On March 14, 2020 Olivier Véran, the health minister of France, released the following tweet. “COVID-19. Taking anti-inflammatory drugs (ibuprofen, cortisone, …) could be an aggravating factor of the infection. If you have a fever, take paracetamol [acetaminophen]. If you are already on anti-inflammatory drugs or in doubt, ask your doctor for advice.”
This tweet initiated some debate about the use of non-steroidal anti-inflammatory drugs (NSAIDS) in COVID-19.
In the cells, membrane lipids are converted into phospholipase A2. This molecule is then converted into arachidonic acid which in turn is converted to Prostaglandin G2 with the enzymatic assistance of Cyclooxygenase 1 and Cyclooxygenase 2 (COX1, COX2). Prostaglandin G2 is further converted to other prostaglandins (PG) and proinflammatory substances including prostaglandin E2 (PGE2). When pathologic conditions exist in the kidney, there is an increased expression of COX1 and COX2. This increase in enzymes causes an increase in PGE2. The increase in PGE2 can maintain GFR by dilating the afferent arterioles of the glomerulus.(1,2)
NSAIDS inhibit the action of COX enzymes preventing formation of these prostaglandins.(3) Some NSAIDS selectively block COX2 (sNSAIDS) while others are nonselective in their COX blockade (nsNSAIDS). When pathologic kidney disease occurs, if COX enzymes are blocked, the kidney cannot increase production of PGE2. Losing this protective feedback mechanism will worsen kidney function.
Patients infected with COVID-19 appear to be at higher risk of acute kidney injury.(4) Once kidney injury has occurred, mortality is higher than in patients without kidney injury. In the setting of COX inhibition by NSAIDS, the kidneys lose the protection of PGE2.
In addition to the known risk of causing and worsening kidney function, further changes are observed in the body after the administration of NSAIDs that may worsen COVID-19 infection. Through an unknown mechanism, ACE 2 levels are known to increase with the administration of ibuprofen.(5) COVID-19 is known to bind to ACE 2. This binding facilitates COVID-19 entry into the cell. The increase in ACE 2 with NSAID use is hypothesized to increase the COVID -19 cell entry which theoretically would increase the severity of infection and likelihood of death. To date, the increase in ACE 2 levels have not been shown to directly affect morbidity and mortality.
The European Medicines Agency has issued the statement “There is currently no scientific evidence establishing a link between ibuprofen and worsening of COVID‑19.” On March 18, 2020, the WHO stated they “do not recommend against NSAIDs” in COVID-19. On March 19, 2020 the FDA recognized the concern for ibuprofen worsening COVID-19 symptoms, but the lack of scientific evidence directly linking NSAIDS with worsening COVID-19 symptoms kept them from making a recommendation. They did note that NSAIDs carry a warning that “the pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.”
While there are postulated risks of the use of NSAIDs in COVID-19, there is no proven direct cause of worsening of infection at this time. However, acetaminophen can be used as an antipyretic without the theoretical risks of NSAIDS. The only potential concern with NSAIDs and COVID-19 is that NSAIDs have been associated with a significantly increased risk of adverse events in geriatric patients and COVID-19 is known to have higher mortality in that same cohort. As in any geriatric patient (with or without COVID-19), NSAIDs should be avoided to minimize the possibility of acute kidney injury, stress ulcers, stroke, and CHF exacerbation.
1. Roth et al. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017; 125: 21-38
2. Radi ZA, Khan KN. Cardio-renal safety of non-steroidal anti-inflammatory drugs J Toxicol Sci. 2019;44(6):373-391
3. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231(25):232–235.
4. Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients. medRxiv. 2020
5. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?. Lancet Respir Med. 2020 Apr;8(4):e21