Here’s What We Know About Long COVID, Three Years Later

KATHLEEN DAVIS: This is Science Friday. I’m Kathleen Davis.

MADDIE SOFIA: And I’m Maddie Sofia. Just a few months into the pandemic, it became clear that the SARS-CoV-2 virus was causing a cascade of symptoms that last months after initial infections, what we call long COVID, and as long as the pandemic barrels on, the population of long COVID patients will continue to grow.

Now, there’s a mountain of research about long COVID seeking to better understand its underlying causes and mechanisms and to improve treatment. Joining me now to give us an update on the latest long COVID research are my guests Hannah Davis, cofounder of the Patient-Led Research Collaborative based in New York City and coauthor of a recently published review on the state of long COVID research, and Dr. Bhupesh Prusty, principal investigator at the Institute for Virology and Immunobiology at the University of Wurzburg in Germany. Thank you both for joining me.

HANNAH DAVIS: Thanks for having us.

BHUPESH PRUSTY: Thank you.

MADDIE SOFIA: OK, Hannah, I think we should start off by saying that even fairly mild cases of COVID can lead to long COVID. This idea that people only develop long COVID if they get really sick is a misconception, right?

HANNAH DAVIS: Absolutely.

MADDIE SOFIA: And can you talk to me a little bit more about that and how many people around the world have long COVID in general? I know that’s kind of difficult to estimate.

HANNAH DAVIS: It seems like there is a minimum of 65 million people worldwide with long COVID, given the amount of infections that have been confirmed but also the amount of infections that have gone unconfirmed due to lack of testing. It is a serious number, and the majority of these cases happened after mild acute cases.

MADDIE SOFIA: Where did this idea that only people that got hospitalized got long COVID, where did that come from?

HANNAH DAVIS: I think that there have been a lot of misframed narratives over the course of the pandemic, and that is a serious one that really got traction, even though there was never really any truth. It is the case that if you are hospitalized, your odds of getting long COVID are much higher, but because hospitalized patients are such a small fraction of infections, the majority of long COVID happens after a mild infection.

MADDIE SOFIA: Dr. Prusty, let’s talk about a disease that can occur after viral infections often called ME/CFS, or myalgic encephalomyelitis, chronic fatigue syndrome. You’ve been studying it for years prior to the pandemic, and now you’re studying long COVID as well. Can you talk to me a little bit about how those illnesses are similar or overlapping?

BHUPESH PRUSTY: I believe that, without knowing ME/CFS, we possibly cannot long COVID. In this regard, we are in a unique position as we are studying both the diseases in parallel, and there are only a handful number of places where this type of parallel studies are going on. And I think this is the key to success.

What we have been doing in the past is to understand the development process of ME/CFS, and ME/CFS is believed to be a postviral illness and is also believed to be a mitochondrial disease. And after the pandemic, we got the opportunity to prove this hypothesis that ME/CFS-like conditions can also arise after a viral infection, so here, the SARS-CoV-2 infection.

MADDIE SOFIA: Right, and so there are a set of symptoms that are very similar that long COVID can cause ME/CFS. Can you talk to me about a few of those?

BHUPESH PRUSTY: So it’s not very clear that if every patient or long-COVID patient will develop into ME/CFS. So certainly, there are small subgroup of long-COVID patients that develop ME/CFS. The common symptoms between ME/CFS and long COVID include the namesake fatigue, but this is not the whole story. Patients have neurological issues, including brain fog– the interesting thing is that not every patient has all the clinical features that we talked about. Some patients have different symptoms.

MADDIE SOFIA: Right, and one thing that struck me, Hannah, when I was reading your paper is just how long COVID can affect almost any part of the body, so many different systems and organs, the heart, the lungs, the gut, the immune system, the reproductive system, neurological symptoms. How does long COVID have the capacity to affect so many different parts of the body?

HANNAH DAVIS: That’s a great question. I think our whole society really thinks of the body as separated parts. The brain is different from the heart. It’s different from the nerves, et cetera.

But really, that’s kind of a misunderstanding. Everything is connected to everything else. And when you have something like long COVID that seems to have a pretty significant endothelial dysfunction, for example, meaning that it affects the blood vessels, you’re going to get symptoms and pathologies across many different organ systems. So it’s not unrelated, actually. It’s related to an underlying systemic pathophysiology.

MADDIE SOFIA: Right, any time you get the blood vessels involved, you’re in trouble, kind of.

HANNAH DAVIS: Absolutely.

MADDIE SOFIA: OK, so we have a pretty good idea of what parts of the body long COVID affects but less of an idea of the underlying causes, right, Dr. Prusty? Researchers like you around the world are trying to get a better understanding of the underlying mechanisms of long COVID. What’s your hypothesis?

BHUPESH PRUSTY: When we talk about hypothesis, there are many hypothesis in the market, and possibly, in my opinion, all hypotheses are correct, but then the question is how to thread them all together, giving a meaningful explanation for the development of this disease. The most important or most widely discussed hypothesis are the presence of persistent virus, causing multisystem damage.

But our hypothesis is a little bit different. We believe that it is not the SARS-CoV-2 which is directly responsible for the disease. We believe that other latent viruses, like herpes viruses, they are reactivated after the SARS-CoV-2 infection. So SARS-CoV-2 infection is the first hit, and afterwards, we get this reactivation of these viruses, which are key players. And they cause widespread mitochondrial abnormalities, including changes in metabolism and energy levels.

These herpes viruses proteins, they are similar to many of our host proteins, so they act like our own protein. And they control secondary clinical features, like auto-antibodies, endothelial dysfunction, the microclots, allergy, overlapping symptoms with other clinical conditions. So many different conditions can be explained. Clearly, there is inadequate information available at this moment, so we need to understand it better and develop more innovative strategies to tackle the issue.

MADDIE SOFIA: So let me see if I’ve got this. So I think a lot of times we think of viruses like, let’s say, you get mono in college, Epstein-Barr. You get that. You heal from it, and you’re done with it.

But that’s not the case. These viruses can hang out in our cells, in our body. And then something like SARS-CoV-2 comes along, and it rewakes it up and causes another cascade of different symptoms. So these viruses are hanging out, and then another virus can activate them. Is that about right?

BHUPESH PRUSTY: Yes, exactly.

MADDIE SOFIA: I understand that this area of research– chronic illnesses in general have been understudied, I think, it’s fair to say. Has the pandemic and the arrival of long COVID brought more attention to your work, Dr. Prusty?

BHUPESH PRUSTY: One benefit from the pandemic is that patients, clinicians, and basic science researchers are now much more in touch with each other now than before, and the knowledge base of long COVID is bringing more and more researchers and innovative tools into the field, which is really good.

MADDIE SOFIA: Right. Let’s talk about some of the opportunities ahead of us. Let’s talk about potentially treatments for long COVID. Rest might actually be the most important, right, Hannah? Talk to me a little bit more about that.

HANNAH DAVIS: I think that’s something that the public needs to know about, which is that rest in the early weeks after the acute infection may be able to prevent long COVID. We absolutely need more research into this, but it seems very promising. And the reverse is also true that people who rest for three or four days after COVID and then try to get right back into their exercise routine often find themselves bedbound for a year, two years, et cetera. We need to understand why that’s the case so that we can do further understanding into what’s happening.

But more important than rest, we need widespread clinical trials both for drugs that can be repurposed for long COVID and drugs to develop for long COVID. And those drugs need to all be based on the hypotheses of people who have been working in the field of ME/CFS for years because this is just not at all a simple disease. This is a really complex multisystemic illness, and we need experts who understand it at the forefront of this research.

MADDIE SOFIA: Yeah, can I talk to you a little bit about the research Hannah? We know that racial and ethnic minorities disproportionately get COVID because of where they work, how much time you can take off, and we’re seeing those disparities in long COVID as well. Do you see this being addressed in research in treatment? Do you see patient-centered and focused research in that area?

HANNAH DAVIS: For the most part, not yet. There’s still a lot of research done without patient involvement. There’s still absolutely no support systems for people with long COVID, financial support, even clinical support. The experts who do know about these conditions number in the dozens, in the US at least, and the waitlists for all of them are nine to 12 months, if not longer.

So right now, yes, all patients are generally being left to flounder and do what they can on their own. But I don’t think it is understood how urgent this problem is and how many resources need to be directed toward it.

MADDIE SOFIA: OK, that makes a lot of sense. I want to ask you about something I read lately, some new research suggesting that getting reinfected with COVID increases your chance of developing long COVID. Dr. Prusty, are you familiar with that? Do you know why that might be the case?

BHUPESH PRUSTY: We can always argue if our hypothesis is, again, correct. Then the more frequently you get infected with COVID infection, the chances of reactivation of these herpes viruses are more and more. So it’s not– it’s nothing to do with the number of– the repetition of the infections, rather the possibility of reactivation, the chances of reactivation are even higher. But definitely, we need more research into this process.

MADDIE SOFIA: Dr. Prusty, let’s turn to identification. You’re working on biomarkers to identify two different subsets of long-COVID patients, and biomarkers are just tests we can run or things we can find in the body to determine if a disease is present. Now, one of these groups are people that just might take extra time to recover from that initial infection and get better after about two months, and the other group are those with symptoms that are much more debilitating and remain for months and months, six months, a year, or more. Why is it so important to differentiate between these two groups?

BHUPESH PRUSTY: So the whole idea of long COVID and its similarity to ME/CFS lies here. So typically, ME/CFS is a disease where patients, they start the symptoms, and over a period of time, like from several months to several years, they just pass on to a stage, where it seems that there is no coming back, yeah. So this is typically the ME/CFS.

Long COVID is still very fresh, very new. We are only knowing it from the last two to three years, so we still do not know exactly if the long-COVID patient will have a similar fate like ME/CFS. But we clearly know that a group of long-COVID patients or so-called long-COVID patients, they revert back. They come back to normalcy.

And we have seen with ME/CFS also that a large number of patients also return back to normal living conditions. So we believe that there is a sort of a switch in our body, and the switch is made on at a certain point of time, where there is not easy coming back. And we want to identify this switch basically.

So what we hypothesize here is that our body’s response system, we call it as a cell danger response system. Every cell knows that there is a danger coming, and the body knows how to switch on and switch off this system. Now, at one point of time in ME/CFS patients, we know that the system is switched on, and it is not made off.

So the body always responds to a threat or infection-like condition going on in the body, and that’s what differentiates the patients with long-lasting symptoms and the patients who will recover. And there is the key, which revolves around the mitochondria, how mitochondria coordinate with other cells, and our core focus of our work is to understand the entire process around here.

MADDIE SOFIA: If you’re just joining us, I’m talking with Hannah Davis, cofounder of the Patient-Led Research Collaborative, and Dr. Bhupesh Prusty, molecular virologist at the University of Wurzburg in Germany. This is Science Friday from WNYC Studios.

Before we let you go, I want to ask you both what needs to happen. Obviously, a lot of our long-COVID problems would be solved if we had adequate COVID prevention, equitable access to health care and rest. But what can medical professionals be doing right now? Dr. Prusty, why don’t you start us off.

BHUPESH PRUSTY: The problem cannot be solved at the ground level with the general practitioners because the disease is so complex. It involves multisystem issues. There has to be centers which can handle these type of patients.

MADDIE SOFIA: Hannah, what do you think? Do you think there’s a role for general practitioners here?

HANNAH DAVIS: I would agree with Dr. Prusty. I really think that one of the things we’re facing is this just serious lack of both provider and researcher education into postviral illnesses. I mean there’s not a lot of research on it, but a study done a couple of years ago showed only 6% of schools actually teach these illnesses. And that has translated into really awful care for patients and also, yes, research where people are starting absolutely from scratch and not building off the massive amount of research done in myalgic encephalomyelitis and dysautonomia.

So I would say that a mass provider and researcher education program needs to happen. One thing we took away from our review is that there’s just so much research that’s out there. We keep hearing there’s not enough research in long COVID and ME/CFS, but we had 300 studies that we had to pare down to the 200 studies that ended up in the review, all biomedical findings, all consistent with work that’s been done before in this field across many different things, like deformed red blood cells, reactivated herpes viruses, neuroinflammation, et cetera. And we just need everyone to get up to speed on these things.

MADDIE SOFIA: Thanks to both of you for being on Science Friday.

HANNAH DAVIS: Thank you.

BHUPESH PRUSTY: Thank you.

MADDIE SOFIA: Hannah Davis, cofounder of the Patient-Led Research Collaborative based in New York City and coauthor of a recently published review on the state of long-COVID research, and Dr. Bhupesh Prusty, principal investigator at the Institute for Virology and immunobiology at the University of Wurzburg in Germany.

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