Opinion | Breaking Down the Latest on Long COVID Research

In this Instagram Live clip, Jeremy Faust, MD, editor-in-chief of MedPage Today, and Ziyad Al-Aly, MD, chief of the Research and Education Service at the VA St. Louis Health Care System in Missouri, discuss the latest long COVID research and what it could mean for potential future treatments.

The following is a transcript of their remarks:

Faust: My first question is how many different diseases do you think long COVID is? Is it one, is it two, is it five? What do you think?

Al-Aly: Well, long COVID is really a multi-systemic disease. There’s no one long COVID; there are likely to be many subtypes.

Our understanding of long COVID now is actually literally embryonic. It’s in its infancy. We’ve made a lot of progress over the past several years, but we need to also recognize that we’ve only been researching this and understanding long COVID for literally only 4 years.

I tell people when we first started thinking and discovering neoplasm or tumor growth or cancer, we sort of defined, “Oh, this is a lump,” or, “This is a cancer” — and now we have 800 different types of cancer because we understand the biology more. We understand the molecular and genetic fingerprints of cancer much more deeply. We understand tissue-based biology of cancer much more deeply than we did, let’s say, 50 years ago. And long COVID is the same thing.

Long COVID is really this post-viral illness or the lingering or enduring problems that happen after SARS CoV-2 infection. We know so far it can affect nearly every organ system. It can affect the heart, the brain, can have metabolic sequela and we’re starting to see studies subtyping long COVID into different types.

There are cardinal manifestations that a lot of the audience might have heard of: brain fog, fatigue, post-exertional malaise, or some form of dysautonomia, or postural orthostatic tachycardia syndrome [POTS], or more broadly dystonia or a dysfunction in the autonomic nervous system that would lead to subsequent manifestation. Those are the cardinal manifestations. But really, there is no organ in the body now, 4 years into it, that long COVID does not touch.

Faust: One of the audience questions was whether you see a similarity between long COVID and ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome. And I’m really interested in this because on one hand I could see it being a good framework to understand these conditions as similar, but also could be a disservice if they’re different. What do you think?

Al-Aly: I think there’s a lot of overlap.

I mean, ME/CFS itself — to start with the origin of ME/CFS — is also thought to be triggered by a viral illness, by a flu-like illness. The onset of ME/CFS doesn’t happen in a vacuum. It actually is triggered initially by a viral illness. So, there are likely common etiologic drivers. It may not be the same virus, but it is triggered by a viral illness.

There’s a lot of overlap in the symptomatology — fatigue, brain fog, post-exertional malaise, POTS — there’s quite a bit of overlap in the symptomatology between ME/CFS and long COVID.

It doesn’t mean that all the facets are identical. It just means that it sort of gives us hints. The viruses are giving us hints that the viruses we thought initially only caused acute problems or acute disease can in some instances lead to chronic illness or chronic disease. ME/CFS is one example, COVID is another example.

And one of the arguments that I actually find really interesting is that had we as a community of scientists listened to ME/CFS patients a long time ago and really understood it better and [did] more research on it, we’d actually be better and more equipped and more able to address the challenges of long COVID more. We just ignored it. We literally had the Spanish flu pandemic, droves of people got disabled as a result. We just ignored them and ignored their plight. ME/CFS happened, and we just ignored them and ignored their plight. And we are now caught unprepared for long COVID.

Faust: This is like three questions in one. I often think of COVID as kind of like we are present at a supernova, and then we’re going to be living in the penumbra of that background radiation for the next billion years. It’s never going to go away. And that every single coronavirus that we call a “seasonal coronavirus” now at one point in the past had that supernova, we just weren’t present for it. Like you just described with influenza, 100 years ago humanity was present for that supernova.

Do you think that because of that, over time as the population gets more immunity and more exposures — which is not good — but over time, 50 years from now or even 10 years from now, that long COVID will become less likely as the population gains a sort of familiarity with it?

Al-Aly: It’s possible. We don’t know this for sure, obviously. I mean, we’re trying to sort of forecast 10 years down the road. It’s possible.

On one hand, it could be that the more immunity from repeated exposure could — I mean that’s a hypothesis, so it’s very, very key to make sure that the audience knows this is a hypothesis, I don’t have data for this — will sort of make then coronavirus infection less intense, coronavirus infection inconsequential, clinically inconsequential.

But it is also possible that repeated exposure can, in some individuals, can also alter the immune system in some ways that make them actually more predisposed to a variety of adverse events down the road. It’s really not clear, but I think this really deserves a lot more fleshing out and vetting over the next several years.

Remember we like sort of think about the pandemic — this is only the fifth year. I mean, our understanding of all of this is still literally in its infancy.

Faust: And related to that, what is your current hypothesis on what the cause is?

I’ll preface this by sharing a conversation I had with David Buller, who’s one of the lead authors of the metformin trial that showed that if you take metformin during your acute illness, there was a big reduction in downstream long COVID. David was really convinced it’s an antiviral property of metformin that is causing that.

And I said, “Well look, David, that may be true, but there also could be an anti-inflammatory component here — that it’s the body’s immune reaction.” And I was trying to convince him, I said, “I don’t know the answer, but if it’s an anti-inflammatory reaction, it’s a bigger deal because that would actually suggest that metformin might help with other viruses that might cause longer-term syndromes.”

Al-Aly: Yeah. So the David data is exciting, that finally something works. Metformin in the acute phase can actually reduce the risk of long COVID later on. We’d like to see that reproduced in other settings to elevate our confidence in that.

But going back to the mechanisms, at this point I sort of think that the viral persistence hypothesis is really compelling. There is clearly evidence, actually, in autopsy studies of people who have severe COVID-19 that there is viral persistence in extrapulmonary sites. Not only in the lung, but in the brain and in the coronary arteries, etc. So that sort of suggests that, at least in people who have severe disease — that’s not everyone — the virus actually might persist for a long period of time in extrapulmonary sites.

There’s also a lot of thinking and literature about that viral persistence potentially mediating some of the consequences that we see in long COVID.

The other hypothesis that I think is actually quite interesting is that of microbiome dysbiosis. So, viruses and bacteria actually interact. Viruses don’t only attack human hosts or human or mammalian cells or human cells, viruses are indiscriminate. They go and wreak havoc in all our systems, and guess what, in our system there are actually more bacterial cells, more microbiome cells, than human cells. The idea is that those are in some way disturbed, that ecosystem is disturbed, and that subsequently might lead to disease.

The immune dysfunction hypothesis is actually very, very interesting. Recently work came out of [University of California, San Francisco], really a wonderful paper, describing discoordinated response between the T and B cells, and that discoordinated response is really what drives much of the manifestations that we see in long COVID.

I think the super clever finding in that interpretation — beautiful, beautiful work — is that this maybe explains why long COVID is a tissue-based disease.

So you think about why is long COVID not a heart disease only or a brain disease only, right? It’s not organ specific; it’s everywhere. There’s no specificity. Actually, that’s one of the things that really puzzled us at the beginning — could this be true? Like, long COVID can do things in the heart and the brain and the GI [gastrointestinal] system and the kidneys — that’s not specific! But then they come up with a really clever explanation. If it’s immune dysfunction, it can actually explain the tissue-based disease hypothesis. So that’s also one other hypothesis that I think needs to also be fleshed out and evaluated further.

There is certainly inflammation during the acute phase — things happen and subsequently an inflammatory cascade is then engaged and then that might result in post-acute sequela.

I have to say for the audience, these are hypotheses. We don’t know that any of this really fully explains the human phenotype. A lot of these results are generated either in vitro, like totally cell-based data, or animal data. We don’t really know if this really actually explains the human phenotype of long COVID.

But I’m really delighted to see this engagement by the research community, immunologists and virologists, to really decipher long COVID and try to help us understand what’s happening here and how we can explain this very diverse phenotype. It’s not only heart disease, not only brain disease, it’s like all of the above. It’s like, can this be true?

Because I’m pretty sure in training we also think of disease as an organ system-based disease. Even specialties are around cardiology, neurology, GI — so even specialties are sort of based around organ systems, right? This is how our brain is trained. Even fellowships are organized around that concept. So this sort of challenges that a little bit because it’s literally a multi-system disorder.

Faust: Yeah. I mean, it reminds me as an emergency physician of sepsis in a way. In terms of that it’s not necessarily just the virus or just the pathogen. It’s the host response to that, and that can be anywhere, anywhere you have an immune tissue in your body — which is everywhere, head to toe.

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