compared to women have higher mortality rates when infected with SARS-CoV-2.

Under lymphopenic conditions, T cells divide to maintain peripheral pool sizes. Deep chronic lymphopenia, characterized by poor T cell recovery in some HIV-1 infected patients, can cause intense homeostatic proliferation and T cell depletion and/or aging [48,49]. Homeostatic proliferation rates of the patients who were unable torecover CD4+ T cell countand have undetectable viral load (<50 copies/ml) among HIV-infected lymphopenic patients were higher than those of the patients using effective highly active antiretroviral therapy (HAART) who were able to recover CD+ 4 T cells [50]. In a cross-sectional study on 334 HIV-infected patients, a lower CD4/CD8 ratio during treatment has been shown to predict residual HIV viremia (≥1 copy / ml) detected by single copy assay [51].

Determining the CD4/CD8 ratio in COVID-19 may be important both for the treatment plan (such as the decision to treat with immune plasma as well as initiation and continuation of antiviral therapy), and for the estimation of viral load in recovered patients (including immune plasma donors). It may also be recommended that patients who have recovered from SARS-CoV-2 infection but have low CD4/CD8 ratio be followed up for undetectable viral load and risk of reactivation in the future, and also be considered for active immunization if a vaccine is found. In this context, COVID-19 patients using ACEI and/or ARB may need to be monitored further for undetectable viremia after they have recovered. While following these patients, virtual reality system can be used to prevent transmission to healthcare professionals [52].

In summary, we believe that ACEIs and ARBs contribute to poor prognosis in patients with SARS-CoV-2 infection. However, it is necessary to quickly prove or refute this with actual patient data. We suggest that scientists should review the drugs used by patients who died or are negatively affected and determine the effect of those drugs on prognosis by comparative studies in countries where COVID-19 infection is widespread, and drugs that are actually found to be responsible should be urgently replaced with alternative drugs.

1. Thomson G (2020) COVID‐19: social distancing, ACE 2 receptors, protease inhibitors and beyond? Int J Clin Pract e13503. Link: https://bit.ly/3hkxLsA
2. Zhou F, Yu T, Du R, Fan G, Liu Y, et al.  (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395: 1054-1062. Link: https://bit.ly/3fh7biy  
3. Yang X, Yu Y, Xu J, Shu H, Xia J (2020) Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 8: 475-481. Link: https://bit.ly/3dZlnMU  
4. Guan W, Ni Z, Hu Y, Liang WH, Ou CQ, et al. (2020) Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 382:1708-1720. Link: https://bit.ly/2UyxRmQ
5. Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, et al. (2020) Clinical characteristics of 140 patients infected by SARS-CoV-2 in Wuhan, China. Allergy. Link: https://bit.ly/2Ap1r7r
6. Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, et al. (2020) Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV. Zhonghua Xin Xue Guan Bing Za Zhi 48:  E004. Link: https://bit.ly/2UycUs1
7. Korean Society of Infectious Diseases and Korea Centers for Disease Control and Prevention (2020) Analysis on 54 Mortality Cases of Coronavirus Disease 2019 in the Republic of Korea From January 19 to March 10, 2020. J Korean Med Sci 35: e132. Link: https://bit.ly/37jDaf7
8.  Li XC, Zhang J, Zhuo JL (2017) The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res 125: 21-38. Link: https://bit.ly/3dW2BFS
9. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan BK, et al. (2005) Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 111: 2605-2610. Link: https://bit.ly/3fikezV
10.  Kirchdoerfer RN, Cottrell CA, Wang N, Pallesen J, Yassine HM, et al. (2016) Pre-fusion structure of a human coronavirus spike protein. Nature 531: 118–121.  Link: https://go.nature.com/2ML8FW1
11.  Xu X, Chen P, Wang J, Feng J, Zhou H, et al.  (2020) Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 63: 457-460. Link: https://bit.ly/2Ynrtjr  
12.  Wan Y, Shang J, Graham R, Baric RS,  Li F (2020) Receptor recognition by novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS. J Virol  94: e00127. Link: https://bit.ly/2znKp9j
13.  Gurwitz D (2020) Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 1-4. Link: https://bit.ly/2XSV5Gi
14.  Diaz JH (2020) Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med 27. Link: https://bit.ly/2UytzMq
15.  Xie X, Chen J, Wang X, Zhang F, Liu Y (2006)  Age- and gender-related difference of ACE2 expression in rat lung. Life Sci 78: 2166-2171. Link: https://bit.ly/3cU9w0W
16. Ingelfinger JR (2009) Angiotensin-converting enzyme 2: implications for blood pressure and kidney disease. Curr Opin Nephrol Hypertens  18: 79–84. Link: https://bit.ly/3hdUuXz
17.  Sun ML, Yang JM, Sun YP, Su GH (2020) Inhibitors of RAS might Be a good choice for the therapy of COVID-19 pneumonia. Zhonghua Jiehe He Huxi Zazhi 43: 219-222.  Link: https://bit.ly/3hise60
18.  Phadke M, Saunik S (2020) Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona Virus infections – Novel mode of treatment. BMJ 368: m406. Link: https://bit.ly/2YtglkW
19.  Kruse RL (2020) Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res 9: 72. Link: https://bit.ly/2YnGZMi
20. Kuster GM, Pfister O, Burkard T, Zhou Q Twerenbold R, et al.  (2020) SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19? Eur Heart J   41: 1801-1803. Link: https://bit.ly/2MQdtsY
21. Bernstein KE, Khan Z, Giani  JF, Zhao T, Eriguchi M,  et al. (2016) Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response. F1000Research 2016, 5(F1000 Faculty Rev): 393. Link: https://bit.ly/30vHcj2
22.  Alfonso C, Han JO, Williams GS, Karlsson L (2001) The impact of H2-DM on humoral immune responses. J Immunol  167: 6348–6355. Link: https://bit.ly/30ud0F2
23.  Abbas KA, Andrew HL, Pillai S (2007) Cellular and Molecular Immunology: 6th edition. Philadelphia, Saunders Elsevier 97-111. Link: https://bit.ly/3cYUwiI
24. Bernstein KE, Ong FS, Blackwell WL, Shah KH, Giani JF, et al. (2013) A modern understanding of the traditional and nontraditional biological functions of angiotensin-converting enzyme. Pharmacol Rev 65: 1–46. Link: https://bit.ly/2MRM35W
25. Danilov SM, Sadovnikova E, Scharenborg N, Balyasnikova IV, Svinareva DA, et al. (2003) Angiotensin-converting enzyme (CD143) is abundantly expressed by dendritic cells and discriminates human monocyte-derived dendritic cells from acute myeloid leukemia-derived dendritic cells. Exp Hematol   31: 1301– 1309. Link: https://bit.ly/2AYIXe1
26. Esther CR, Howard TE, Marino EM, Goddard JM, Capecchi MR, et al. (1996) Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest  74: 953-965. Link: https://bit.ly/2MQJTnn
27. Harmer D, Gilbert M, Borman R, Clark KL (2002) Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett 532: 107-110. Link: https://bit.ly/30w1DMN
28.  Kool M, Soullie T, Van Nimwegen M, Willart MAM, Muskens F, et al. (2008) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J Exp Med 205: 869-882.  Link: https://bit.ly/2AnQByo
29.  Neefjes J, Jongsma ML, Paul P, Bakke O (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11: 823-836. Link: https://go.nature.com/3cR27Q7
30.  Roche PA, Furuta K (2015) The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 15: 203-216. Link: https://bit.ly/2BWGCke
31.  Zhao T, Bernstein KE, Fang J, Shen XZ (2017) Angiotensin converting enzyme affects the presentation of MHC class II antigen. Lab Invest 97: 764-771. Link: https://bit.ly/2MQnXZE
32. Saijonmaa O, Nyman T, Fyhrquist F (2007) Atorvastatin inhibits angiotensin-converting enzyme induction in differentiating human macrophages. Am J Physiol Heart Circ Physiol 292: H1917-1921. Link: https://bit.ly/37jHk6J
33. Shen XZ, Lukacher AE, Billet S, Williams IR, Bernstein KE (2008) Expression of angiotensin-converting enzyme changes major histocompatibility complex class I peptide presentation by modifying C termini of peptide precursors. J Biol Chem 283: 9957–9965. Link: https://bit.ly/2Yo8fu2
34. Khan Z, Shen XZ, Bernstein EA, Giani  JF, Eriguchi M, et al. (2017) Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils. Blood 130: 328–339. Link: https://bit.ly/2XWfvyp
35.  Pouwels KB, Visser ST, Hak E (2013) Effect of pravastatin and fosinopril on recurrent urinary tract infections. J Antimicrob Chemother 68: 708-714. Link: https://bit.ly/3fhIUZF
36. Liu ZY, Li TS, Wang Z, Xu ZJ, Wang HL, et al. (2003) Clinical features and therapy of 106 cases of severe acute respiratory syndrome. Chinese J Intern Med 42: 373-377. Link: https://bit.ly/2MO7EMP  
37. Li TS, Qiu ZF, Han Y, et al. (2003) The alterations of T cell subsets of severe acute respiratory syndrome during acute phase. Chinese J Lab Med 5: 40-42.
38. Taisheng L, Zhifeng Q, Linqi Z, Han Y, He W, et al. Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome. J Infect Dis 189: 648–651. Link: https://bit.ly/2XRxYvJ
39. Ko JH, Park GE, Lee JY, Lee  JY, Cho SY, et al. (2016) Predictive factors for pneumonia development and progression to respiratory failure in MERS-CoV infected patients. J Infect 73: 468-475. Link: https://bit.ly/3dZqnkE
40.  Mohn KG, Cox RJ, Tunheim G, Berdal JE, Hauge AG, et al. (2015) Immune responses in acute and convalescent patients with mild, moderate and severe disease during the 2009 influenza pandemic in Norway. PLoS One 10: e0143281. Link: https://bit.ly/30rPgkW
41.  Lin L, Lu LF, Cao W, Li T (2020) Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. Emerg Microb Infect 9. Link: https://bit.ly/2B2ME20
42. Bermejo-Martin JF, Lejarazu ROD, Pumarola T, Rello J, Almansa R, et al. (2009) Th1andTh17hypercytokinemiaasearlyhostresponse signature in severe pandemic influenza. Crit Care 13: R201. Link: https://bit.ly/2ApEIYU
43.  Wang D, Hu B, Hu C (2020) Clinical characteristics of 138 hospitalized patients With 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 323: 1061-1069. Link: https://bit.ly/2B0gmVo
44. Serrano-Villar S, Moreno S, Fuentes-Ferrer M, Sánchez-Marcos C, Avila M, et al. (2014) The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery. HIV Med 15: 40–49. Link: https://bit.ly/37neBO9
45.  Kroger L, Vahasalo P, Tynjala P, et al. (2012)  Medical treatment of juvenile idiopathic arthritis. Duodecim 128: 477-486.
46. Wikby A, Månsson IA, Johansson B, Strindhall  J, Nilsson SE  (2008) The immune-risk profile is associated with age and gender: findings from three Swedish population studies of individuals 20–100 years of age. Biogerontology 9: 299–308. Link: https://bit.ly/2Uyt9Wl
47. Shao MJ, Zhu YJ, Qiu YE, Hu M, He YQ (2017) Changes in the Level of Immunoglobulins and CD4/CD8 Ratio in Young and Aged Mice with Estradiol Deficiency. Immunol Invest 46: 305–313. Link: https://bit.ly/2N13YYl
48. Bell EB, Sparshott SM, Drayson MT, Ford WL (1987) The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells. J Immunol 139: 1379–1384. Link: https://bit.ly/2Yt81BK
49. Rocha B, Dautigny N, Pereira P (1989) Peripheral T lymphocytes: Expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo. Eur J Immunol 19: 905-911. Link: https://bit.ly/2zo7Oax  
50. Marchetti G, Gori A, Casabianca A, Magnani M, Franzetti F, et al. (2006) Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART. AIDS 20: 1727-1736. Link: https://bit.ly/2MQtM9a
51. Riddler S, Aga E, Bosch R, Bastow B, Bedison M, et al. (2016) Continued Slow Decay of the Residual Plasma Viremia Level in HIV-1-Infected Adults Receiving Long-term Antiviral Therapy. J Infect Dis 213: 556-560. Link: https://bit.ly/2XWtdBn
52. Singh RP, Javaid M, Kataria R, Tyag M, Haleem A, et al.  (2020) Significant Applications of Virtual Reality for COVID-19 Pandemic. Diabetes Metab Syndr 14: 661-664. Link: https://bit.ly/3dUwjLs

© 2020 Acik DY. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.