Q: Does ibuprofen make COVID-19 worse?



A: There is no evidence that ibuprofen or other non-steroidal anti-inflammatory drugs can make COVID-19 cases more severe. You should consult your doctor before changing medications.

FULL QUESTION

Is it true that using ibuprofen has been shown to worsen symptoms of Coronavirus?

I’m getting warning that Advil makes coronavirus condition worse in affected patients. Patients should only take Tylenol. Is there any evidence this is true?

Is it unsafe to use ibuprofen in the current outbreak of Covid-19 virus? Some state that it magnifies the symptoms of the virus by 10-fold?!

FULL ANSWER

Many readers have written in to ask whether ibuprofen or other non-steroidal anti-inflammatory drugs, or NSAIDs, can worsen COVID-19, the disease caused by the novel coronavirus. Other NSAIDs include over-the-counter painkillers such as naproxen (Aleve) as well as prescription-only pills such as celecoxib (Celebrex), which is used to treat arthritis.

The idea has been circulating on social media and also has been promoted to some degree by a few national governments. While there are some good reasons for certain patients to avoid NSAIDs generally, there is no evidence that ibuprofen — which is sold under the brand name Advil — or other similar drugs exacerbate the disease. Instead, the notion is simply a hypothesis that has not been tested.

Much of the hubbub over ibuprofen appears to have started with comments from the French health minister, Olivier Véran, who said in a March 14 tweet that taking anti-inflammatory drugs such as ibuprofen “could be a factor in worsening the infection.” He advised people with fevers to take paracetamol, the European name for acetaminophen, or Tylenol, instead. He also suggested that people already taking anti-inflammatories should consult with their physicians.

A few days earlier, a letter published in the British medical journal The Lancet Respiratory Medicine hypothesized that ibuprofen could make it easier for the new coronavirus, SARS-CoV-2, to enter cells. As we’ll explain, that’s possible, but there is no evidence yet to suggest that’s the case. There could also be positive effects of NSAIDs on the virus.

Soon after, inaccurate messages sounding the alarm about ibuprofen flooded social media networks and messaging apps. One of the viral warnings many of our readers asked about claims a lab in Vienna found that the “vast majority” of people who died from COVID-19 had taken ibuprofen and that a nurse at Vancouver General Hospital said, “Advil makes the virus 10x worse” and “kickstarts the virus into pneumonia.”

The message appears to be a modified version of a fake WhatsApp phone message circulating in Germany that also cited an institution in Vienna. The Medical University of Vienna called the messages “fake news” and told Politico that it had neither discussed the issue internally nor done any research on ibuprofen and COVID-19.

The name-checked Vancouver hospital has also been similarly targeted, with someone circulating a fake memo about ibuprofen and COVID-19 bearing the hospital system’s logo. The hospital system explains on its website that the memo “was not an authentic memo,” and told us in an email that they “did not issue” the message our readers asked about.

After an initial news report that a World Health Organization spokesman endorsed the recommendation to avoid ibuprofen, the WHO clarified that it did not advise “against the use of ibuprofen.”

The group said in a tweet that in its consultations with physicians treating COVID-19 patients, it has not heard of any negative effects of ibuprofen beyond its known side effects, and that it “is not aware of published clinical or population-based data on this topic.”

Q: Could #ibuprofen worsen disease for people with #COVID19? A: Based on currently available information, WHO does not recommend against the use of of ibuprofen. pic.twitter.com/n39DFt2amF — World Health Organization (WHO) (@WHO) March 18, 2020

Other medical groups and health agencies also chimed in, iterating that there isn’t evidence linking worse COVID-19 symptoms to ibuprofen.

For example, the National Institute of Allergy and Infectious Diseases, or NIAID, said in a statement that more research is needed, but there currently is “no evidence that ibuprofen increases the risk of serious complications or of acquiring the virus that causes COVID-19.”

Still, some governments are advising against ibuprofen for COVID-19 patients or recommending other medicines. England’s National Health Service, for instance, acknowledges that there is “currently no strong evidence” that ibuprofen can worsen COVID-19 symptoms, but recommends acetaminophen for people treating COVID-19 “until we have more information.”

So how legitimate is the concern? Experts told us that it’s possible ibuprofen could have a negative effect on COVID-19 patients, but it’s purely hypothetical at this point.

Potential Mechanisms

To begin to think about whether NSAIDs are a good idea or not for COVID-19 patients, it’s useful to review their chemistry and what they do in the body.

The drugs relieve pain and reduce fevers by blocking an enzyme known as cyclooxygenase, which prevents the formation of molecules called prostaglandins. Prostaglandins have a variety of effects, but generally promote inflammation, which is part of the body’s immune response.

In news articles, some scientists and physicians have proposed that ibuprofen or other NSAIDs could dampen the immune response to COVID-19 or otherwise make the infection worse, as some have contended is true for other respiratory infections. But as the NIAID has said, there is “no conclusive evidence that taking ibuprofen is harmful for other respiratory infections.”

And scientists who study these mechanisms say it’s not necessarily the case that NSAIDs would tamp down the immune system and hamper the body’s efforts to eliminate a pathogen. That’s because while prostaglandins are thought of as pro-inflammatory, some can have the opposite effect. And it’s not always clear whether a more or less active immune response is better. While a patient wants a robust enough response to clear the virus, too strong of a response can be deadly.

“The prostaglandins suppressed by NSAIDs can be harmful or beneficial in an inflammatory reaction like the one that proves fatal in COVID-19,” University of Pennsylvania prostaglandin researcher Garret FitzGerald told us.

In a letter published in the journal Science, FitzGerald called the French minister’s advice on ibuprofen “misguided,” and he outlined examples from the literature that demonstrate a number of different possibilities.

In one instance, mice infected with a different coronavirus were more likely to die when a particular prostaglandin was reduced because the molecule played an important role in limiting an overactive immune response.

But on the flip side, one prostaglandin can inhibit replication of the SARS virus, which is highly similar to the coronavirus behind the current pandemic. And researchers have previously found that the anti-inflammatory drug indomethacin can actually prevent the SARS virus from assembling its RNA genome.

There’s also some evidence that the SARS virus boosts prostaglandin production.

“Based on these findings, if we see a clinical signal, we can rationalize it,” FitzGerald wrote, “but therein lies the challenge. Many clinical anecdotes remain stalled in biological plausibility.”

In an email, FitzGerald cautioned that all of these pieces of evidence are from in vitro experiments in cells or in animal models with related, but distinct viruses. “So the message is that we need to do the basic research with COVID-19 itself and carefully model different stages of the human disease to see if there might be a place for NSAIDs or that they make things worse,” he said. “We are a long way off a public health advisory either way.”

He also found the recommendation for acetaminophen to be curious, since it also acts on cyclooxygenase to inhibit prostaglandin formation, albeit to a lesser extent than standard NSAIDs. So if there is a problem with the drugs and COVID-19, that doesn’t necessarily mean acetaminophen is a good choice.

Other scientists agree that it’s plausible that ibuprofen could affect COVID-19 patients, but that it’s simply impossible to say without more research.

“You could imagine that by using NSAIDs that you do change the balance of these prostaglandins and other small lipid mediators, and that that changes your immune response,” said University of Iowa coronavirus researcher Stanley Perlman.

“That being said,” Perlman added, “there’s not lots of data showing that you make an interpretable difference in these levels, and then how that affects outcomes. So right now, it’s really more speculative than anything else.”

The other main hypothesis for why ibuprofen might be especially dangerous for COVID-19 patients comes from a March 11 correspondence letter in the The Lancet Respiratory Medicine.

Much of the article, which was not peer-reviewed, discusses potential reasons why people with high blood pressure or diabetes appear to be more susceptible to COVID-19. The basic claim, which the authors later emphasized was only a hypothesis, is that these patients could be at higher risk because of the medications they take to manage these conditions.

Drugs known as angiotensin-converting enzyme, or ACE, inhibitors and angiotensin II type-I receptor blockers, they said, raise the levels of a protein called ACE2, which happens to be the protein the novel coronavirus uses to enter human cells. As a result, the authors argued, the drugs might “facilitate infection” and increase “the risk of developing severe and fatal COVID-19.”

Ibuprofen is not one of these drugs, but got a nod in a single, unsourced sentence that claimed that it, too, can increase ACE2 levels.

That fundamental claim, however, appears to have little to back it. Rachel Graham, a coronavirus expert at the University of North Carolina Gillings School of Global Public Health, told NPR that there’s virtually no evidence that ibuprofen raises ACE2 levels.

Indeed, we could find very little in the literature to support the idea — just one study suggesting ibuprofen could increase ACE expression in diabetic rats, and nothing about an impact in humans.

Even if it is the case that ibuprofen raises ACE2 levels in humans, that doesn’t necessarily mean taking the drug would make people more likely to catch the virus.

“Virus entry into cells is a funny business because viruses need very, very little receptor on the surface of a cell to enter it,” said Perlman. “So if you went from having zero to some, that would make it susceptible, but some to more may not do very much.”

Studies have shown that ACE2 is present in a variety of human cell types, including the epithelial cells that line the lung.

There is also some research to suggest that ACE2 may actually have a protective function — so it’s not a given that more ACE2 would be a bad thing for a COVID-19 patient. Although limited to a specific set of circumstances, one study found that ACE2 protects mice against lung failure.

“If there are effects on ACE2, ACE2 has both positives and negative effects in the infection by itself,” said Perlman. “So we just don’t know where it’s all going to come out.”

So, there are some possible ways ibuprofen or other NSAIDs might negatively impact COVID-19, but the biological plausibilities can also be spun in the other direction — and there’s certainly no evidence that ibuprofen makes the disease 10 times worse, as some of the viral messages claim.

There are nevertheless valid reasons for COVID-19 patients to avoid NSAIDs, if only because of their previously known drawbacks. NSAIDs have gastrointestinal, kidney and cardiovascular side effects, which may be especially dangerous in very ill or elderly patients or in those with preexisting conditions.

Stanford University pulmonologist Angela Rogers told NPR that most patients in the hospital for an infection would receive acetaminophen rather than NSAIDs, since those patients are at a higher risk of organ damage.

Given the side effects, Perlman said that not using NSAIDs is “probably a good thing” generally. But, he added, “that has nothing to do with COVID-19. That’s just the way NSAIDs work.”

For his part, FitzGerald does not recommend NSAIDs for COVID-19 patients, but doesn’t think patients in chronic pain, for example, should stop taking their NSAIDs and switch to opioids.

Indeed, without more evidence, no one can come to a firm conclusion about the effects of these drugs on COVID-19. In the meantime, patients should not change their medications without speaking with a physician.