- The mere suspicion that the mechanism of action of particular drugs might have a negative influence on the risk of infection with, and the course of, COVID-19 disease is no reason to discontinue an existing treatment.
- Simply discontinuing drugs with a presumed, but unproven, negative effect on COVID-19 may have serious consequences for the illness for which these drugs are being used.
Concern about drug use
In a recent publication in The Lancet Respiratory Medicine, the authors argue that there is a possible relation between COVID-19 and certain drugs.1 Articles in the lay media have also regularly recommended not to use ACE inhibitors, angiotensin II receptor blockers, NSAIDs and corticosteroids in view of the risk of a severe clinical course of COVID-19. These recommendations derive from an argumentation consisting of several steps.
RAAS inhibitors and COVID-19
According to the following line of argumentation, RAAS inhibitors (ACE inhibitors and angiotensin II receptor blockers) could have a negative effect on COVID-19:
1. SARS-CoV-2 makes use of ACE2 to penetrate into host cells.
2. Animal studies have revealed a possible association between the use of RAAS inhibitors and an increase in ACE2 expression.
3. Observational studies in Wuhan found that hypertension and diabetes mellitus appear to be associated with a more severe course of COVID-19.2,3
4. Patients with hypertension and diabetes often use RAAS inhibitors.
Safety of drugs in relation to COVID-19
Influence of ACE2
The notion that certain drugs affect the clinical course of COVID-19 is based on the mechanism by which coronaviruses infect host cells. Coronaviruses (SARS-CoV and the current coronavirus SARS-CoV-2) make use of ACE2 to penetrate into host cells. The spikes on the virus bind to ACE2, after which the host cell absorbs the virus, which is then followed by active intracellular virus replication. ACE2 thus acts as a receptor for coronaviruses.4
Figure 1 A virus penetrating into a cell
ACE: Angiotensin-converting enzyme
SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2
The ACE2 enzyme, also known as ACE2 receptor, is part of the Renin Angiotensin Aldosterone System (RAAS), which is also the target of many drugs. ACE2 is attached to the cell membrane of alveolar cells, but also found on other body cells.5,6 The most likely site of infection is the ACE2 bound to lung tissue. Although it is difficult to quantify membrane-bound ACE2 receptors, people are known to differ in the amounts of ACE2 circulating in the plasma. It is particularly the membrane-bound ACE2 which is involved in the uptake of viral particles by body cells.
Research into risk factors for a severe clinical course of COVID-19
Two recently published observational studies on the Wuhan outbreak show that having hypertension and/or diabetes mellitus is associated with a severe clinical course of COVID-19.
The first of these observational studies assessed the characteristics of 1099 Chinese patients with COVID-19.2 Their average age was 47 years, and 41.9% were female. Of these patients, 23.7% had at least one co-morbidity, the most common being diabetes mellitus and hypertension. Patients with a more severe clinical picture were more likely to have a co-morbidity (38.7%) than patients in whom the course of the COVID-19 infection was milder (21.0%). The primary outcome measure was admission to an intensive care unit (ICU), mechanical ventilation or death. This occurred in 6.1% of the patients. Patients with hypertension (35.8 vs 13.7%) and patients with diabetes mellitus (26.9 vs 6.1%) both had higher mortality rates than patients without co-morbidities.
A second observational study conducted at the Wuhan hospital investigated 191 patients for the association between the clinical course of COVID-19 and co-morbidities.3 A total of 54 patients died while on the ICU. An unadjusted association was found between ischemic heart disease and mortality on the ICU, with an odds ratio of 21.40 (95% confidence interval [CI] 4.64 to 98.76). The odds ratio for diabetes mellitus was 2.85 (95% CI 1.35 to 6.05) and that for hypertension 3.05 (95% CI 1.57 to 5.92).
Limitations of the studies
Major limitations of both studies are the lack of adjustment for the use of medication, for the underlying disease entity or for the patients’ age. This makes it impossible to say whether serious complications of COVID-19 are associated with higher age, with co-morbidity or with the medications patients were using.
Drugs and ACE2
ACE inhibitors and angiotensin II receptor blockers
ACE inhibitors and angiotensin II receptor blockers are potent blood pressure lowering agents, and are indicated, for instance, after a myocardial infarction, for heart failure and to prevent nephropathy. ACE inhibitors and angiotensin II receptor blockers have no direct effect on ACE2, but it has been suggested that an increase in angiotensin I caused by these agents indirectly increases the number of ACE2 receptors. However, animal experiments have reported contradictory findings. Some animal studies support a possible relation between ACE2 gene expression and angiotensin II receptor blockers and possibly also with ACE inhibitors7,8,9, but there have also been several animal studies that did not find such a relation.10,11 One study among patients with atrial fibrillation and another study among patients with ischemic heart disease found no effect of the use of ACE inhibitors or angiotensin II receptor blockers on the amounts of ACE2 in circulation. The effect on membrane-bound ACE2 on body cells was not assessed.12,13
There is no need to suspend treatment with pioglitazone because of COVID-19. Patients who are infected should be carefully monitored to ensure adequate blood sugar regulation, which may involve temporarily switching to alternative/supplementary oral antidiabetics or insulin.
Several studies of pioglitazone have been done using rats with kidney or liver disorders. These animal studies found elevated expression of the ACE2 protein in the kidneys, liver, adipose tissues and skeletal muscle after administration of pioglitazone.14,15,16 This was assumed to be due to upregulation of PPAR-γ.15 Expression of ACE2 in lung tissue after administration of pioglitazone has not been investigated or described. No research in humans is available on the relation between ACE2 expression and the use of pioglitazone or other thiazolidinediones. For the other oral antidiabetics, no association has been found between their use and ACE2 expression.
There is no reason to discontinue the use of NSAIDs by patients infected with COVID-19. Nevertheless, the general advice for fever reduction and pain relief is to use paracetamol as the drug of first choice, as paracetamol has a stronger antipyretic effect and fewer adverse reactions or interactions than NSAIDs.17 Patients using NSAIDs for another indication do not need to stop using these agents.
A very few animal studies have found that ibuprofen can increase ACE2 levels.18 As regards other NSAIDs, no studies are known, and there is no evidence that these could increase the expression of the ACE2 receptor. Although no human studies have been performed, the letter by Fang1 and comments by the French Minister of Health on Twitter19 have wrongfully created the image that ibuprofen, or the entire group of NSAIDs, is associated with a negative advice in COVID-19.
Depending on the indication, corticosteroids are important drugs, which should only be adjusted after consultation with the treating doctor. If COVID-19 symptoms are mild, the use of corticosteroids can usually be continued without changes to the dosage. For instance, low-dosage inhalation corticosteroids have little influence on the immune system, but are very important for the treatment of asthma. Suppression of the immune system by corticosteroids takes place mostly at higher dosages. When patients with COVID-19 are using corticosteroids, each individual patient’s situation should be carefully considered. These considerations should take into account the fact that sudden discontinuation of corticosteroids, which are often used for serious diseases, can have very serious consequences for patients, such as adrenocortical insufficiency.
Corticosteroids have not been associated with elevated expression of the ACE2 receptor. One comment discussed corticosteroids as possible agents for the treatment of COVID-19.20 There is, however, no reason to assume that there might be any favourable effect, so COVID-19 is not an indication for corticosteroids. The authors of the comment also suggested that it might be better to avoid systemic corticosteroids in people with COVID-19. This suggestion ties in with the fact that corticosteroids have an immunosuppressant effect, and have been associated with an increased risk of infections, including airways infections, for instance among people with COPD.21 This association between corticosteroids and infections is now being extended, and an unjustified view is held that discontinuing corticosteroids might be useful to reduce the risk of COVID-19 or the damage it causes. Corticosteroids are indicated for, for instance, the treatment of asthma, immune suppression after transplantation or to promote foetal lung maturation if a pregnant woman is suspected of a risk of giving birth prematurely, even if the patient has a COVID-19 infection.22
ACE2 in the human body
The Renin Angiotensin Aldosterone System (RAAS) is largely responsible for blood pressure regulation. Various physiological processes involve angiotensin II, including blood pressure regulation through vasoconstriction, activation of the sympathetic nervous system (via the AT1 receptor) and release of the mineralocorticoid aldosterone. In addition, activation of RAAS induces inflammation. To this end, ACE converts angiotensin I into active angiotensin II. In this process, ACE2 has the opposite role of ACE. The carboxypeptidase ACE2 converts angiotensin I into angiotensin (1-9), and angiotensin II into angiotensin (1-7). Via the MAS receptor, angiotensin (1-9) and (1-7) have the opposite effect of angiotensin II, which is assumed to lower the blood pressure and inhibit inflammation.
Figure 2 Relation between RAAS and ACE2
ACE2 is involved in the conversion of angiotensin I into angiotensin (1-9) and angiotensin II into angiotensin (1-7). Angiotensin (1-7) lowers blood pressure and inhibits inflammation via the MAS receptor.
The SARS-CoV-2 virus can penetrate into a body cell via ACE2, and induce it to replicate the SARS-CoV-2 particles.
ACE: Angiotensin-converting enzyme
AT1 receptor: Angiotensin II receptor type 1
MAS receptor: Angiotensin (1-7) receptor
- Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? [published online ahead of print, 2020 Mar 11]. Lancet Respir Med. 2020;S2213-2600(20)30116-8. doi:10.1016/S2213-2600(20)30116-8
- Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China [published online ahead of print, 2020 Feb 28]. N Engl J Med. 2020;10.1056/NEJMoa2002032. doi:10.1056/NEJMoa2002032
- Zhou 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 [published correction appears in Lancet. 2020 Mar 28;395(10229):1038] [published correction appears in Lancet. 2020 Mar 28;395(10229):1038]. Lancet. 2020;395(10229):1054–1062. doi:10.1016/S0140-6736(20)30566-3
- Hoffmann 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 [published online ahead of print, 2020 Mar 4]. Cell. 2020;S0092-8674(20)30229-4. doi:10.1016/j.cell.2020.02.052
- Zou 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 [published online ahead of print, 2020 Mar 12]. Front Med. 2020;10.1007/s11684-020-0754-0. doi:10.1007/s11684-020-0754-0
- 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;94(7):e00127-20. Published 2020 Mar 17. doi:10.1128/JVI.00127-20
- Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605–2610. doi:10.1161/CIRCULATIONAHA.104.510461
- Ocaranza MP, Godoy I, Jalil JE, et al. Enalapril attenuates downregulation of Angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48(4):572–578. doi:10.1161/01.HYP.0000237862.94083.45
- Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. 2004;43(5):970–976. doi:10.1161/01.HYP.0000124667.34652.1a
- Burchill LJ, Velkoska E, Dean RG, Griggs K, Patel SK, Burrell LM. Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions. Clin Sci (Lond). 2012;123(11):649–658.
- Burrell LM, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J. 2005;26(4):369–324. doi:10.1093/eurheartj/ehi114
- Ramchand J, Patel SK, Srivastava PM, Farouque O, Burrell LM. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLoS One. 2018;13(6):e0198144. Published 2018 Jun 13.
- Walters TE, Kalman JM, Patel SK, Mearns M, Velkoska E, Burrell LM. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017;19(8):1280–1287. doi:10.1093/europace/euw246
- Ali RM, Al-Shorbagy MY, Helmy MW, El-Abhar HS. Role of Wnt4/β-catenin, Ang II/TGFβ, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone. Eur J Pharmacol. 2018;831:68–76. doi:10.1016/j.ejphar.2018.04.032
- Zhang W, Xu YZ, Liu B, et al. Pioglitazone upregulates angiotensin converting enzyme 2 expression in insulin-sensitive tissues in rats with high-fat diet-induced nonalcoholic steatohepatitis. ScientificWorldJournal. 2014;2014:603409. Published 2014 Jan 14. doi:10.1155/2014/603409
- Zhang W, Li C, Liu B, et al. Pioglitazone upregulates hepatic angiotensin converting enzyme 2 expression in rats with steatohepatitis. Ann Hepatol. 2013;12(6):892–900.
- EMA. EMA gives advice on the use of non-steroidal anti-inflammatories for COVID-19. 18 March 2020 EMA/136850/2020. Via: https://www.ema.europa.eu/en/documents/press-release/ema-gives-advice-use-non-steroidal-anti-inflammatories-covid-19_en.pdf Geraadpleegd op 21 maart 2020.
- Qiao W, Wang C, Chen B, et al. Ibuprofen attenuates cardiac fibrosis in streptozotocin-induced diabetic rats. Cardiology. 2015;131(2):97–106. doi:10.1159/000375362
- Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ. 2020;368:m1086. Published 2020 Mar 17. doi:10.1136/bmj.m1086
- Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473–475. doi:10.1016/S0140-6736(20)30317-2
- Singh S, Amin AV, Loke YK. Long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis. Arch Intern Med. 2009;169(3):219–229. doi:10.1001/archinternmed.2008.550
- Royal College of Obstetricians & Gynaecologists. Corona virus (COVID-19) Infection in Pregnancy. Via: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/coronavirus-pregnancy/covid-19-virus-infection-and-pregnancy/. Geraadpleegd op 28 maart 2020.