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March 17, 2020 -- A warning from French health officials suggests that grave adverse events have been reported with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, in people with COVID-19, and they recommend treatment instead with acetaminophen.

But many doctors, particularly outside of France, reacted on social networks saying there isn’t enough evidence for such a recommendation.

The Spanish Ministry of Health stated on Sunday that there is no evidence that ibuprofen (or other NSAIDs) makes COVID-19 infection worse.

British doctors broadly agreed, although they say acetaminophen is a better choice for infection in general.

One U.S. expert says evidence of risks to people with COVID-19 beyond those already well-known with infections in general and NSAIDs hasn’t been established.

On March 14, the French government reported "serious adverse events" linked to NSAIDs in people with COVID-19. Soon after, French Health Minister Olivier Véran tweeted that "taking anti-inflammatory drugs (ibuprofen, cortisone...) could be an aggravating factor of the [COVID-19] infection."

"If you have a fever, take paracetamol," Veran tweeted. "If you are already on anti-inflammatory drugs or in doubt, ask your doctor for advice."

Paracetamol is a generic term for acetaminophen commonly used outside the United States.

In a statement on its website, Reckitt Benckiser, maker of the Nurofen brand of ibuprofen, said: "Appropriate use of ibuprofen and paracetamol is still currently being recommended by most European health authorities as part of the symptomatic treatment of COVID-19. Reckitt Benckiser is not aware of any evidence that ibuprofen adversely impacts the outcome in patients suffering from COVID-19 infection."

The company "has neither received new safety information nor been involved in the evaluation of any adverse events regarding the use of ibuprofen in COVID-19," it adds. "As with any medicine, we would remind consumers and their caregivers to carefully read and follow the instructions provided on the packaging and in the patient information leaflet."

No Evidence of Any Unique Risk of NSAIDs in COVID-19

Gregory Poland, MD, a professor of medicine and infectious disease and director of the Vaccine Research Group at the Mayo Clinic in Rochester, MN, said that without clarification of any new data detailing effects, additional risks of NSAIDs related to COVID-19 are questionable.

Poland told Medscape Medical News: "I think there is far inadequate information to make a blanket statement like that [which the French Health Minister has made]."

NSAIDs, often recommended to relieve fever and symptoms of influenza as well as COVID-19, are well-known to have potential side effects on the stomach and kidneys in the very groups considered at higher risk of COVID-19 -- older people and those with other conditions or compromised immune systems. In those people, doctors commonly recommend acetaminophen as an alternative to treat fever for any cause.

"I think what [the French] are recommending is an overextension of the known concerns," Poland said. "I know of no published data on the use of NSAIDs with COVID-19 that represents any sort of unique risk," he stressed.

Poland cautioned against a rush to draw conclusions in times when stress and panic are exceptionally high. He mentioned a report from a colleague in which four severe COVID-19 cases were described as being among people who were taking NSAIDs, seeming to draw an association between the two.

"There was an inappropriate inference of cause and effect," he said. "This is a mistake we commonly see; people will assume causality and more often than not, it's not the case."

Meanwhile, the Spanish Ministry of Health stressed that while there is no evidence that NSAIDs make COVID-19 infection worse, ibuprofen package inserts mention that taking the drug might mask the symptoms of infections, which could delay diagnosis until more severe stages. But that refers to infections in general, not specifically to COVID-19.

The Spanish ministry is looking further into the issue of NSAIDs and COVID-19 and will publish its findings by May 2020.

French Experts Stand Their Ground

In exclusive interviews with Medscape France, a rheumatologist and an infectious disease expert gave their takes on the stance of their health ministry.

Francis Berenbaum, MD, PhD, a rheumatologist at Saint-Antoine Hospital in Paris, told Medscape France that in people with rheumatological diseases who are on long-term treatment with NSAIDs, therapy should not be stopped unless a patient starts to have COVID-19 symptoms such as fever.

For other people, Berenbaum says that if they develop a fever and COVID-19 symptoms, they shouldn’t take NSAIDs because it can worsen the disease (although he acknowledges this is also known in several other viral diseases including flu), and that it's better to take paracetamol unless there is a liver condition that prevents doing so.

Christian Perronne, MD, PhD, an infectious disease specialist in Garches, France, told Medscape France he believes the advice to avoid NSAIDs in COVID-19 infection is common sense.

Perronne told Medscape Medical News he has not personally witnessed cases of COVID-19 worsening with NSAIDs, noting that there isn’t yet enough perspective in France, but said this has been shown by Chinese results.

NSAIDs are not suitable for respiratory infections, Perrone stressed. He said he never gives NSAIDs in principle in respiratory infections, only in exceptional cases.

Perrone notes that an investigation requested by the French National Agency for the Safety of Medicines and Health Products (ANSM) last year confirmed that NSAIDs can have an aggravating role in the event of severe infection. He notes that ANSM stated in an April 2019 press release that there was a risk of serious infectious complications, with NSAID use in such instances.

France has tighter restrictions on the sale of NSAIDs than other countries. Beginning this year, the products, including paracetamol and ibuprofen, aren’t available over-the-counter there.

UK: Acetaminophen Better for Some, but Not Necessarily Due to COVID-19

UK experts agree that acetaminophen is a preferable choice over NSAIDs in those at risk for COVID-19 because of the known safety reasons.

"There is a good reason to avoid ibuprofen as it may exacerbate acute kidney injury brought on by any severe illness, including severe COVID-19 disease," Rupert Beale, MB, PhD, group leader in cell biology of infection at the Francis Crick Institute, London, UK, told the UK Science Media Center. But he added, "There isn't yet any widely accepted additional reason to avoid it for COVID-19."

Tom Wingfield, PhD, a senior clinical lecturer and honorary consultant physician with the Liverpool School of Tropical Medicine, UK, agreed.

"In the UK, paracetamol would generally be preferred over NSAIDs such as ibuprofen to relieve symptoms caused by infection such as fever," he told the UK Science Media Center.

"This is because, when taken according to the manufacturer's and/or a health professional's instructions in terms of timing and maximum dosage, it is less likely to cause side effects."

He underscored that more clarity is needed to determine the significance of the message from the French Health Ministry regarding the effect of NSAIDs on COVID-19.

"It is not clear from the French Minister's comments whether the advice given is generic 'good practice' guidance or specifically related to data emerging from cases of COVID-19, but this might become clear in due course," Wingfield said.

Corticosteroids and COVID-19

Poland noted that the French Health Ministry also recommends against the use of cortisone in COVID-19, which is consistent with recommendations by the World Health Organization and the CDC.

"Corticosteroids, though having a different mechanism of action than NSAIDs, are still noninflammatory and therefore seem [ideal] to use in an inflammatory disease," Poland said. "But the reasons for the recommendation against them is the observation that with SARS I, they not only did not improve the clinical course, but in fact appeared to have short-term and mid-term adverse effects in delaying viral clearance.”

But experts recommend that people taking cortisone or other steroids for chronic diseases shouldn’t stop them, except on advice from their doctor. Berenbaum, the French rheumatologist, reiterated this in his interview with Medscape Medical News.

Separately, the UK Society for Endocrinology has issued advice on coronavirus for people with adrenal or pituitary insufficiency who take hydrocortisone or other steroids.