Role of Ibuprofen and Other Medicines on Severity of Coronavirus Disease 2019

It has been suggested that ibuprofen might be associated with more severe cases of
coronavirus infections, based on the observation that severe COVID cases had been exposed to
ibuprofen, resulting in a warning by the French authorities (published in a french journal
called "Le Monde" = The world).

This was attributed to:

1. a suggestion that ibuprofen might upregulate ACE-2 thereby increasing the entrance of
COVID-19 into the cells.This is based on a single study in streptozotocin-induced
diabetic rats where ibuprofen decreases cardiac fibrosis. There seems to be no study in
man. (https://www.dw.com/en/coronavirus-confusion-about-safety-of-ibuprofen/a…)
These authors noted an increased risk of severe COVID-19 in patients with hypertension
or diabetes, and a possible role of Angiotensin converting enzyme inhibitors (ACEI) or
angiotensin receptor blockers (ARB) which also upregulate ACE-2, as do also
thiazolidinedione antidiabetic drugs. The relevance of this up-regulation seems
disputed.

2. an analogy with bacterial soft-tissue infections where more severe infections on NSAIDs
are attributed to an immune-depressive action of NSAIDs, or to belated treatment because
of initial symptom suppression.

3. fever is a natural response to viral infection, and reduces virus activity: antipyretic
activity might reduce natural defenses against viruses. However fever reduction in
critically ill patients had no effect on survival. A meta-analysis of fever reduction in
children found no difference on outcomes between paracetamol and ibuprofen.

However, these assertions are unclear: upregulation of ACEII would increase the risk of
infection, not necessarily its severity, and would only apply to the use of NSAIDs before the
infection, i.e. chronic exposure. It would be irrelevant to the infection once the patients
are infected, i.e., to symptomatic treatment of COVID-19 infection.

Anti-inflammatory effect masking the early symptoms of bacterial infections resulting in
later antibiotic or other treatment is not applicable: there is no treatment of the virus
that might be affected by masking symptoms.

Antipyretic effect increasing the risk or the severity of infection would apply equally to
all antipyretic agents including paracetamol, which share the same mechanism of action for
fever reduction.

EMA remains prudent about this assertion (EMA gives advice on the use of non-steroidal
anti-inflammatory drugs for COVID-19, 18 March 2020 EMA/136850/2020).

These findings raise the question of

1. an indication bias, where more severe cases with more symptoms and higher fever might
not respond well to the first line antipyretic paracetamol, so that ibuprofen was then
used. (reverse causality) The same has been described with soft-tissue infection

2. the reality of an increased risk in patients chronically on drugs that upregulate ACEII,
such as NSAIDs, antihypertensive drugs and especially ACEI or ARB, or antidiabetic drugs
and especially thiazolidinediones.

3. the impact of concomitant or pre-existing diseases such as diabetes, hypertension or
heart failure.

In addition, excess reliance on paracetamol while discouraging the use of ibuprofen might
increase the risk of hepatic injury from paracetamol overdose. Paracetamol is the prime drug
associated with liver injury and transplantation, in voluntary and inadvertent overdose or
even at normal doses. This might be increased by COVID-related liver function alterations.

It is therefore proposed to conduct a case-control study in a cohort of patients admitted to
hospital in France with COVID-19 infection, to explore these different questions.