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Coronavirus (COVID-19) Update: Early Safety Signals Around Ibuprofen and Renin-Angiotensin Inhibitors

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Ed Livingston: The world shut down because of COVID-19. Some wonder if the very substantial disruption in daily activities is worth it. The severe reaction to this problem has created something of a panic within the population. As a consequence, there are many rumors about what is or is not happening with this disease, much of it being spread through social media. To understand the reality of COVID-19 as it exists today, March 18, 2020, we spoke with one of the world's authorities on infectious diseases, Dr. Carlos Del Rio from Emory University about what is known about COVID-19 as of today. And we specifically asked him to comment on concerns people have raised about the use of ibuprofen, and the commonly used antihypertensive drugs such as ACE inhibitors, and angiotensin receptor blocking drugs (ARBs). In this special edition of JAMA Clinical Reviews, a conversation with Dr. Carlos Del Rio about COVID-19.

Female Voice: From the JAMA Network. This is JAMA clinical reviews. Interviews and ideas about innovations in medicine, science, and clinical practice. Here's your host, Ed Livingston.

EL: Could we start by having you tell me your name and title?

CDR: Carlos Del Rio, and I'm a professor of medicine and global health here at Emory University. I work in the division of infectious disease, and I'm also the Executive Associate Dean of Emory here at Grady.

EL: And you've been in the center of a lot of discussions about COVID-19, so could you give us a very brief thumbnail overview of where we are today, March 18, 2020, with the COVID-19 problem?

CDR: Well so here, let's limit to the US. I think in the US we're at a very critical time. We are at a time where we are concerned about where the epidemic is going. A lot of cases are coming in where an exponential pace of growth, and as a result of that we are seeing a significant increase in cases, and that is causing already strained our healthcare system, and we may even get more cases very, very rapidly. So we're all worried, we're all concerned. And we're all really trying to - I feel like I'm drinking out of a fire hydrant, right?

EL: Yeah, everybody is just overwhelmed by this. And it's been such a --

CDR: Right. And I'm and I'm very concerned about two things. I'm very concerned about people not necessarily taking it seriously. And I still see people reluctant to do what we need to do, especially social distancing, and sort of staying home, et cetera. And I also see the healthcare systems already getting overwhelmed. And I see that as being problematic, because, you know, this is going to be a marathon, not a sprint, and we need to be ready for that.

[00:02:46] EL: One of the reasons I wanted to talk with you today is because there are a lot of discussions going around in the popular media, in social media, about this disease that may either cause concern for people, or cause them to react this way you just described it, and not take it seriously. One of them is that the case fatality rate seems to be very low. So, some of the critics of the actions that have been taken to try to limit the spread of the disease have said, well, it's, it's really not that much worse than the common flu. Why are we doing all this? How do you respond to that?

CDR: Well, I respond three ways. Number one, it is 10 times more lethal than common flu. Number two, it's a new virus, so we're all - I tell people we're immunologically naked, right? We don't have immunity. With common flu even if you don't get the vaccine, you've had flu in the past. You got a vaccine at some point in time, you probably have some degree of immunity at a population level. And number three, for flu we have a vaccine. For this one we don't have a vaccine. But number four, for flu we have treatment. We have oseltamivir and other drugs. For this we have nothing. So that in my mind makes it very different than flu.

EL: The other issue that has been covered a lot in social media is ibuprofen and the possible risks for treating fevers or myalgia with ibuprofen and for patients who have COVID-19. What's the situation with that?

CDR: So, I have been, I mean, this is how rapidly things are changing, you know. Yesterday, two days ago, talking to colleagues and others. I was talking to a colleague in France Jean-Michelle Molina, and saying, you know, this is an exaggeration, why do we need to worry about this? Today, I read a lot of stuff, and feel very different. And, you know, we're learning a lot. There's a lot of hypotheses and observations being out there. But there is evidence. I mean, this virus binds and acts through the ACE-2, the angiotensin-converting enzyme 2 receptor, and therefore medications which up-regulate ACE may lead to worsening and bad outcomes. And I use may, because I think the evidence is still not very clear. And this medication may include ibuprofen as well as ACE inhibitors, and angiotensin blockers. And many of those medications are taken by the elderly and in patients with diabetes with hypertension and heart disease. And there was a paper, short communication, not even a paper in Lancet Respiratory Medicine on March 11 suggesting this as a possible mechanism. So, WHO has proceeded to alert us to avoid ibuprofen in suspected or confirmed cases of COVID-19, and recommended instead using paracetamol for fever.

On the other side of the evidence regarding the ACE inhibitors, ARBs, since too preliminary and most are not suggesting to discontinue ACE or ARB inhibitors. And again, that may change in a couple days. And I wish there was more information coming from China. China told us that, you know, hypertension was a risk factor. But, I mean, can they tell us what those people were receiving, because maybe we could have better information if they could analyze their data and give us more data. But there's very limited data. Talking to a colleague of mine in France, he says that it's one physician in an ICU in Paris who reported four severe cases among young men who had used nonsteroidals (NSAIDs). And, you know, this could be consistent with what we've seen in other viral infections. So, but there is very limited evidence, and I think a lot of decisions in this disease are being taken with very little evidence. But that's the case when you have a new disease. You know, I tell people, we're building the boat as we sail it.

[00:06:15] EL: Yeah. We're certainly in the middle of that at JAMA, and as you well know, we're getting as many as 100 papers a day describing various phenomena with this disease. It's hard to sort out what's really going on.

CDR: Very hard to sort out what's working, what's not, exactly.

EL: And especially since, like, one of the discussions we had this morning about the situation with ACE inhibitors and ARBs was that there's confounding in that population. Those are also those patients who have...

CDR: Absolutely. Absolutely, there's a lot of confounding. You're absolutely right.

[00:06:45] EL: So given the state, can you review for me, again, what belief the mechanism is for the nonsteroidals or ibuprofen and ACE inhibitors and ARBs, and the worsening of this disease? You said there's a receptor involved.

CDR: Well, it's the, you know, the angiotensin converting enzyme 2 receptor, and it's present in the lungs. It's present in large numbers in lung cells. So that's, and that's where the receptor through which the virus actually enter cells.

EL: I see. Okay. Well this is really helpful. So, I think your basic recommendation is to avoid ibuprofen given I guess this limited information?

CDR: I guess that's where I am today.

[00:07:25] EL: Yeah. And do you have any thoughts about the ACE inhibitors and ARBs?

CDR: So, what I've learned from ACE inhibitors and ARBs is that is we're probably okay, continuing. I'm personally taking an ARB, so I had a lot of questions about this. But after reading the literature, I feel comfortable continuing my ARB and not changing my antihypertensives.

EL: COVID-19 is a serious problem and merits concern by everyone, because it's a new infectious disease for which there is no immunity and no treatment. It's best to pay strict attention to what public health experts recommend for trying to minimize the risk of this disease's spread. Although the evidence is incomplete, there have been reports that people who have COVID-19 may do poorly if they take ibuprofen. Even though not much is known about this possibility, it's not a good idea to use this medication in the presence of COVID-19, and the World Health Organization recommends against ibuprofen's use for patients with known or suspected of having COVID-19. Similar data exists about ACE inhibitors and angiotensin receptor blockers, but this situation is more complicated because they're needed to treat hypertension. Currently, according to Dr. Del Rio, it's probably best to continue using these medications until more is known about their role in modifying the disease course of COVID-19.

Stay tuned to JAMA clinical reviews. We will be posting podcasts about the latest information about COVID-19 as new information comes our way. The other major source of information from JAMA about COVID-19 can be found in our new podcast, Conversations with Dr Bauchner. Our editor-in-chief Dr. Howard Bauchner has been interviewing international experts on COVID-19 who provided the most up-to-date information about this disease, and recommendations for how to manage it. Notably, there's been an interview with Dr. Anthony Fauci, the Director of the National Institutes for Allergy and Infectious Diseases at the NIH every week since coronavirus has been identified as a problem. I'm Ed Livingston, Deputy Editor for clinical reviews at JAMA. Thanks for listening.


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