Negative influence of drugs on COVID-19

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.

Assessment of the safety of using certain drugs focuses on the balance between efficacy and adverse effects. The favourable effect of the drugs discussed here has been confirmed by official drug registrations for various indications, professional guidelines and extensive clinical experience. A negative effect of registered drugs on either infection with COVID-19 or its course has so far not been confirmed by sound research. Animal experiments have investigated a possible association between certain drugs and the expression of ACE2. So far, however, no evidence has been found for a relation between an increased expression of ACE2 and the risk of contracting COVID-19 or the severity of symptoms in COVID-19 infection. In addition, much remains unknown about the relation in humans between drug use, ACE2 expression and the risk of contracting COVID-19 or an unfavourable course of the disease. The currently available data provide insufficient arguments to avoid certain drugs for persons at risk of infection with SARS-CoV-2, or persons being treated for COVID-19.
 

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.

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.

Study findings

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.

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 inhibitors^7,8,9, 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

Pioglitazone 

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.

NSAIDs

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.

Corticosteroids

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

Legend:
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
Ang: Angiotensin
AT1 receptor: Angiotensin II receptor type 1
MAS receptor: Angiotensin (1-7) receptor