Exclusive Interview with Dr. Anthony Fauci on his Perspectives on Long Covid

With medical anthropologist Dr. Emily Mendenhall

*Look for an analysis of this interview published in Scientific American this week!

There are few people in public health as notable and needlessly controversial as Dr. Anthony Fauci, the former head of the National Institutes of Allergy and Infectious Diseases at the National Institutes of Health. An embattled public figure who has served seven presidents and became a household name while leading the nation through the worst of the COVID-19 pandemic, Fauci has since joined the faculty of Georgetown University. As scientists delve deeper into Long Covid, the mysterious post-viral syndrome that has plagued thousands of people long after their initial infections, I sat down with Dr. Fauci to hear his thoughts on post-viral syndromes, and what we should be thinking about as more and more people who develop COVID-19 find themselves still sick, months later.  This interview has been edited for clarity and length.

Dr. Emily Mendenhall: It’s really wonderful to sit down with you. Thanks for making time to speak with me about Long Covid generally and your perspective on how research on post-viral syndromes have changed over time. Let’s begin by talking about the backstory of many of these conditions. Can you talk about your engagement with post-viral syndromes at NIAID?

Dr. Anthony Fauci: One of the main reasons I wanted to go to Georgetown is I am really excited about interacting with people in different schools like yourself and particularly the students, not only the medical students, but the undergraduate students. They really are a very inquisitive group of people who stimulate my thinking.

I have been asked, if I were to do it over again now, what would I consider to be a “hot” field in   my arena at the interface between immunology and infectious diseases? Because as you know from my history, I am a board-certified internist. But I am also board certified in infectious disease and I am a board-certified clinical immunologist. This is the classic example of being over trained. (Chuckle!)

Post-acute sequelae of infections have fascinated me from my very early years at the NIH -- and when I say early years, I came to the NIH 54 years ago. I did a fellowship from 1968 to 1971. I did my chief residency in medicine in 1971 and 1972 back in New York. When I came back to the NIH, because I was so well-trained clinically, I would get to see these unusual cases, many of whom were people on the NIH staff who needed a doctor, or “VIP” types in Washington a city with many highly educated health-seeking kinds of people who would present with interesting  symptomatology. And I was very struck by the fact that there were some people--and this was before chronic fatigue syndrome even had a name --who were very sick following what they perceived as viral infections. These infections were not diagnosed because we did not have the capability to do a PCR of somebody's nasal swab back then. Among my fellows and students, I used to call it post-viral asthenia. These patients would get a viral infection, and instead of the usual bounce-back recovery, there would be things about their demeanor and their ability to function, which were markedly compromised for variable periods of time.

And I could not figure out what it was. We did not measure inflammatory markers. We did not test for C-reactive proteins. We did not have D-Dimer tests. We did not have all the tools we now have to look at persistent inflammatory responses. But it was a real phenomenon. And then I thought back on what we all accepted when I was a kid: the sequelae of mononucleosis, the famous kissing disease. Unlike other infections, people who would get “mono” sometimes would be out of school for months at a time. They could not go back to school because they were so tired. I started to get really fascinated by this -- but then my interest turned to other things like HIV.

With SARS-CoV-2 infection, in-depth studies will be very useful, now that you have a well-defined, easily diagnosed viral illness. Years ago, when I was seeing all these people who would have something that triggered a prolonged change in their capabilities, you never knew what that original infection was. They would say, well, I had a sore throat, or I was sneezing a little bit a few weeks ago or a few months ago. Then, as the years went by, I became interested in some of the studies that showed that, following large outbreaks of severe influenza, there was a peak in myocardial infarctions, six months or so later. Some good research showed that a lot of cardiovascular myocardial infarctions are due to inflammatory responses on the intima which leads to unstable plaques. Over the years, and I am talking about over decades now, I found myself asking, “Well, why would it cause cardiovascular disease?” And then the studies from Harvard by Libby and others showed the intimal proliferation associated with inflammation.

So could it have been that something was going on with some people -- but not everybody. And that is the critical issue. There is going to be a group of people who somehow or another have a genetic predisposition, just the way you have a genetic predisposition to diabetes, or to rheumatoid arthritis, or to lupus. When these people get a viral infection, it somehow dysregulates multiple functions and organs systems. Activities of the brain, dysesthesias, autonomic nervous system, POTS syndrome, sleep disorders, all those kind of things.

That is the reason when people ask me, “What would you do now to combine infectious disease and immunology? I often reply that I would start looking at post-viral modulation of normal, immunoregulatory responses. For patients, this must induce psychological stress when you have a syndrome that nobody can explain, one that has something to do with your brain. For instance, brain fog can be a very frightening thing. Why can't I concentrate? To me, that is going to be one of the most important things, clinically, and that is a field that a lot of people are starting to get interested in.

One other comment is that when you look at all of the COVID-19 cohort studies, including the one at the NIH that was published by Mike Sneller and those  from other institutions, there is a large proportion of women. Maybe it is because they have a different kind of immunoregulation, and it is why they tend to get hyperactivity and autoimmune diseases more than men do. Perhaps they are more susceptible to the dysregulation of whatever immune response is triggering Long COVID. That may be the reason, just like you have more lupus in women, you have more dysregulation that is triggered by a virus.

Dr. Emily Mendenhall: What can Long Covid inform us about ME/CFS? How do you think about ME/CFS, and how have you seen the politics of chronic fatigue or post viral syndromes change?

Dr. Anthony Fauci: The uncertainty about the triggering element of the generic umbrella term of Myalgic encephalomyelitis/chronic fatigue syndrome made it very difficult to do studies. Even studies of factors that could be temporally related to the inciting event. The thing about COVID is that you know exactly what and when the inciting event was. You know about the antibodies that follow that inciting event. We never had that prior to COVID. It was always guesswork: do an immunological profile and do a screen of antibodies and what the patients had been exposed to. And often you find antibodies to everything. So, you do not have any idea whether it was this infection that triggered it, or another one that was a year later. Whereas with COVID, you have a window into the etiologic agent.

Dr. Emily Mendenhall: From your perspective, do you think we are in any position to say what makes someone more vulnerable for Long Covid?

Dr. Anthony Fauci: Say you get Covid and really get sick and you go to an intensive care unit and your body gets beat up badly. People who get very sick, who have organ system damage, who have trauma from almost dying, they may have lingering symptoms that get thrown in with Long Covid that is not Long Covid. They are just sicker than hell, and I have taken care of a lot of people who ultimately wound up in the ICU. And when they come out of the ICU, they are not the same for quite a while, particularly when they have been deathly ill.

Now let us assume Emily, and I do not know for sure, that there is some dysregulation that is triggering true Long Covid. You need to screen out all the others and really study the people who are not showing prolonged symptoms because their body got beat up. They are showing prolonged symptoms because of the virus. The virus may not have made them very sick. So now, if you only had a small-to-modest number of people who were infected with SARS-CoV-2, you would have to dump everybody in to get an “n” that is big enough. But if you design the study with very strict entry criteria -- not that the others are not Long Covid -- you may then be able to figure out what that genetic predisposition is. You know all kinds of stuff will get diluted if you throw everybody in the bucket. I am just giving you my scientific opinion as my experience as an immunology, virology, infectious disease guy. You have to get very pristine on the cohort that you study, because otherwise the dilutional effect will be too much. Having said that, we have millions and millions of people who fall into the Long Covid category. We surely will be able to get a study going that can track that down.

Dr. Emily Mendenhall: There is this group I have been following, called the Patient-Led Research Collaborative that is doing some really interesting work. People with Long Covid who have research backgrounds and have come together to generate hypotheses and do research and then inform the medical community. I know you have worked with a lot of patient communities over time, what is the role of these researcher-activists?

Dr. Anthony Fauci: I dealt with a lot of constituency groups, dating back from the original work that I did with the HIV/AIDS activists such as Act Up. So, I learned always to pay attention to activist groups. I think one of the things that is frustrating  is when you have people where you don't have a ready answer to them, and they're desperate for the answer. They get desperate and they act desperate. And that puts off the scientists a bit because when the scientists cannot do something, they just do not know what to do when they keep getting pushed by the group: You have to do something! You have to do something! I do not blame the people for doing that. If I had something that I knew was real, and I was not getting any answers to it, I would get very frustrated. But some scientists run away from it because they do not have an answer, but they get continually approached and pressured. And I am not saying the pressure is not justified. It is. But that is a negative signal to a scientist who likes to have their usual world where they see a concrete question, a way to get the answer. You get the answer. You publish the answer, and you build on that.

Given our biomedical research funding system, Emily, you know, people go to things that are almost sure bets for a result. What you need is young, imaginative, energetic investigators. But the system is geared that at the end of a certain time, where is your Nature paper? Where is your Cell paper? Where is your New England Journal of Medicine paper? And if you say I do not have it, I am working on something, I am working on something, you are not going to get funded next time.

So Long COVID really needs one of those long-range funding mechanisms like we had in the intramural program NIAID where we were able to work on things for years. If it was clear, you were doing good work, you were not pressured or feared that you were going to lose your job if you did not produce a result. So, this is a long, long-range project that should get long, long-range funding.

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Emily Mendenhall is a medical anthropologist and professor at the Edmund A. Walsh School of Foreign Service at Georgetown University. She was recently awarded a Guggenheim Fellowship for Anthropology and Cultural Studies for her work on COVID.