#32 Hidden Virus, Immune Exhaustion & the Brain: Long Covid, ME/CFS and post-viral illness with Dr Avindra Nath (NIH)

Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Avindra Nath (00:00):
If you're going to develop treatments to modulate the immune system, you have to take into consideration that their immune responses are going to be different in different individuals, and you've got to pre select them before you treat them. And you can't just helter-skelter treat everybody

(00:23):
with the same drug and expectthat you're going to get the same answer. A virus can infect a cell and it can now affect the function of the surrounding cells. It doesn't have to infect all the cells within the brain, it can infect very few cells within the brain and yet cause very widespread dysfunction.
Just the viral protein alone issufficient to cause toxicity. If you have an infection, you've got to go after the pathogen. It's as simple as that.

Emily Kate Stephens (00:53):
Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host Emily Kate Stephens,
Welcome back to Make Visible.And hello, Gez, how are you doing?

Gez Medinger (01:12):
I'm doing okay today. Thank you very much, Emily.

Okay and tell me. Tried to talk to you yesterday, and you said you were not doing well, but you didn't know why, and I pressed you on that. I just wanted to talk to you about that. What you've learned over six years in terms of listening to your body about the days that you're not feeling
great, and whether these thingsdo come out of the blue, whether you can sort of see the patterns?

Well, so the funny thing here is that you're trying to measure something that's so difficult to measure and get a sense on it. So there is as much as your symptoms are probably if you are suffering from energy limiting complex chronic illness, they are probably correlated to how much you try
and do. And there will be somesymptomatic consequence of that, whether it's 24 or 48 hours later. I've got used now to the pattern that when I have a really busy day and on my Visible... my Visible device, my pace points, normally, I try and keep them under seven a day. And obviously it's going to be

(02:03):
different depending on what yourheart rate zones are set to. But I did well over 30 on Saturday, and so Sunday, I felt pretty bad. On Monday, I felt really quite bad. And that's my standard pattern, is that I have one day directly afterwards that's pretty grim, and then the one off, that's worse then on

(02:27):
Tuesday. So that's day threeafterwards. I thought, I've come out the other side of this. It was just a two day that's perfect. That fits the pattern. I'm very happy about it. And only then this guy jumped out the bushes with a big wet fish and slapped me around the face on Wednesday, and told me, yeah,
not this time. So what I guess,what I'm trying to say is that some of the correlation is due to what you've been doing, and sometimes there's some ebb and flow, because the condition is, by its nature, relapsing and remitting. So there's a degree of that going on, and then there's a degree of cumulative

(02:57):
effect as well. And actually,I've just been doing too much for too many weeks, and I think that's what got me. It was essentially just a delayed PEM from having been pushing it for three weeks. So there usually are some reasons, but you can't always pin all of them down.

And I think that's it, isn't it? Sometimes it can be really frustrating because you think, Okay, I've got this down in terms of what I can manage and when I'm going to take the hit, and when you get the hit out of the blue, when you get that real crash, when you weren't anticipating it,
there's something emotionallythat's slightly harder because you're prepared sometimes, other times.

It's more crushing. It's more crushing. If you know you're going to be slammed, you're like, okay, it's fine. I was expecting this, but when it gets you by surprise. Yeah, there is something that's emotionally much harder. And personally, I also find that my mood is often lower on those
days where I'm crashy as well.And it's not just because I'm crashy. It genuinely feels like I wake up and there's just a default level of misery. I'm normally quite a happy person. It's almost like that happiness has been replaced with some misery that goes along with the crash, which makes the crash

(04:04):
even harder to deal with,because you don't quite have the emotional tools to handle it as well as you might otherwise.

That's very interesting. I don't think I've said this on the podcast yet. I'm out of this perpetual migrainous cycle that I was in for five years, and I had a day a couple of weeks ago where I was in this black mood. I thought everyone was quite an annoying person. I was sensitive

(04:33):
to everything, and because I'mnot in the pattern anymore, I didn't equate that it was a migraine coming on. But I always had that black mood with the crash, and I think that's something to do with a depressive state that the brain puts you into. And this goes right back to actually what I

(04:54):
researched when I was in thevery early days of Long Covid. And it's this idea of the Edward Bullmore book, that the brain is essentially trying to protect you by putting you into a state that makes you want to withdraw from the world.

I need to double check and brush up on how well validated this research is. But for a long time, there have been theories that neuroinflammation is connected to depression as well, and as we have discussed previously with Professor Todd Davenport, neuro-immune exhaustion and neuroinflammation
are heavily correlated with postexertional malaise and post exertional symptom exacerbation. So I think there's also just a physiological - and whether that's an intentional physiological thing, that's the body trying to shut you down, or whether it's just a side effect of that inflammatory process of

(05:41):
PEM, I don't quite know, but - Ido think it's quite common amongst people who suffer with complex chronic illness.

So this week, we are bringing you this interview with Dr Avindra Nath, which looks at exactly this, the way in which viruses enter the brain and the potential impact that they can have on the brain. Avindra Nath is the Clinical Director at the NINDS for the NIH in America, and he has done

(06:09):
a huge deep phenotyping studyinto ME/CFS a year or so ago. And here is the entry point of his work.
You the setup that you actuallyhave here - you have that clinical side. You have all of these labs here yourself. You're running a huge lab here, and I believe that your focus of study is how the human brain adapts to those viruses. What we want to do in our podcast is really try and help our audience to

(06:52):
understand what is going on inthese situations. So can you first of all tell me the way that a virus impacts, and I'm asking for generalized explanation, the way that a virus impacts the human brain.

Yeah. So virus, first of all, enters through some mechanism, either through the nose or the GI system. So the virus has the ability to bind to those cells get into the human body, but in order to get into the brain, it has to adapt, and it has to change its properties to be able to stay

(07:31):
there. And lot of viruses likegoing to the brain, but once they get there, the advantage to the virus for getting to the brain is that these cells in the brain are very long lived. So if a virus enters a neuron, it can live there for the extent of the neuron is going to survive, which is the lifespan of the

(07:52):
individual. So if it were toinfect only a lymphocyte, the lifespan of a lymphocyte is very short. The virus is not going to live very long.

And the lymphocytes is that - that's in the blood rather than when it's got into the brain.

That's correct, right? So that's what I study. So I try to understand how do viruses adapt themselves to enter the brain, and once they get into the brain, then what do they do to the rest of the brain? So in a way, the virus becomes a tool for me to try and understand how neuronal
dysfunction or neurodegenerationtakes place in the setting of virus.

And that term neuro-degeneration, neuro-dysfunction. Could you explain those two terms for me, so that we understand that impact that the virus has once it enters the brain?

So use the term degeneration to say that the cell is dead or has lost a lot of its function.

But that's on a cellular level, as you're looking at it, rather than necessarily the impact or the symptomatology that it causes in the human?

That's correct. So you know, if you lose enough cells, eventually you will drop some symptoms, depending on where those cells are within the brain, right? But we use the term neurodegeneration to state that the neuron has now lost its ability to really function, at all. Either it's totally dead or
it's close to it. We use theword dysfunction, whereby a neuron may be impaired, but it may still be able to recover, right?

Ok that's a really interesting distinction between the two. So are you saying that not all viruses necessarily enter the brain?

That's correct.

But those that enter there are differing impacts in terms of the way that they impact those brain cells?

That's correct. So, you know, traditionally, we used to think that a virus would infect a cell and it will impair its ability to do whatever it does, or could kill it. But what we found with HIV, and subsequently, now we've learned with a number of other viruses that a virus can infect a cell,

(10:08):
and it can now affect thefunction of the surrounding cells. So it doesn't have to infect all the cells within the brain. It can infect very few cells within the brain, and yet cause very widespread dysfunction within the brain, and because what it does is it will cause either release of
viral proteins that can be toxicor it can cause harm to these glial cells, which are these word glia comes from glue. And so they are these cells that are in between the neurons, and once they get activated, they can produce all kinds of substances, like cytokines that can be toxic to the neurons. So the virus has

(10:51):
the ability to amplify itsresponse to affect a much broader area within the brain without actually infecting all the cells.

It sounds like once a virus enters the brain, it has the ability to do so much. Obviously, the brain is the control center of the entire body. In these viruses, in the post-infectious or where you've got an infection that remains persistent, such as HIV, such as the after effects of something

(11:22):
like Zika or Covid. Is it thatimpact on the brain that drives the bodily symptoms?

Yeah, so you use the word post infection, I think that's a very important distinction. So you have the acute infection, whereby the virus is there, it's replicating, and you know, you're really sick, and you get all kinds of symptoms, but then what happens is - and some
people recover from an acuteinfection, and you're doing just fine - and the other individuals and whom you get an infection, you cover from that acute infection, but then symptoms persist, and the question is, why, right? And what you're asking is, is the virus still hanging around or not? For

(12:05):
example, post-Covid, same thingwith ME/CFS and a variety of other post-infection syndromes. They're not infectious. They're, you know, these people are not transmitting any infection, right? So they don't have actively replicating virus. They can even donate blood, they can do organ transplants, and
they're not spreading anything.But yet, if you were to look, you know, very closely, for example, with the post-Covid patients, you may be able to find some of the viral protein. Sometimes you'll find a little bit of viral RNA. So bits and pieces of the virus can probably hang around for a long period of

(12:43):
time. And what we've shown overdecades is that you don't need the complete virus. Our thing has been that just the viral protein alone is sufficient to cause toxicity to the brain.

Okay? Because I think that term post-infectious some people, particularly amongst the Long Covid or post-Covid community, people in the ME/CFS community, perhaps have found it offensive, because they think, but I'm not post this virus. This is still an ongoing situation in my body.

(13:17):
So I think in terms of theterminology, some people find it can be offensive, but what you're saying is that they are no longer infectious, whether or not the so maybe post-viral is incorrect, but post-infectious is... can, can be used as a correct terminology. You have historically done a lot of work
into MECFS, and you did a, Ithink, a study in 2019 with a study in 2024 as well, looking at what you describe as post-infectious MECFS. Do you believe that MECFS can always be attributed to a virus, whether or not we know what the specific virus is? Do you believe that all MECFS is a viral

(14:05):
consequence?

No, and a lot of things can trigger MECFS. Because my expertise is in viruses, so I chose to study that subgroup of individuals in whom there was a clear infectious trigger. So they very clearly said, Yes, we had an infection. It was very well documented. And then the

(14:26):
infection went away, and thesymptoms, new symptoms came while symptoms persisted. So I studied a sub-population of those individuals where my expertise could be of use.

Okay, and that's interesting. That's where you actually knew what the specific viral trigger was. So in those instances, what do you think is the normal pathogen that's caused or driven?

We we never knew what the pathogen was. Because what happens when you talk to these patients? Well, you know, I got the flu, I went to the doctor. The Doctor documents that, yes, they had an infection, but they never actually, yeah, really don't do because to a clinical lab, those
tests are not always reallyavailable to the physician, right to determine exactly what it is. I mean, you and I always get some mild infection every year, right? But we assume it's a flu or some kind of, well, I got the cold, but you never really know what the passage and what, yeah, of course.

And unless you end up with a long term situation because of it, you wouldn't necessarily know at the time to test whatever had caused it.

So all we can tell is yes, they had a respiratory infection, or they had a GI infection, or, you know, some thing of that sort. But beyond that, we won't be able to tell you exactly what the pathogen was.

And in your experience, what is it that determines whether someone's body is able to eliminate that virus or whether you remain with some kind of persistent residual symptoms from it?

So we don't know. Really, we suspect that there's some genetic susceptibility, and so that for some reason, either the genetic acceptability, or it could be that you're on some other medications that suppress your immune system, or something is wrong with the immune system whereby it's unable to clear it.

(16:31):
And so, because normally youwould think that even if there are bits and pieces out there there, your immune system will recognize it being formed and I'll get rid of it. But at some point, the immune system actually is getting exhausted and it's not really able to do what it's supposed to do. And
same thing happens in cancer. Alot of cancer, people think the same way that, you know, we probably have cancer cells developing in us all the time. Our immune system keeps checked and gets rid of them, but the immune system sometimes fails and and then those cells proliferate. Right. Here you

(17:10):
have, if you have bits andpieces of the virus, they don't have the ability to proliferate, but yet they hang around and they can cause harm.

Then can you talk me through the way that some kind of persistence or residual impact from the virus in terms of the brain, how does it then form a prolonged disease stage?

Yeah, so one possibility is that the bits and pieces are sitting in the brain themselves, right? And if they are, then they can impact the function of the brain, because they will damage some cells, and then those cells produce all damaging things, and then they affect the other cells, and so
on, so forth. Cascade from that,yeah. So that's one way to do it. The other thing is, maybe it doesn't even have to enter the brain in certain situations, what can happen is there's some really interesting mice models whereby they just give them a immune stimulant, for example, what's called LPs. It's a

(18:11):
derivative, like an endotoxin,you know, and you give it into the peritoneum of mice. And what you if you look at the brain, you'll see that they're actually the brain is impaired, and you can see activation of glial cells within the brain. So it tells you that sometimes toxins, even elsewhere in the body, can
impact cells within the brainitself, so they can produce various kinds of cytokines and other things that can cross into the brain and then affect their function. So the brain can be affected in both ways, either directly or indirectly.

Gez, that short conversation, what areas does that open up for you? Because I would love for our audience to feedback to us again, as with last week, it was amazing to receive feedback directly to us from the audience. So I would love to hear what catches people's
attention when you hear Dravindra Nath talking about that, what were your thoughts?

Well, I think firstly, from the patient perspective, hearing about viruses in your brain is scary. On a very intuitive level, we don't like the idea of viruses being in our brain and the idea that they're sort of rampaging around in there, killing our brain tissue that struggles to
grow back and the rest of itthat's that's a scary idea. I think, where I would like to sort of reassure our listeners is that whilst we do have some evidence for the fact that SARS COV-2 can get into brain tissue. It's very unlikely that that's the case for the vast, vast, vast majority of us.

On what basis do you say that Gez?

So we've got a couple of important studies that looked at autopsies of people who died from severe Covid infection. There's one from the NIH and there's one from Columbia University. The Columbia University study didn't find any SARS cov two in brain tissue in those 41 patients in
that study, there was some foundin the NIH study looking at 44 patients. So we've got a slightly mixed picture. But even in severe Covid infection that resulted in the deaths of those patients early on in the pandemic, we're still not a lot of virus that made it to the brain. So with mild initial

(20:23):
infection, the type which mostpeople will have had gone to develop Long Covid, the odds of there being virus in the brain, it would seem from the brains that have been looked at, that the probability would be low.

Yeah, and that's specifically related to Covid. There is implication in other viruses that they do enter the brain, some of the herpes viruses, but equally, we feel the neurological effects of some of these viruses, such as EBV, SARS COV-2 without there being a direct viral infiltration of the

(20:53):
brain. So I guess there's justthat balance. We're not trying to scare people with this conversation. But actually what Dr Nath was talking about there was his long history of looking at the way that viruses do or do not infiltrate the brain and the way in which they cause neurological complications

(21:14):
across multiple viruses, notjust specific to SARS COV-2.

We can broadly explain a lot of the symptoms we have from a neurological consequence of the virus being elsewhere in the body that can cause the neuroinflammation that has impact on the brain, which is actually good news, really, because when it comes to trying to get viruses out of brains, we
don't have many tools in thetoolbox. It's not it's not an easy thing to go after, mostly because we just can't get drugs to that point of the body right? The blood brain barrier exists for a reason, and it kind of goes both ways. Kind of a scary topic, but I do think it's one that we have to scientifically

(21:52):
curious about. And I'm sopleased that people like avindra Nath are actually doing the research on this properly.

And like he references at the end of that interview, you can have these neurological symptoms without the virus actually going into the brain. And that actually harps back to an interview that I did with Dr Kevin Tracey several episodes ago, which is looking at the vagus nerve and
once again, looking at how allof the body is connected, back to the conversation with Dr Nath.

(22:31):
Going back to the deepphenotyping study that you did of Post infectious ME/CFS patients in 2024 Tell me about that deep phenotyping and the results that you found from it. You actually, I believe, came to understand more of the biological basis of what is driving ME/CFS. And there's

(22:56):
three different areas that itreally, really impacts. Can you tell me about that?

So what we can do at NIH is, we cannot do very large studies here. We cannot bring in hundreds of patients to study. What we do really well over here is study small sample sizes, but study them in depth. So the study that we designed was such whereby we brought in about 20 patients. We wanted to
bring in some more, but thepandemic kind of occurred at the same time, so that impaired our ability to do so. But nonetheless, we brought in these patients with controls, healthy controls, and we kept them for two weeks, one week at a time, here in the hospital. And that's the other nice thing we can do

(23:37):
at NIH, is we can admit patientshere at the Clinical Center, and we can study them otherwise in an academic institution, it's very hard to do that elsewhere. And then we asked all kinds of experts here at NIH to help us with it, and just really so grateful to about 70 some researchers here at NIH really

(23:58):
contributed their own resourcesand time and expertise to study everything.

And that's all in the neurology section, or that was cross disciplinary?

So, you know, the cardiologist looked at the heart. We had the immunologist looked at the immune system. We had the electrophysiologist do the electrophysiology. It had muscle biopsies with skin biopsies. We did spinal taps. We exercise them. We did brain MRIs. We did transcranial
magnetic stimulation. We putthem in a metabolic chamber for two to three days. We did sleep studies on them. We monitored their glucose intake, oxygen uptake, CO2 production, control their diet, so we can look at their microbiome, how they metabolize food. You know, we looked at every single aspect

(24:47):
that we possibly could. Wewanted to go in unbiased, and we say, let's just look at the entire thing the best that we can. And then we did every single omics that you can think of, you know, metabolomics, proteomics, and look at the immune profiling and transcriptomics, right? And so
we collected a huge amount ofdata, and we said, Okay, now let's put this together. Can we make any sense of it? So this is probably the largest study I've ever done in my career. And so we found a few things. Now, you know, I cannot be an expert in all these aspects, but I'm grateful to all the experts who

(25:21):
then helped us interpret theiraspect of it, and then we tried to put it together and make some sense of it. So at least from my area there, with the way I look at it, what we found was that there was evidence of immune activation and persistent immune exhaustion in these patients.

And those were ME/CFS patients who had how long with the illness?

the entry criteria required that symptoms should have been at least six months and not more than five years,

Okay, so even some up to five years, you can still see that immune activation in the profiling that you did?

Yes, that's correct. And the other fascinating thing was it was different in men and women. Tell me about those differences. Yeah. So what we found was that we found more B cell activation in men and T cell activation in women, but they're also exhausted cells both and so
they're more naive cells andless of the more differentiated cells in these individuals, suggesting that there was a block.

Explain for our audience, what do the B cells and the T cells do?

Yeah, so the B cells are ones that produce antibodies, and the T cells are ones that directly interact with whatever pathogen it is, and go and kill them. Now, antibodies can also kill but they do it on a totally different mechanism. So one of the interesting observations was that if you

(26:44):
were to now, because we had asmall sample size, if you were to just mix the men and women and then compared with the healthy control minimum, you probably wouldn't find any difference, right? But when you say, Okay, I want to compare men to men and women to women, they just, you see this night and
day, they just separate out.

Totally. Does that suggest that there's a difference in the way that our immune systems operate generally, or just when we're under that type of situation?

Oh, is it normally different? Okay, so here we are looking at a pathological circumstance. So what I can certainly tell you, I'm sure there are differences in men and women anyhow and normally, but that's not an area that I have studied that much, but I'm sure there's abundant literature to
show those kinds of subtledifferences. But here it's very clear that in response to a pathogen, the response, at least in this situation, is certainly very different. Now are there genetic factors on top of it that are really making these kinds of difference? Because ultimately, you know, neither of

able
them are clearing things right,and that's why the immune system is exhausted, so that, I think, requires some further investigation. But to me, what it means is that if you're going to develop treatments and to modulate the immune system, you again have to take into consideration that you know

(28:05):
their immune responses are goingto be different in different individuals, and you got to pre select them before you treat them, and you can just helter skelter treat everybody with the same drug and expect that you're going to get the same answer.

that's the stage we are at. We can do flow cytometry on these things. We can define the patients, but it's not really available to a clinical lab at the moment, but once we sorted these things out, then it becomes feasible to develop a test, because then we'll narrow it down, we'll say,

(29:29):
I've figured out, okay, theseare one or two or three markers that are really going to differentiate these individuals. Now let's make it available on a broader and wider scale. And that's how most tests evolve, right? And so my hope is that this will follow the same course.

So that gives you a sort of marker or biomarker for potential treatment. Is there something from your study that gives you the idea for what might be an actual biomarker for the condition itself, for ME/CFS?

That's harder, you know? Because if you knew what the pathogen was, then it's easier. If you have an infection, you got to go after the pathogen. It's just simple as that, right? If I say you have AIDS, you've got a virus - that's HIV, right? So same thing here. The problem here is that
oftentimes, with ME/CFS, therewas a pathogen, we don't know what is. And if there are bits and pieces of it stuck somewhere in the body, you're not going to find them in the blood.

Because you don't necessarily know what you're looking for?

Now you're looking at indirect evidence. And the indirect evidence are the abnormalities in the immune system. The problem with the abnormalities immune system, they're not going to be specific, because you could probably see them in other conditions too. So that will
remain a challenge, but it stillgets you closer to the answer.

So that is... various people that I've spoken to have said that Long Covid actually puts us in a unique position, because it enables us to study this viral associated consequence when we actually know what the pathogen is, and we can do it on such a wide level, because we have so

(31:08):
many patients with Long Covid Sothat, in a way, makes it easier to study than ME/CFS, would you say?

So you know, as I told you, we were in the unfortunate situation whereby we were studying ME/CFS, and we had to stop it abruptly because Long Covid came around. But was also a fortunate situation, because, in a way, as soon as covid came, we became aware here in January of 2020, by March, I already had

(31:37):
put out editorials saying thatthese patients are going to develop something like ME/CFS.

Really ?

Okay? And so I started looking for that possible. And then people started calling it. They call it a long haul covid. So we went after it immediately.

How did you know? How did you know that it was going to have a that long term consequence? Because you -

It was a respiratory infection.We knew a lot of these respiratory infections, yet people were developing these ME/CFS like things. We knew for a lot of other viral infections, you get these kind of long term symptoms. So to me, it wasn't that much of a leap in thinking
that this could potentially haveit too, and we need to look out for it. It'll be good if it didn't, but if it does occur, we better be looking out for.

Let's talk about post exertional malaise that you, oh, yeah, see in your patients, because you actually did study in 2019 looking at post exertional malaise, and at that time it was specifically in ME/CFS, because we didn't have this long covid cohort. But you believe that there are, there's
so much variability in the postexertional malaise that patients experience that it's actually to do with breaking them out into subtypes to try and understand the way that the patient is affected. Is that correct?

So there are other people who are better experts in post exertional malaise than myself, but it is a very fascinating, it's a very, very fascinating symptom that you don't see with anything else. So normally, if you do some exercise... mental or physical, you may get exhausted for a
little while, and then you and Iwill recover. But these patients is very fascinating. They will do something they may not feel anything that day, next day, or something they get totally wiped out. That is so characteristic of ME/CFS and ME/CFS like symptoms, in a subset of patients with Long Covid. To me,

(33:34):
that is understanding thatpathophysiology would be very, very fascinating. I don't think we really understand why that happens. Then, in my mind, is an area where we really need to try to understand what it is. And it can be triggered by physical exercise, by mental exercise, by various kinds of things. And

(33:54):
then people describe it indifferent ways, and people call it malaise. And what do they really mean by the term malaise? I mean exhaustion. Some people say it was pains to use different terms to describe it. Even then there is this common phenomenon you have a trigger of some thing that you exerted,

(34:15):
there is a latent period afterthat, then comes this malaise or exhaustion, at the end of it, and that is devastating to these patients. I mean, that's what really impairs them from their ability to do in their daily lives, and it's very pathognomonic. So I think that is an area that really requires

(34:36):
a lot more research in my mind.

But do you believe that that post exertional malaise is actually something that's triggered in the brain?

The brain has to be part of it. It will not be the entire thing, right? Okay, but I think it's part of that problem, not the entire problem.

Okay, there was some criticism actually lost of your 2024 study, but it came out in October 2025 there were various members who are quite prominent in the ME/CFS community, Todd, Davenport, Oysten Fluge, Carmen Scheibenborgen who wrote a paper criticizing your description in

(35:16):
your 2024 deep phenotyping,study of alteration of effort preference as as your terminology for the way that PEM is driven. Talk to me about the wording that you used in the study, because there was a specific time to actually work out how to describe this. Talk to me about altered effort

(35:42):
preference, because I think whatpeople in the community have had a problem with is that it sounds like they have a choice in it.

So that was not really our intention ever. It's not my area of expertise. Yeah. I mean, I'm a virologist. I study immune system. That said, we brought in a lot of different experts too. So the experts in this field were Mark Hallett and there was Nick Madian. When we first published the study, the
same issue came up. A lot ofpeople wrote to us, and they were concerned that the use of this term could be misinterpreted as suggesting that maybe it was willing to and that was never our intention, ever. So what we did was we did a one day, full day symposium here at NIH, and we discussed -

(36:26):
I was available too, virtuallypeople could... a lot of patients and other people, advocates and others are allowed to dial in - and so I had them present their view of what they thought effort preference really meant - how they studied it and what their physiological abnormalities were. Because

(36:47):
they showed that there was acorrelate in the brain. And they use this transparent magnetic stimulation and functional MRI to show that at the junction of the parietal, temporal and frontal lobe, there's an area there, and that was abnormal, and that's what they think is the pathological correlate of
this physiological term "effortpreference'. And they think that it is a electrophysiological term, and that's the way they were looking at okay.

Okay. And no offense was intended.

Yeah, never was. And so they, if you could go back and look at it, you can see their explanation.

Okay, wanted to give you the opportunity to respond to that. So the other question that was levied about the 2024 study is that you only used a single CPET test, whereas, I think traditionally, it has been that people are using two day CPET tests, or two day invasive CPET
testing to look at ME/CFS,because of the way that post exertional malaise often impacts on the second day. Talk to me about the differences there between the CPET that you used and the potential for a two day CPET.

For us, one way, it's a research study, right? So you want, you design your study for the question you want to ask. So for us, one day was sufficient for the questions we were trying to address. As I said, we were interested in trying to understand the immune system and how that works. It
was sufficient. You know, someof these patients actually got pretty exhausted, even after one day CPET. So trying to ask them now to do a second day was kind of really, yeah, I just couldn't think we could do that. So for for us, one day was sufficient. People use that to for diagnostic purpose and

(38:37):
everything, so for us, that wasnot an issue. Our patients were very well characterized when they came in the study, so I think we were fine with one day.

Gez, tell me what you thought were interesting in the findings of that study.

Well, first of all, I think having really well, as far as they can be crystal clear, physiological differences found between men and women

absolutely fascinating.

I thought that was fascinating, because so far we've been thinking, Well, why do women seem to get with the conditions with twice the frequency that men do? What's the difference? Is it hormonal? Is it immune system? And if it is the immune system, well, what part of the immune system is it?

to break it down, your data can be completely different, and it can have such different implications, as he said, for the potential immunotherapy, the potential targets, the way in which we treat these people, is completely altered on the basis of the way that the immune
And I think what we've foundhere is that we've got a pretty clear idea that it's the difference between the T cell and the B cell function that differentiates men and women, and not just that. I thought the other thing that was particularly interesting about this was that if you were just

(39:37):
randomizing the selection ofpeople and comparing it, you wouldn't have found the differences. It's only when you separate out that data, when you separate out the data and compare men suffering versus men who were not and the same with women only, then do you start to see the differences? And I think
this has huge implications aboutabout -

(41:01):
system has been impacted?

Yeah, I think one of the huge challenges here is that we don't have agreement on how to stratify people yet. We don't know how to phenotype people. We don't know in what ways we need to split people up and put which peoples into what trials we need to have more of exactly this kind of research so
that we can start to phenotypethe conditions better. And only then can we start to design trials better. It's such a complex puzzle. It really is. Maybe when we finally find the missing piece that ties everything together, we go 'aaah' if only we'd done that from the start, but we are still

(41:32):
hunting for that missing cogthat sort of makes this whole Connect for kind of machine start to work, and all the bits fall out the bottom.

The differences between male and female is absolutely one of it's a subject of huge passion for me, because of the way that historically so much of the medical system, it is only men that have been studied. And a lot of the time in terms of drug regimens, in terms of treatment

(42:01):
protocols. A lot of the time,women are given men's treatment with the dosage altered for the size of a female body. And this kind of science opens up for me how inappropriate that might be. And yeah, I don't want to be too heavy into the breaking down of the patriarchal medical system.

But for some conditions, it's obviously absolutely critical. For broken leg, probably less so, but for something like this, where we're starting to get the evidence, and the evidence is actually fairly obvious that we ought to be considering men and women differently when we see that
women have twice the frequencyof the condition, that tells you something straight up front, that something different is going on there physiologically. So it almost raises the question, why have we not been separating people for the last six years already? Because we knew this six years ago. We did

with the with the covid. And also remember that if we look specifically at covid, this study was about MECFS, but if we bring the relevance of covid into this. Remember how different the immediate reaction was in the middle of the pandemic, it was men that were
being hospitalized, men that hada higher mortality rate from the acute version of it, it is women that have been impacted in Far, far greater numbers in terms of the long term, and that alone shows that the immune systems have mounted a different response to the same virus.

Absolutely. Look, I mean, fantastic work. His other research that he talked about, I was punching the air when he was describing these studies. I'm like, Yes, I'm really pleased to hear that some of this research is happening.

Let's hear the rest of the conversation with Dr Nath, where he shares a couple of his other current studies.
If we just go back to this pointof immune exhaustion and your area of expertise, what you are seeing. What is the primary thing that we as patients Long Covid or ME/CFS can be doing right now to try and handle that immune exhaustion, or try and help our B cells or our T cells, and what do we have to look

(44:25):
forward to in the future interms of the developments that are coming out?

Yeah, so there's not a whole lot one can do. People think that, can I take something that will stimulate my immune system? Maybe that'll help me, or something? A lot of quacks out there will sell all kinds of products, and the best thing you can do is keep away from them, because you can drain
a lot of money down the toilet.We really need more precise treatments in order to properly store the immune system. You don't want to just do something Helter Skelter, and it can cause more harm than good. Best thing you can do is, if you get another infection, make sure you treat it as fast as possible,

(45:03):
prevent new infections fromoccurring the best that you can. I mean, still have to function in society. If you do get an infection, treat it aggressively, depending on what it is, then that'll prevent further complication from it.

Is that an antiviral treatment? That would be your recommendation.

Yeah, if you have the influenza, then you take the antiviral for influenza it's a bacterial infection or superimposed bacterial infection, treat that with antibiotics. If it's just a viral infection, you know, drain your nose, do your gargle, whatever you need to do, get the
secretions out so that you canrecover sooner. You don't have antivirals for all viruses, but you can still do a lot to recover from these things and try to prevent infection the best that you can. So wear a mask or whatever you need to do. Somebody in the family gets ill, try to isolate as best you can.

And for those that have the infection associated chronic condition currently, is it just a matter of riding our time until that scientific?

No, no, no. So there's a lot that can be done symptomatically. So they are a whole host of these clinics that have come up. The Long Covid clinics or ME/CFS slash Long Covid clinics, and they're multidisciplinary clinics. They can make a huge difference in your lifestyle. And so they can

(46:20):
treat things symptomatically,depending on whether there's a brain fog. They can give you something.. if there's depression. Depression can be treated or sleep abnormalities. They can be helped with autonomic disturbances. They can be treated in various ways. People have neuropathies, they
can be treated. So there are alot of treatments that can still be done. There's rehab that can be done to definitely get involved in one of these clinics.

And in terms of the work that your lab is doing going forwards or in the near future, what do we have to look forward to coming out of your lab's research?

So I can tell you, we have several ongoing studies. Number one is what we call the viral reservoir study. So here small subset individuals, only six that we'll be bringing in who have Long Covid and six who recovered from covid, and we're going to biopsy everything that we possibly can. So nasal,

(47:14):
tongue, skin, muscle, gibiopsies, you know, try to look for the virus, and we take every body fluid that we possibly could and look for viral remnants to try and understand what it is. So that's one. Then the second

is that one of the most comprehensive studies looking for that viral reservoir that's been done in terms of biopsies,

That's correct, yes. Then the second study that is ongoing right now is an IVIG study. It's a placebo controlled study crossover design, whereby everybody gets it, but you get placebo, or you get IVIG, and then after a few weeks you got one, you get the other, but patient is never told which one
they're getting. That is ongoingright now.

What size is your cohort in that?

40. Then the third study that hasn't yet been started, that is to use a checkpoint inhibitor, and that's a drug called pembrolizumab, and that blocks a molecule called PD1, and that is to reverse immune exhaustion. And I had mentioned that in the ME/CFS paper, that that's what I like

(48:18):
to do, but we came across a lotof resistance from pharma and other people. They thought that by reversing the immune system, you could actually cause auto immune syndromes, but we only wanted to give one dose in order to try and see what really happens to the immune system, and the FDA finally approved it.

(48:40):
So we got an FDA approval. I'vegot approval from a scientific review committee, and now the IRB, and we're ready to recruit, okay?

And then what that does is essentially resetting the immune system by taking the brakes off the B and T cells. I believe that's what I read you had written. So it's almost firing your B and T cells into fully activating and therefore hopefully clearing, clearing the virus. Is that the

(49:10):
theory?

That's the goal. But it's still research, right? We don't really know, so we're going to give it our best shot and see what happens.

Great. Well, I look forward to hearing the results of that and all your studies, and to the continued work that you do. Does the fact that you are part of the National Institute of Health give you any more weight in terms of what is able to then be put out as a directive

(49:42):
nationally or globally in termsof recommendations of treatment

and care. No, the NIH doesn't have the mandate of meeting directives. Those things are done by professional societies. They produce guidelines, but we hope that our research will inform them to incorporate that into their guidelines and suggestions.

Fabulous. Well, thank you so much for joining me today. Very much. It was a real pleasure. Thank you.
Gez?

So his his viral reservoir study. Let's biopsies from everywhere. Yes, yes. I mean, we need this smoking gun. Let's go in there with our torches, like detectives in the smoky house and start poking around in there and see and see where we can find the hidden treasure. I got
my metaphors a bit mixed there,but I think you know what I'm trying

to say, and that is a really interesting one, Jez, because that's a very small study that he's talking about. But those people have all agreed to be poked and prodded and have pieces of them taken. And that actually goes back to the controversy that he spoke about in the middle section of
that interview, which was one ofthe things that the two day CPET, they had really been picked up by people highly regarded in the ME/CFS community for their one day CPET. And Dr Nath said, "but it had such a detrimental effect on on patients that I couldn't bring myself to put them through it".

(51:08):
That is something that I hadraised with a doctor when I had wanted to have various testing, and I think it was asking for CPET testing, and they said they wouldn't do multiple because of the stress that it put on my body, and it wasn't fair to induce that crash, and I was asking for it. So there is this

(51:29):
interesting point that comeshere of the consent of patients. If patients are saying yes, take this piece of me. Try this on me. I am willing to give my body to understanding science, not give my entire body, but give certain parts of my body to understanding this science. I do feel that patients should be

(51:50):
listened to on that and patientsshould be given the choice there is this ethical consideration, and patients should be given that consideration as to how far they want to be pushed to help advance this knowledge Absolutely.

And it doesn't surprise me that it's a relatively small sample in this viral reservoir study, because it's going to be invasive and it's going to take a long time. It's going to take a huge amount of patient time to do this, but essentially, it's a pilot study, I'm assuming. And if they find
the smoking gun, there's like,Kate, great, let's roll this out, and let's do it over 50 people and see if it's replicated.

Yeah. And I liked nath's Humility on that, because I was quite excited about the immune checkpoint inhibitor study, and thinking, wow, this is something that could potentially actually spin things for people that have B cell or a T cell issue going on. And him saying, Yeah, but this

(52:40):
is a study we are still we'relooking at the science of it. So I did actually quite appreciate his humility in terms of him saying, Whoa, whoa, whoa, put your brakes on. Don't jump at it before we have that science. And I think that is something that in this community, we can be so prone to getting so excited
about some of these studies andreally, really rooting for them to come up with that answer for us.

It's understandable, isn't it, because we're so desperate for any bone that could be thrown in our direction that we start to, you know, Sniff a bit of the butchers, and we're on it like a hungry dog.

You are coming up with some metaphors, analogies. Great. I just wanted to reference the controversies that had been raised from it, because some people in the community said

You have to raise this,

raise this. And, yeah, the altered effort so weird.

Choice of language. I'm sure it was accidental, but to somehow have got to that place where you don't understand the community well enough to realize that language will be challenging, it's going to be challenging that feels a bit of an own goal, really an unnecessary own goal.
You only need to speak to onepatient for them to have gone, choose a different word or two.

Yeah, and they were challenged on it multiple, multiple times. I really don't understand why they didn't just go. You know what? We could just call it something different and not raise an alarm amongst people who want to be invested in our research, but are going to be put off by us
sounding like we're patientblaming, even if that was never their intention.

I think a lot of these academics, doctors, researchers, may be very high in the IQ stakes, not so much the EQ. And they'll be a little bit blind to some of that I suspect.

To the impact of that, yeah,

They'll be so narrowly focused on the technical meaning of this word they want to try and communicate. They won't necessarily think beyond that to the subtleties of how it will be perceived on the patient side, because they're so laser focused on their specialty.

So an own goal there, but some excellent studies and research coming out of this department at the NIH, the checkpoint inhibitor study has started enrolling this week, and we'll put the links to those trials and the studies in the show notes. But some of the research that came out from that
now ME/CFS deep phenotypingstudy has actually been instrumental then, in terms of the NIH creating an MECFS roadmap, which we can delve into further in a future episode, we have further interviews about the direction in which we need to take the research into ME/CFS at large, and the areas that

(55:12):
those findings coming out ofthat deep phenotyping study, along with multiple other studies, are enabling us to actually channel what we need to find out and the direction that the research needs to be taken. So just finished with a little story of I have been really relatively well these past
months, but I actually have torna disc in my back. So that is why I am late publishing this episode, because I slightly struggling with sitting down and slightly struggling with pain. But I wanted to share a little bit of the way that I reflected on this. And much as you your body this week telling you

(55:57):
you've done a bit much, we'regoing to slap you down again. I was ramping up my life to quite an extensive degree. And I do think that the body has an amazing way of sending you signals, sending you signals, sending you little signals. And when it really is over what you are trying to push it to do, it
sometimes just sends you a bigsignal that makes you stop. So I have stopped for a week. I had to stop for a week, but I'm getting back to it, and just wanted to share that idea of sitting with it and learning from it. I'm not sitting with it because I can't sit down, but theoretically, sitting with it.

(56:41):
It's not an easy thing to do.It's not but that acceptance, we'll get there eventually we will. Thank you so much for joining me, Gez and I look forward to our next installment.

Me too. Pleasure as always.

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#32 Hidden Virus, Immune Exhaustion & the Brain: Long Covid, ME/CFS and post-viral illness with Dr Avindra Nath (NIH)

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