74 - Dr Walter Koroshetz - Director of NINDS on Long Covid Research at the NIH

Episode 74 of the Long Covid Podcast is a chat with Dr Walter Koroshetz, Director of the National Institute of Neurological Disorders & Stroke, part of the National Institute of Health in the US.

We chat through the RECOVER Initiative which is a huge study looking into all aspects of Long Covid, and also talk a little about ME/CFS research done by Dr Avindra Nath.

Links:
https://www.ninds.nih.gov/about-ninds/who-we-are/directors-corner

Transcript available under the "transcript" tab HERE
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For more information about Long Covid Breathing courses & workshops, please check out LongCovidBreathing.com

(music credit - Brock Hewitt, Rule of Life)

Transcript

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Jackie Baxter  0:00  
Hello, and welcome to this episode of the long COVID Podcast. I am absolutely delighted to welcome my guest today, Dr. Walter Koroshetz, who is the Director of the National Institute of Neurological Disorders and Stroke. I think I've got that right - part of the NIH and the US. So there's absolutely loads up for discussion today. And I'm really looking forward to it. So welcome to the podcast. 

Walter Koroshetz  0:26  
Thanks Jackie, it's a pleasure to be here today

Jackie Baxter  0:29  
Fantastic. So to start with, would you mind just introducing yourself a little bit and just saying a little bit more about what it is that you do?

Walter Koroshetz  0:37  
Yeah, pleasure to be here. I'm Walter Koroshetz. I'm Director of the National Institute of Neurological Disorders and Stroke. And we're the agency here in the US with regards to future health, and we fund research on a whole bunch of different neurological disorders, stroke, epilepsy, rare genetic disorders. Then about 10 years ago or so we became involved in trying to understand what was the source of trouble in people suffering from myalgic encephalomyelitis/chronic fatigue syndrome. We're working with Dr. Fauci's Institute NIAID. And then when covid came we put together to try and develop treatments that can prevent death and neurologic disability, after acute infection. 

Then what happened after that is that, you know, many clinics started to take care of people, as they came out of intensive care units. However, these quickly got filled with people who are never even hospitalized, but who had Covid, and still suffering from long COVID. And then Congress appropriated over a billion dollars - $1.15 billion to the NIH, to study what we call the post acute sequelae of COVID. That includes long Covid, but it includes a lot of other things that are related to the long term health of people after they've had COVID. 

And so with the National Heart, Lung, and Blood Institute, which is really the lead to what's called the RECOVER initiative, we've been working to try and understand the problem, then hopefully move on to testing treatments to see if they can bring relief to people who are still suffering with these symptoms, long after their acute infection. So that's kind of how we got here today.

Jackie Baxter  2:44  
Sure, thank you so much. And you kind of just touched on it there. Obviously, people with long COVID. We just want someone to come along and give us something that will fix us. That's the goal, right? But in order to get to that, there's so much research and so much work that has to go into it, isn't there?

Walter Koroshetz  3:06  
I think that, you know, the lesson that we learned in working with ME/CFS was that it's a really hard problem. So the conditions are quite similar. Not identical but very similar. And they come under this group of conditions where people continue to feel bad, weeks or months, or sometimes years after their acute infection is over. And that occurred in the past in infections like Lyme disease or Epstein Barr Virus. But now we're seeing it to a degree we've never seen before with Covid. And we've never been able to figure it out. 

But there's a lot of hope because in the past, people would come to attention years and after they had what sounded like an acute infection. But no one could ever figure out what the infection was or if it was really an infection at all. So the situation has really changed now where now you have millions of people, all have the same infection, very similar syndrome to ME/CFS. And you can actually study people from the time they get infected right through to where they either make a good recovery or not. So the chance of getting at this underlying problem that vexed us for so long, is really right in front of us and the RECOVER initiative was really put together to try to attack this problem.

Jackie Baxter  4:43  
Yeah, exactly. The sort of sheer well number of people all at once, isn't it? Yeah. You mentioned the RECOVER initiative. I'd love to talk a bit more about that. I mean, I think it's a really big thing, isn't it? 

Walter Koroshetz  4:59  
Well, now as we were just talking, you know, we thought that this was going to be an easy problem, then you know, people all over the world are studying it and, you know, someone will come up with the answer very quickly. But it's not an easy problem. And that's what we've built RECOVER to kind of be the backstone, should there not be a quick answer. RECOVER was set up to be kind of all comprehensive study of this condition. And it has multiple different components to it. As we give thought to one unique ability we have now exactly to enroll people who are now just getting infected, we can then follow them over time to see who makes a good recovery, who doesn't, and then to compare them to see if we can see what the difference is. So that's really a neat situation. Certainly, we could never do that with ME/CFS, because we just didn't have the numbers. Now we can actually study right from the beginning. 

So one of our cohorts is the Covid acute infected cohort. The other cohort - we actually have the numbers, our latest numbers are acute infection in adults we have 2635 people already enrolled in that study. Then we have people who have long COVID, and we compare them with people who had COVID but then became normal again, so that allows us to compare those people. And we actually have now 6488 of those folks inrolled in the study. And we have a comparison group that's the uninfected of 1000 people. And about, like 945 people who had Covid and are asymptomatic there, we have the ability to compare these different patient groups, which is really quite an opportunity to see what the differences are. 

Those are the cohort studies, you also have live electronic health record studies going on. And they're the ones that have come up with data most quickly, because they have access to about 60 million individuals in the US, their health medical records. Unfortunately, the UK is in much better shape because they have access to the National Health Service data. The US we have to kind of pull it together. But we have indeed been able to do that. And so they're off and working. And the other thing about that group was that that can be set up to look 10-20 years down the line, see what the effects of Covid are on things - like common things like heart attacks, or strokes, and maybe even uncommon things like different autoimmune disorders. So that set up for a long way. 

Now, the other thing about a condition like this is that you study people who have the disorder, and you are stuck with examining say blood or urine or saliva. But those tissues may not have the answer. So we also have in Recover is an autopsy study, who are looking, talk to the families of people who die for whatever reason, but if they had post acute sequelae of Covid or Long Covid. And their families allow their tissues examined. That's when we can look you know, under the microscope at the heart or the brain or the GI tract. And that gives you a really powerful ability to look for abnormalities. So that's also up and  going. Then we are just beginning now to set up to do clinical trials. And people would want those. So that's all the different components to the RECOVER Initiative, as I said it was built to be kind of all comphrehensive, leave no stone unturned type of study.

Jackie Baxter  9:32  
Yeah, I mean, it sounds amazing. I mean, the sheer numbers that you just mentioned. I'm sure I spoke to somebody whose name I cannot remember. He was saying that actually a lot of the problem is getting people involved in research and getting the numbers in order to then get the data to look at. So it sounds like you've got a lot of numbers there, which hopefully will allow you to find something useful.

Walter Koroshetz  9:58  
Well, let me just say that. you know, that was a really good point that we have now, upwards of 14,000 people have already enrolled in the study. So they're the real heroes who want to you know, volunteer to get poked and prodded and get all these tests done. And you think about it, people have symptoms that they might join that they want to find the answer for themselves. But also, we have a lot of people who have made a great recovery and  they volunteered to help us out, so they're the real heroes.

Jackie Baxter  10:33  
Yeah, I mean, that's a good point. And we were talking about comparing the people with long COVID, with the people without long COVID, and the people who've recovered. And that's a really good point, because, you know, looking at the people who have recovered, what makes them different to the people who haven't? And I guess that's going to hopefully give some answers, isn't it?

Walter Koroshetz  10:50  
That's exactly right. That's really the goal of RECOVER. What's different between those two groups? Now, there's two things to think about, it could be that the infection affected them differently. Or it could be that they respond differently to the same insult. So that's kind of the two major groups that you'd be trying to understand. And that's, you know, incredibly important if you're trying to develop treatments - to know what it is that's the underlying cause.

Jackie Baxter  11:25  
Yeah. And that's the million dollar question, isn't it? What is the underlying cause?

Walter Koroshetz  11:30  
Well, there's no shortage of culprits, unfortunately. So it's really a matter of trying to nail down. And it could be different culprits for different people. But you know, the, there's about four things at the top of most people's list. One is that the virus is still present somehow in the body. And it's still stimulating the immune system, whether it's live virus that's still replicating, or whether it's dormant virus or, or whether it's just particles of the virus that just got incorporated into his tissues. Well, any of those things could be creating continuous stimulation of the immune system. And of course, it's stimulation of the immune system that is known to cause all these symptoms of long COVID. 

And then, I mean, the other possibility is that there's an autoimmune disorder. Because when you do have COVID, your body makes a big immune response. And it produces antibodies and produces cellular response to kill the virus. But we know that that response kind of overflows, and causes antibodies against your self antigens. So normal parts of your body can also be misinterpreted by the immune system as being part of the virus. And that's what we call autoimmunity. 

Another possibility is that the infection affected the immune system, and made it really rev up and never kind of resets. And that would be a immune dysregulation problem. And then the other one is that turns out that there are a lot of viruses, that we get infected with that lie dormant in our bodies. And when you have an infection of any kind like COVID. Similarly, you can get reactivation of these viruses, they start to pop up again. So I think those are the kind of four leading theories, which we, you know, we're trying to track down. And as I said, it could be different in different people.

Jackie Baxter  13:43  
Yeah, of course, so the same virus. So COVID, in this instance, could have triggered any of those sorts of reactions that you just said, or I suppose even a combination of more than one of them possibly?

Walter Koroshetz  13:57  
Yeah, no, that's true. Yeah. I mean, in the acute infection, all those things happen. The issue is what happens over time after the virus is cleared from your respiratory tract, and you're no longer positive on those tests. Which of those four is still not calming down?

Jackie Baxter  14:16  
Yeah, definitely. And I found it really interesting what you were saying about being able to track people from literally from date of infection all the way through to say 20 years down the line, which seems a sort of insane amount of time in the future, doesn't it when you think about it right now, but I suppose having that amount of data would be amazing, because, you know, I have all of my kind of, you know, what am I almost three years down the line now, and you know, and I sort of know this happened at this point, and this happened at this point, but that's completely unscientific, because it's just my Stuff. So having this in, you know, an actual kind of, I don't know, scientific way for a huge amount of people would be awesome.

Walter Koroshetz  15:02  
I wouldn't discount the scientific value of you as an individual, because the answer is going to be in, you know, a couple of people, basically, well studied will provide the clues. So the initial question is what's wrong? So in your case, what's wrong in you? And then the second question is, how does that generalize out? So an in depth study in small numbers of people could give clues, but then you need these large numbers to generalize. So you have to kind of hit the problem from all different angles. 

Jackie Baxter  15:39  
Yeah, yeah. That's a really good point, actually. Yeah. So the the RECOVER study, I mean, you said that it's running for a long time. But do you know, sort of at what point you might start getting - I was gonna say answers, I'm not sure if that's quite the right word. But you know, that that can start feeding into other avenues of research that might start presenting treatments, perhaps or, you know, something, something along those lines?

Walter Koroshetz  16:06  
Yeah, no, that's certainly the most important question. Now, as I mentioned, the electronic health record studies have already been producing data and publications, you know, they can look at the demographics. And they noted that, so less frequent after Omicron and Delta, it's less frequent if you've been vaccinated, the chances of developing long COVID or greater the more severe the infection is, in our country ethnic minority groups with long COVID were more likely to be hospitalized. It seems to be although the different variants have different chances of getting long COVID, symptoms always seem fairly consistent across all the patients. Pretty uncommon in children, except if they have a really severe infection, requiring an intensive care unit. And, yeah, the electronic health records study coming out, because they get their data, helping a lot of people and analyzing quickly. 

The more biological studies is certainly taking time. And I guess that, you know, some of it's because we've spent so much time collecting, now we have to kind of we're spending more time and money on analyzing all of what we've taken in. We're hoping that we'll get some answers. certainly in the autopsy study, you know, they'll be able to say whether they see anything or not on that one level, probably not gonna be the final level, they'll have to go deeper. 

Our studies - the cohorts, they're tiered - the first tier, what everybody gets is a fairly wide net type of valuation samples taken, then if you have a certain set of symptoms, then you move into tier 2 where you get more intensive tests related to a particular problem. There's actually a tier three that are even more intensive testing for people who have come out of the tier two with somes abnormalities. So most of what we're doing so far is tier one stuff. Now, as we've pretty much closed enrollment, move into the tier two and tier three, which is more intensive studying. 

And then the clinical trials, we have two strategies here. The first is to try to understand if there's something that hit at one of those core major culprits as the kind of underlying cause. And they are the first thing we're working on to test the antiviral agents on the chance that there's still virus present and replicating that, that antiviral might help. But then, the other strategy is to try to develop treatments for the symptoms. So, one is what we call disease modifying treatments to get at the underlying biology. 

The other is symptomatic treatments, which get at how to improve, for instance, the sleep disorder, the postural orthostatic tachycardia, the cognitive troubles, exercise intolerance, those are all kind of symptomatic trials that we are hoping to get going and we have basically had groups who have consulted with patients, people who are affected, to understand what the problems are that are most bothering folks. And then we had groups come together develop what we call master protocols, which we test, you know, the sleep disorders, or a master protocol for the exercise trouble, Master protocol for autonomic trouble. And these master protocols would then allow you to test one thing after another in them in sequence or in parallel, to try and get answers to people to help with their symptoms. So those two strategies are active now.

Jackie Baxter  20:31  
Fantastic. Yeah. So you're trying to kind of hit it from both sides, almost aren't you? Trying to kind of, to test the theories on the underlying cause, but also deal with the stuff that you can literally see in front of you. So you mentioned things like PoTS and sleeping disorders, just to name a couple. So I suppose you're kind of covering both bases?

Walter Koroshetz  20:55  
Yeah, no, that's the idea. You know, you'd like to have a magic pill that makes everything go away, you know, that gets at the underlying disease. But it's really going on so long now that we don't have that kind of answer yet. So I think it's really important to try and help people feel better. That's what medicine is all about - is making them feel better. Right? 

Jackie Baxter  21:19  
Yeah, exactly. Yeah. You know, the things that you can do to help, you know, they might not fix everything. But if you can make someone feel even 1% better, then, you know, that's 1% better than they felt yesterday. And personally, I would take that.

Walter Koroshetz  21:34  
Yeah, good point. 

Jackie Baxter  21:35  
Yeah, that's awesome. You mentioned earlier before Long COVID came along, you know, the research into ME/CFS. And it was actually Dr. Avindra Nath's research that I came across first. It was someone else put me on to it. So would you be able to talk a little bit about that? And is that something that might be able to, I don't know, feed into or enhance or work with in any way, some of the long COVID research?

Walter Koroshetz  22:05  
Yeah, so I'll try and do justice, but very caring physician and scientist, he's the Clinical Director of our intramural program. So not sure if you will know what that is. But the NIH, most of our work is funding science that goes around at the hospitals and universities around the country. But there's also laboratories, and there's actually a research hospital, here on the campus in Bethesda. And it's the largest research hospital in the world, and the people who are here, they are federal employees, and they are here only to do research. 

So when we were first involved, in ME/CFS research, Dr. Nath started a protocol to do intensive study in small numbers of people with ME/CFS, to see if we could get at the underlying troubles. And, you know, he basically designed the tests, designed, you know, what samples to take, and then now has been analyzing those samples. And I think he's coming to the point where he be able to publish his results, I don't actually have those results myself, he's still working on it. 

But then when COVID came and post COVID came, He basically took that same protocol that he had used for ME/CFS, maybe a couple of modifications, but not much. And then enrolled people who had long COVID into that protocol. And so that's going on now. And he's also - there's a somewhat similar syndrome called Gulf War Syndrome that occurred in the veterans who went into that war in Kuwait. And that has ME/CFS-like symptoms, Long COVID-like symptoms, and so he's also working with the VA, studying patients with that condition. 

So the advantage of Dr. Nath is he has all this experience. He's actually a neuro-virologist, so a specialist in viruses that affect the nervous system and neuro immunology. And so he's looking at these three different conditions, which have, you know, some overlap in their symptoms, trying to see if there's something that falls out when he looks at them in toto.

Jackie Baxter  24:23  
Yeah, that's fascinating. The kind of, I don't know if we call them related conditions. I'm not sure what the sort of slightly more scientific word for it, but, you know, all of these conditions, they have so much in the way of crossover, don't they? 

Walter Koroshetz  24:38  
In terms of the symptoms, yeah

Jackie Baxter  24:40  
Yeah, and I sort of when I was starting to look into long COVID and long COVID research, and, you know, it's all so over my head because I'm not a scientist, but, you know, realizing, you know, how, I'm not sure if useful is the right word, but you know, certainly you know, if you looked at research into ME/CFS, and if you looked into you know, what people might have found to help them? Actually a lot of them is very similar to what is helping personally, me with with long COVID. So it's, it's really interesting isn't it?

Walter Koroshetz  25:14  
You can't let any clue or not get followed up, you're right, yeah. So what do you think is helping?

Jackie Baxter  25:21  
And for me, the most helpful things have been training my breathing, yoga nidra for sort of the deep rest kind of thing, and actually cold swimming. So I live quite close to Loch Ness. So I've been dunking myself in there. And I find that to be the most useful thing that I've found so far. 

Walter Koroshetz  25:43  
Ok that's interesting, yeah

Jackie Baxter  25:45  
So I don't know if that's any use for you!

Walter Koroshetz  25:48  
You know, the the exercise protocols, I was just looking at them the other day. And so breathing exercises are a big part of that, and trying to get more coordination between the breathing and the exercise to see if that will help. So there's people I know, is a little bit of upset about exercise therapy. But it's really we're trying to do things to allow people to be more functional, in terms of being able to do more, quote, unquote, muscle work. 

But we do have to be very careful, you probably know from ME/CFS patients, that there's a condition called post exertional malaise, where they become very sick after exercise. So that's built into the protocol, there's these different tiers, you know, in terms of exercise, if you develop any signs of post exertional malaise,  you don't go to the next step, you stay at the easier level. So we are paying really close attention to that. But then, in some people, COVID effected the lungs, and they still have kind of trouble with their breathing coordination. Some still have persistent cough. So the pulmonary part of that is also important for some people.

Jackie Baxter  27:07  
Yeah, I mean, you mentioned earlier, you know, the long COVID, but, you know, also post COVID complications. And I think these terms are used kind of interchangeably, aren't they? And I'm not sure if that's a good thing or not. But you know, long COVID is such a kind of umbrella term that covers so many different things. I suppose it makes it quite difficult to study it in some ways, doesn't it? If you're looking at somebody who has actual physical organ damage, and also somebody who has post exertional malaise and fatigue and things like that, you know, that they're, they're two quite different things. But are they related? And I guess that's what we're trying to work out, isn't it?

Walter Koroshetz  27:49  
I think that's the issue with long COVID. It's the number of symptoms that occur in long COVID, the estimations are sometimes over 100, the most conservative are about 70. I think that's what we saw in our study, almost about 70 different symptoms, and they occur in clusters. So nobody has one symptom, they generally have seven to 13. But there are these little groups that we found. We found an autonomic group, we found a cognitive group without an exercise trouble, breathing group. And then some people have sleep disorders, some don't sometimes, some sleep disorders people can't sleep, some sleep disorders they're sleeping too much. There's a lot of variability. Right? 

One thing to caution people, though, is that the symptoms in long COVID are very common, occurring without COVID. So if you - so some of the studies if you ask people well, do you have fatigue? And you look at the people people have had COVID, and you get a certain percent of people have fatigue. If you ask people who don't have COVID, if they have fatigue, a certain percent are going to say they have fatigue. So they're very common symptoms. And one thing to really be careful about is not to blame everything on long COVID, before you know that there's not something else going on. Because the symptoms can be caused by a lot of other things. 

So if you are, say, you're hypothyroid - your thyroid isn't making enough hormone, you're gonna feel fatigued, you'll have sleep trouble, probably sleep too much, I guess, and can't exercise. And if you had COVID, and obviously think, Oh, I must have long COVID. But no, you have hypothyroidism and you know, you need thyroid hormone and you'll be fine. So really important to listen to people as to when they're having these symptoms, talk to their doctor and just get checked out that there's not something else going on. For sure.

Jackie Baxter  29:49  
Yeah, definitely. Because some of these things actually can be treated. 

Walter Koroshetz  29:53  
Yeah. 

Jackie Baxter  29:53  
And I've definitely noticed people talking about things - I'll use your example of hypothyroid, that actually has been triggered by COVID. But it's something that could actually be sorted. So I suppose that's the same warning, isn't it? You know, get it checked out, because you might be able to do something about it that will at the very least help

Walter Koroshetz  30:15  
Most thyroid conditions in adults are autoimmune in their nature. So whether it was started by COVID, hard to know but, again, the treatment is pretty standard, and not to miss it.

Jackie Baxter  30:29  
Yeah, definitely. So we've talked about RECOVER. And we've talked about Dr. Nath's research a little bit. Is there anything else going on in the sort of long COVID research arena that you're kind of involved in?

Walter Koroshetz  30:43  
Well, I think in the US, at NIH, we're a government agency. And so we work with multiple other government agencies. And so the Department of Health has, basically a task force on Long COVID, which involves people from you know, education, because there's kids involved, disability because some people can't work, Medicare in terms of payment. So in the US, we have, you get paid based on what's called billing codes, and it's now a billing code for long COVID. 

So a lot of work going on at the different agencies. The Veterans Administration, in the US has pretty close to what you have in England, for your population they have for the veterans in terms of electronic health records. So they've been able to do some really good electronic health record level studies. So yes, there's a lot going on in this space. And I think we got to keep pursuing it, to try and get relief to people who are still suffering.

Jackie Baxter  31:44  
Yeah, definitely. And, you know, you've just mentioned a whole load of things, but you know, including, you know, finance. And one of the things that, you see it all over social media all the time, the way people are struggling - they have long COVID. And they feel terrible, and they can't do things, which is terrible. It's awful. But on top of that, they can't work. So they can't maybe afford medical care, or they can't afford their houses, they can't afford to eat. So, it's not just a medical problem, is it? It's a very wide ranging... social, that's exactly the word. Yes. That's what I was looking for. So yes, it's huge

Walter Koroshetz  32:21  
The people who listen to you and give you input. I think that's also critical to know what's happening out there. Particularly to know, you know, how things go over time, because most of the studies we're looking at people, you know, first it was like three weeks after COVID, then it was a month after, then three months, but now we have people who are out two years, so to find out how they're doing, I think, is also really important now. 

Jackie Baxter  32:52  
Yeah, definitely. And I suppose that's where your sort of patient input comes, isn't it? You know, and that's something that I've noticed, again, coming from my background of absolutely not medical whatsoever, and coming into this kind of space of looking at research and what it means. And I had not really realized that patient involvement in research was even a thing, let alone how important it was. And that's definitely really opened my eyes to that. And you mentioned that you've got patient involvement - I can't remember which bit of the study it was that you mentioned. But you said you'd had input from patients. And how helpful is that? I mean, it must be vital. 

Walter Koroshetz  33:34  
Yeah, well, certainly for long COVID. It's all about a new condition. Maybe not entirely new, but it's now post COVID is new, you know, the ME/CFS is unfortunately not new. But I mean, certainly to be going after symptoms. The key thing is to know what symptoms are most important. In neurology, for instance, there's been studies where the doctors have a rating scale on how people are doing. The patients have their own sense, and sometimes they don't match up. So certainly, when you're going after symptoms, you have to know what's most important to people. 

And then in terms of doing these studies, you have to know that you're not overburdening people with all the testing so that they can't participate, or it's too onerous for them to participate. And so yeah, having patients at all different levels, particularly in kind of design, when you're designing things, because sometimes the doctors sitting around a table they have this wild imagination and they think people can do anything. But in real life, you have to test it out and find out what's really going to work in the patients you're trying to help. 

So have people at the design level and also have patients, so people with lived experience, you know as you try to adjust - because whatever you do in the beginning, it's not going to be perfect, you have to keep looking and improving your research protocols. And so getting that kind of input is really important. And then I think getting the answers out to people is also really important. And so doctors are usually not the best communicators in that space. So if you want to tell people who have Long COVID what's going on in the research and what it means to them - best people to help you with that would be with Long COVID. So

Jackie Baxter  35:32  
yeah, yeah, that's a really good point, actually. Yeah. And it totally takes us full circle back to what you were saying earlier about the point of medicine being to help people to get better. 

Well, thank you so much for joining me today. It's been an absolute pleasure hearing about everything that's going on. So thank you so much for taking your time to do it. And perhaps you'd come back and talk to me in the future when you've got some more results?

Walter Koroshetz  36:00  
Oh, yeah. Happy to do so. And yeah, thanks for the work that you're doing for the community. Appreciate it.

Transcribed by https://otter.ai