Medical Examiner

We’re Not Going to Know How to Treat the Coronavirus for Some Time

A debate over whether you should take Advil or Tylenol right now is a window into the complicated medical situation facing experts.

A bottle of Advil and a bottle of children’s Tylenol.
Slate

Should you take ibuprofen right now? Does doing so make you more susceptible to the coronavirus? Even mainstream news agencies have conflicting headlines and information on this. The BBC says it is probably fake news. The Guardian says it might be true. The original advisory is in French and does not provide data backing up its position. What is going on?

The mixed-up information in the press traces back to uncertainty in the medical community. The origin of the advice can be tracked to a paper in a major medical journal, the Lancet published last week. Some scientists suggested that, since coronaviruses bind themselves through an enzyme on lung cells, then drugs that act via that same enzyme might make patients taking these drugs more likely to get sick from COVID-19. Such drugs include certain anti-hypertension drugs, as well as nonsteroidal anti-inflammatory drugs (“NSAIDs”) like ibuprofen (Advil). It quoted data from three other studies on COVID-19 to posit that maybe this was why most of the sickest patients had diabetes and hypertension, because those populations would have been on this kind of drug.

It’s difficult, but in these uncertain times, academic letters in prestigious medical journals (many of which are rushing COVID-19/Coronavirus/SARS-CoV-2 articles) should not be taken as gospel. They should be translated in our nonacademic sphere as “Hi guys, we noticed this. We are not sure yet, but let’s all keep an eye out. It might be dangerous, and meanwhile, we’ll keep one another posted.” In military speak in the Air Force, it is a bit like “check your six” (look out for a possible enemy at your 6 o’clock position — no, we don’t know who they are, and they haven’t fired yet, but what else could someone be doing in that position, apart from attacking you from behind?).

The main problem with interpreting early epidemiology data like this is “correlation does not imply causation,” a common phrase that is perhaps particularly tricky to remember when things are tense and our desire for information is high as it currently is. Here is a simple illustration I remember from my medical school days: If the number of hairdressers in a City A increases over time, in proportion with the number of brothels, while the number of hairdressers in City B decreases over time, also in proportion with the number of brothels, does that mean that brothels are the cause of the increasing number of hairdressers (or vice versa)? Not necessarily—a third factor could be behind the increases or the decreases; one city could be experiencing growth for another unrelated reason while another is dwindling. But there’s also a potential of a connection, a factor that makes us take a correlation more seriously, which we call “biological plausibility.” Biological plausibility means that, based on how we think our cells work, the theory might be true. In the brothels/hairdresser example, the “biological plausibility” link could be that the only customers of hairdressers were brothel workers, so more brothel workers needed more hairdressers.

In last week’s Lancet paper, there were many patients with diabetes and hypertension in the three studies, and there was a “biological basis” proposed, in that the drugs and the virus both focus on the same enzymes. But it could still be a hairdressers-and-brothels correlation, because patients with diabetes and hypertension are probably not as healthy as patients without any other medical problems at all. Also, the data for this letter was drawn from three different studies, which makes it less likely to be a fluke (for the nonmedical readers, that is like reading the same headline across three unrelated, competitor newspapers).

Now, for the French warning. The website says avoid nonsteroidal anti-inflammatory drugs (NSAIDs, or “anti-inflammatoires non stéroïdiens (AINS)” in French), of which ibuprofen/Advil is one of the most commonly used. Some of the (unverified and possibly untrue) social media messages say, young people are especially at risk if they take ibuprofen.

Without better data, it is difficult to get scientists to put their reputation behind both parts of this advice—that drugs like ibuprofen might make you sicker and that this is especially if you’re young. The conundrum is: Ibuprofen is such a commonly taken over-the-counter drug that the stakes are high if we stand by the warning to avoid it. At the same time, with that earlier paper pointing out the ACE2 enzyme with its “biological plausibility,” and the whole world dealing with a disease we know so little about, it is also dangerous to completely discount it, if it does turn out to be true.

But even as we get more information, it will be hard work to sort out causation. This is a disease with fever as the primary symptom. Generally, patients are advised to take acetaminophen (Tylenol) first, and only take ibuprofen if the fever still does not go down. This will introduce another wrinkle in the data eventually, as it will be hard to differentiate between, say, the patients who had much a higher fever and took both Tylenol and Advil, because they had a much more severe disease, and the patients who were less sick, and just took Tylenol, because that was enough to control their fever.

As for the “young people” rumor, there might be an entirely different explanation for this association. Older patients are often warned not to take ibuprofen, because ibuprofen has more side effects on the kidneys and a higher risk of stomach ulcers than acetaminophen. So, if there were data showing that more of the younger sick COVID-19 patients took ibuprofen/Advil than the older patients, it is hard to conclude that that is definitely why they were sicker, without knowing how many healthy young patients with only mild COVID-19 also took Advil. (And, in many overwhelmed countries, the authorities are telling us to self-quarantine for mild illnesses, so we don’t even know if this data will ever be collected.) This number is what we call the “denominator” (people not sick or mildly sick who were exposed to ibuprofen) in statistical comparison, and without it, it is difficult to come to conclusions, even if we have the “numerator” (people very sick who were exposed to ibuprofen).

There is still a possible biological link (based on that ACE2 enzyme in the Lancet paper), but again, the hairdresser-brothel conundrum remains, without any data this time. That is why it is hard to get a coherent “expert opinion” on this study. Meanwhile, the physicians, data collectors, and scientists who are behind the warning are too busy dealing with the epidemic to “clean up” the data for any formal public or academic presentation or analysis. The rest of us armchair analysts are left with our “expert opinions.”

The conclusion, for now, really is that there are some things on which we don’t know what to advise, which is why the media is all over the place on this. The strongest advice I can give is: If you want to act out of an absolute abundance of caution, take acetaminophen and do good old-fashioned other cooling measures (like wet sponging) first. But the one thing we know for certain is that there are some things that even the experts aren’t sure of precisely what to do right now. If it makes you feel better to clean everything with a round of vinegar after you’ve washed with soap—no harm doing it (as long as we don’t have a vinegar run on supermarket shelves). Realize specific medical advice around treating this virus is going to be touch-and-go for some time. Something the experts are sure about, and unanimous about though: We should all keep our distance and our hands clean.