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

If you're going to develop treatments, from modeling 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 help or scout or treat everybody with the same drug and expect that 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 is sufficient to cause toxicity. If you have an infection, you've got to go after the pathogen. It's just simple as that. Welcome to Make Visible, the podcast shining a light on complex chronic illness. I am your host Emily Kate Stevens. Welcome back to Make Visible and hello, Jess. How are you doing? I'm doing okay today. Thank you very much, Emily. Okay, and tell me, try 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 what you've learnt over six years in terms of listening to your body about the days that you're not feeling great. Whether these things do come out of the blue, whether you can see the passions. The funny thing here is that you're trying to measure something that's so difficult to measure and get a sense on it. 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 some symptomatic 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 device, my pace points, normally I try and keep them under seven today. Obviously it's going to be different depending on what your heart rate zones are set to, but I did well over 30 on Saturday. So Sunday I felt pretty bad and Monday I felt really quite bad. That's by standard pattern is that I have one day directly afterwards that's pretty grim and then the one after that's the worst. And on Tuesday, so that's day three afterwards, I thought, I've come out the other side of this. It was just a two day. That's perfect. That fits the pattern and 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 so I'm going to, 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. And then there's a degree of cumulative 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 pen from having been pushing it for three weeks. So they 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 emotionally that's slightly harder because you're prepared sometimes the other time. 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 not only quite a happy person, but it's almost like that happiness has been replaced with some misery that goes along with the crash. It makes the crash 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 meagre and a 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 to everything. And because I'm not in the pattern anymore, I didn't equate that it was a meagre 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 researched when I was in the very early days of Long COVID. And it's this idea of the Edward Bulmar 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 post-exertional 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 pain. I don't quite know, but I do think it's quite common amongst people who suffer with complex chronic illness. So this week we are bringing you this interview with Doctor of Indranath, which looks at exactly this, the way in which viruses enter the brain and the potential impact that they can have on the brain. Indranath is the clinical director at the NINDS for the NIH in America and he has done a huge deep phoenotyping study into MCFS a year or so ago and here is the entry point of his work. The setup that you actually have 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 understand what is going on in these 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 there. And a lot of viruses like going 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. It's going to survive, which is the lifespan of the individual. So if they were to infect only a lymphocyte, the lifespan of a lymphocyte is very short. The virus is not going to live very longer. And the lymphocyte is that that's in the blood rather than when it's got into the brain. That's correct. 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? And then the virus becomes a tool for me to try and understand how neuronal dysfunction or neurodegeneration takes place in the setting of a virus. And that's neurodegeneration, neurodisfunction. 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 if you lose enough cells, eventually you'll have some symptoms depending on where those cells are within the brain. But we use the term neurodegeneration to say 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 the word dysfunction whereby a neuron may be impaired but it may still be able to recover. Right? So. Okay, that's a really interesting distinction between the two terms. 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 traditionally we use to think that a virus would infect a cell and it will impair its ability to do whatever it does or could kill it. what we found with HIV and subsequently now we will learn with a number of other viruses that a virus can infect a cell and it can now affect the function 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 toxic or it can cause harm to these glial cells which are these, the word "glia" comes from glue. And so they are the 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 the ability to amplify its response 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 like Zika or COVID, is it that impact on the brain that drives the bodily symptom? 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're really sick and you get all kinds of symptoms. And then what happens is and some people recover from an acute infection and you're just fine. And the other individuals and whom you get an infection, you recover from the acute infection but then symptoms persist and the question is why. And what you're asking is is the virus still hanging around or not. For example, post-COVID, same thing with ME/CFS and a variety of other post-infection syndromes, they're not infectious. And these people are not transmitting any infection. 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 very closely, for example, with the post-COVID patients, you may be able to find some of the viral proteins. Sometimes you'll find a little bit of viral RNAing. So bits and pieces of the virus can probably hang around for a long period of time. And what we've shown over the decades 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. So I think in terms of the terminology, some people find it can be offensive. But what you're saying is that they are no longer infectious. That's correct. So maybe post-viral is incorrect, but post-infectious can be used as a correct terminology. You have historically done a lot of work into ME/CFS. And you did a, I think, a study in 2019, a study in 2024 as well. Looking at what you describe as post-infectious ME/CFS, do you believe that ME/CFS can always be attributed to a virus, whether or not we know what the specific virus is? Do you believe that all ME/CFS is a viral consequence? No. And a lot of things can trigger ME/CFS 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 infection went away and the symptoms, new symptoms came, well symptoms persisted. So I studied a subpopulation 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 out of the skin? So we never knew what the pathogen was because what happens when you talk to these patients and 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 through a clinical lab, those tests are not always really available to the physician, to determine exactly what it is. I mean, you know, you and I always get some wild infection every year, right? But we assume it's a flu or some kind of, well, I got the call, but you never really know what the pathogen was. 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. 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, or what is it that determines the constant residual symptoms from it? Okay. So we don't know really. We suspect that there's some genetic susceptibility. And so that for some reason, either the genetic susceptibility 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. And so, because normally you would think that even if there are bits and pieces of their immune system, what recognize it being foreign, 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 the same thing that happens in cancer, a lot 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 check and gets rid of them, but the immune system sometimes fails. And then those cells proliferate. Here, if you have bits and pieces of the virus, they don't have the ability to proliferate, but yet they're hanging around and they can cause harm. And 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 state? 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 end to damage some cells and then those cells produce all damaging things and then they affect the other cells and so on and so forth, right? So it's sort of 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. There are certain situations what can happen is, and there's some really interesting mice models whereby they just give them immune stimulants, for example, what's called LPS. It's a derivative, like an endotoxin, you know. And you give it into the peritonium of mice and what you, if you look at the brain, you'll see that the 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 brain itself. So they can produce ways, kind of the side of the lines, 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. Jess, 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 Dr. Avindranath talking about that. What were your thoughts? 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 round in there, killing our brain tissue that struggles to grow back and the rest of it, that's a scary idea. I think where I would like to 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, Jess? So we've got a couple of important studies that looked at all the topses of people who died from severe COVID infection. There's one from NIH and one from Columbia University. Columbia University study didn't find any SARS-CoV-2. of two in brain tissue in those 41 patients in that study. There was some found in 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, there was still not a lot of virus that made it to the brain. So with mild initial infection, this hype, which most people will have had with gonorrhond developed on 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 brain. So I guess there's just that 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 across multiple viruses, not just 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 the toolbox. 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 be scientifically curious about, and I'm so pleased that people like Evendranath 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 helps back to an interview that I did with Dr. Kevin Tracy several episodes ago, which is looking at the Vegas nerve, and once again, looking at how all of the body is connected. Back to the conversation with Dr. Neh. (Music) Going back to the deep phenotyping 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 three different areas that it really, really impacts. Can you tell me about that please? 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. Well, we wanted to bring in some more, but the pandemic kind of occurred at the same time, so that it paid our ability to do so. But nonetheless, we brought in these patients with health 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 at NIH. We can admit patients here 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. And then just really so grateful to about 70 some researchers here at NIH, who really contributed their own resources and time and expertise to study everything. And that's all in the neurology section, or that was cross-disciplinary? Oh, cross-disciplinary. So the cardiologists looked at the heart. The immunologists looked at the immune system. Yeah, the electrophysiologists do the electrophysiology. It had muscle biopsies, with skin biopsies. We had spinal taps. We exercised them. We did brain MRIs. We did transcranational magnetic stimulation. We put them in a metabolic chamber for two to three days. We did sleep studies on them. We monitored the glucose intake, oxygen intake, CO2 production, control their diet so we can look at their microbiome, how they metabolize food. We looked at every single aspect that we possibly could. We wanted to go in unbiased. And we said, 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, metabolism, mixed proteomics, and look at the immune profiling and transcriptomics. So we collected a huge amount of data on these patients. 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. You know, I cannot be an expert in all these aspects. But I'm grateful to all the experts who then helped us interpret their aspect of it. And then we try to put it together and make some sense of it. So at least from my area, 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 there was different in men and women. Tell me about those differences. So what we found was that we found more B-cell activation in men and T-cell activation in women. But they also exhausted cells both. And so there were more naive cells and less of the more differentiated cells in these individuals, suggesting that there was a block. But 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 another totally different mechanism. So one of the interesting observations was that if we were to now, because we had a small sample size, if we were to just mix the men and women, and then compare it with a healthy controlled man, you probably wouldn't find any difference. Right. But when you say, okay, I'm going to compare men to men and women to women, they just, you see, there's night and day. They just separate out totally. Does that suggest that there's a difference in the way that our immune systems? Yeah. Operate generally or just when we're under that sort 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 they 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 subtle differences. But here it's very clear that in response to a pathogen, their 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, neither of 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 model the immune system, you again have to take into consideration that your immune responses are going to be different and different individuals, and you've got to pre-select them before you treat them. Yeah, so one of your recommendations from it was to have tailored immunomodulate therapies for each patient, which is a disease-modifying treatment essentially. But what you're saying is that you have to treat everyone differently. In terms of that, how would it be possible to scale out that kind of profiling to be able to establish what treatment is required for which individual? Were there markers from the study that you did that could give you that indication in patients on a clinical level, perhaps a normal clinical level, rather than when people have access to the NIA? Yeah, with any discovery, initially it's complex because it starts at a research lab, you make some observations that only you have made. So 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 sort these things out, then it becomes feasible to develop a test. Because then we'll narrow it down, we'll say, I figured out, okay, these are 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 almost test evolved. 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. Because So if you knew what the pathogen was, then it's easier. If you have an infection, you got to go after the pathogen. If I say you have AIDS, you've got virus, it's HIV, right? So same thing here. The problem here is that oftentimes with ME/CFS, there was a pathogen, we don't know what it is. And if it's the 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. The indirect evidence are the abnormalities in the immune system, the problem with the abnormalities in the immune system, they're not going to be specific. Because you can probably see them in other conditions too. So that will remain a challenge, but it still gets you closer to the answer. Right? So that is various people that I've spoken to who 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 many patients with long COVID. So that in a way makes it easier to study than ME/CFS, what do you say? So as I told you, we were in the unfortunate situation whereby we were studying ME/CFS and we had to stop it abruptly because the long COVID came around. I 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 put out editorial saying that these 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 a long-haul COVID. So we went after it immediately. How did you know that it was going to have a long-term consequence because you were still here? Because the respiratory infection, we knew a lot of these respiratory infections, yet people were developing these ME/CFS-like things. You know, 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 have it to. I mean, you need to look out for it. It would be good if it didn't, but if it does occur, we better be looking out for it. Let's talk about post-exertional malaise that you 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's so much variability in the post-exertional malaise that patients experience. That it's actually to do with breaking the mountain to subtypes, to try and understand the way 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 symptom that you don't see with anything else. So normally, if you do some exercise or mental or physical, you may get exhausted for a little while and then you and I will recover. But these patients is very fascinating. They'll 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 subset of patients with long-covid. To me, that is, understanding the pathophysiology 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 then people describe it in different ways. People call it malaise and what do they really mean by the term malaise? I mean, exhaustion. Some people say it was pain. People use different terms to describe it. Even then, there is this common phenomena. You have a trigger of something that you exerted. There is a latent period after that. Then comes the malaise or exhaustion. 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 a lot more research in my mind. But do you believe that that post-exertion on the lase is actually something that's triggered in the brain? Because it's. The brain has to be part of it. It may not be the entire thing. But I think it's part of that problem. It may not be the entire problem. OK. There was some criticism actually last of your 20-24 study, but it came out in October 2025. There were various members who were quite prominent in the ME/CFS community, Todd Davenport, Euston Flueger, Carmen Scheibner, who wrote a paper criticizing your description in your 2024 Deep Fiener typing study of alteration of effort preference as your terminology for the way that PPM is driven. Talk to me about the wording that you used in the study because there was a specific. Yeah, so it's not an area. I'm to actually work out how to describe this. Sure. Talk to me about altered effort preference because I think what people 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, right? Yeah. I mean, I'm a viralologist and I study immune system. As I said, we brought in a lot of different experts too. So the experts in this field were Mark Hallett and there was Nick Meridian. When we first published the study, the same issue came up. A lot of people wrote to us and they were concerned that the use of this term could be misinterpreted as suggesting that maybe it was willing. Cheering up. Yeah, it should be not too. And that was never our intention ever. So what we did was we did a one-day-fold symposium here at NIH and we discussed it was available to virtually people 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 they showed that there was a correlate in the brain and they used this transcanomagnetic stimulation and functional MRI to show that the junction of the pyridol 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 effort preference. And they think that it is an electrophysiological term and that's the way they were looking at it. Okay. And no offense with intended. Yeah, never it was. And so if you could go back and look at it, you can see their explanation. Okay. So you 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-issue professional 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. Yeah, for us, it's a research study, right? So you designed your study for the question you want to ask. So for us, one day was sufficient for all the questions we were trying to address. And as I said, we were more interested in trying to understand the immune system and how that works. It was sufficient. Some of 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 us, one day was sufficient. People used that for diagnostic purposes and everything. So for us, that was not an issue. Our patients were very well-correctized when they came into the study. So I think we were fine with one day. Jess, 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 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? And I think what we've found here 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 randomising the selection of people and comparing it, you wouldn't have found the differences. It's only when you compare-- Separate 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 about the entire medical system. Everything. But about all of the research that's going to be happening specifically for long-term and MECFS. Because what else do you think is going to be the difference? does this mean? If we've got disc clear difference in the immune system reaction between men and women, are we going to need to be selecting people accordingly for trials and raises questions everywhere? Absolutely, and you and I have had this conversation before and we've had this conversation with experts before. The way in which everyone is potentially bucketed together when it comes to these studies is possibly causing detrimental impact on the results of the studies because if you group everyone together you don't get the results. If you break them out into subsets, be that men and women, be that symptom set wise. However you choose 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 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. Yes, we don't know how to phenotype people, we don't know in what ways we need to split people up and put which people into what trials. We need to have more of exactly this kind of research so that we can start to phenotype the conditions better and 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're like, oh, if only we'd done that from the start. But we are still hunting for that missing cog that 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's only men that have been studied and a lot of the time in terms of drug regimens in terms of treatment 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 well, there's some conditions it's obviously absolutely critical for a 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 frequency of the condition. That tells you something straight up front that something difference 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 hospitalised men that had a 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 point of immune exhaustion and your area of expertise what you are seeing what is the primary thing that we as patients long covid of MECFS 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 forward to in the future in terms of the developments that are coming out. Yeah so there's not a whole lot one can do the people think that can I take something that will stimulate my immune system maybe that'll help me or something. There are a lot of quacks out there who will sell all kinds of products and the best thing you can do is keep away from them because you can train a lot of money down the toilet. We really need more precise treatments in order to properly stimulate the immune system and you don't want to just do something help us culture and they can cause more harm than good. The best thing you can do is if you get another infection make sure you treat it as fast as possible preventing infections from occurring at the best that you can. You still have to function in society. If you do get an infection treated aggressively depending on what it is and that will prevent further complications 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. If it's a bacterial infection or superimposed bacterial infection treat that with antibiotics. If it's just a bio-infection you know and drain your nose, do your gargles whatever you need to do get the secretions out so that you can recover 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 infections the best that you can. So if we're a mask or whatever we need to do somebody in the family gets ill try to isolate if you 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 benefit? No no no so there's a lot that can be done symptomatically. So there are a whole host of these clinics that have come up. The Long COVID clinics are ME/CFS/Long COVID clinics and they're multidisciplinary clinics. They can make a huge difference in your lifestyle and so they can treat things symptomatically depending on whatever is 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 a lot 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 forwards 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 wild reservoir study. So here in small sub-subdominal drills 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, tongue, skin, muscle, GI biopsy you know try to look for the virus and take everybody fluid that we possibly can and look for wild remnants to try and understand what it is. So that's one and the second one is that one of the most comprehensive studies looking for that virus 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 control study crossover design whereby everybody gets it but you get placebo or you get IVIG and then after a few weeks if you got one you get the other but patient is never told which one they're getting. That is ongoing right now. On what size is your cohort in that? 40. Okay. Then the third study that hasn't yet been started that is to use a checkpoint inhibitor and that's a drug called Pembrolyzumab and that blocks a molecule called PD1 and that is the reverse immune exhaustion and I had mentioned that in the MECFS paper that that's what I like to do but we came across a lot of resistance from pharma and other people they thought that by reversing the immune system you could actually cause autoimmune 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. So we got an FDA approval. I've got a approval from my scientific review committee that now the IRB and will be ready to recruit. Okay and then what that does is it's essentially resetting the immune system by taking the breaks off the B and T cells. I believe that's what I read you had read. So it's almost firing your B and T cells into fully activating and therefore hopefully clearing the viruses that they were behind it. That's the goal. That's the goal. That'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 works 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 nationally or globally in terms of recommendations of treatments and care? No and they and I it doesn't have the mandate of making direct us. 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. lens and suggestions. Fabulous. Well thank you so much for joining me today. Oh very much. It was a real pleasure. Thank you. Jazz. So his viral reservoir study. Let's just go and take 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. Go on metaphors a bit mixed there but I think you know what I'm trying to say. And that's a really interesting one, Jazz, 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 of the things with the two-day CPET. They had really been picked up by people highly regarded in the MECFS community for their one-day CPET and Dr. Nath said but it had such a detrimental effect on patients that I couldn't bring myself to put them through it. That is something that I had raised with a doctor when I had wanted to have various testing and I think I was asking for a 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 interesting point that comes here 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 listened to on that and patients should 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 the 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 okay 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 I mean checkpoint inhibitor study and yeah 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 is a study we are still we're looking at the science of it so I did actually quite appreciate his humility in terms of him saying well well well 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 and really 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. Yeah great I just wanted to reference the controversies that had been raised from because some people in the community saying you have to raise this raise this and yeah the altered effort. It's a weird choice of language and I'm sure it was accidental but to somehow have got to that place where you don't understand the community well enough to realise that language will be challenging. Just going to be challenging. That feels a bit of a known goal really. An unnecessary own goal. You only need to speak to one patient 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 patient blaming even if that was never their intention. I think a lot of these academics, doctors, researchers maybe very high in the IQ stakes not so much the EQ and there'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 weren't necessarily think beyond that so the subtleties of how it will be perceived on the patient side because they're so laser focused on their specialty. 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. MECFS deep phenotyping study 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 MECFS at large and the areas that those findings coming out of that 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 finish with a little story of I have been really relatively well these past months but I actually have torn a disk in my back so that is why I am like publishing this episode because I am slightly struggling with sitting down and slightly struggling with pain but I wanted to share a little bit of the way that I've reflected on this and much as you your body this week telling you that you've done a bit much we're going 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 big signal 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. 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 Jess and I look forward to our next instalment. Me too. Pleasure as always. Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. 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