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NIH ME/CFS Advocacy Call – August 26, 2022

Ms. Barbara McMakin: Good afternoon, everyone. My name is Barbara McMakin and I'm from the NINDS Office of Neuroscience Communications and Engagement. On behalf of the NIH, I would like to welcome you to this afternoon's call and to thank you for your interest in participating in this discussion with us today.

Today's call is being recorded. If you have any objections, please disconnect at this time. Dr. Walter Koroshetz, Director of NINDS, will introduce the speakers, each of whom will make some remarks, after which we will open the webinar to questions.

During the question and answer session today, if you have a question for our speakers, please select the raise hand button at the bottom of your Zoom screen and we will call on you to unmute. You can also submit questions using the Q and A box. We will try to make our remarks brief so that we can answer as many questions as possible in the time we have available to us this afternoon. Now I would like to hand the call over to Dr. Koroshetz.

Dr. Walter Koroshetz: Thank you very much Barbara, and thanks everyone for your attention today and interest in our research and ME/CFS. Welcome. This is our second ME/CFS briefing of 2022 and since the last call been a number of developments at NIH related to ME/CFS and we look forward to sharing these with you.

On the docket for today, Dr. Avi Nath from the NINDS Intramural Program will give us updates on the intramural ME/CFS study, which took place, and the data is being analyzed now at the NIH Clinical Center. Dr. Joe Breen from NIAID will let us know what is happening in the consortia, the clinical and data coordinating centers, and the recent annual meeting of the ME/CFS consortia. Dr. Vicky Whittemore from NINDS will talk about the activities of the Trans-NIH ME/CFS Working Group. We're really excited to have a guest speaker this afternoon, Dr. Lily Chu, who is the Vice President of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Today she'll discuss highlights from the IACFS/ME conference that took place last month, which was partially supported by an NIH R13 conference grant.

I've been working with the collaborators from NIAID and NHLBI on the RECOVER Initiative, which we think is very important for ME/CFS because it's looking at the persistent symptoms that occur in people after COVID, most of which overlap, unfortunately, quite well with what people with ME/CFS are suffering from. And so, as I've said before, this massive pandemic, and now the impetus to understand the post-viral consequences, gives us an opportunity like we never had before to understand what has happened to people with ME/CFS probably before COVID. But also, thousands of people with COVID are developing ME/CFS. We think this is incredibly important to all of those with ME/CFS, in addition to its importance for those suffering from long COVID.

I wanted to start off by saying that the entire effort has had patient engagement at the very top of the priority list. There's a national community engagement group consisting of patients and caregivers, people who work with those affected by COVID, people from different communities, African American communities, tribal communities, and some people with ME/CFS on that group. And they've been integrated into the work as this moves forward. They just posted their strategy for patient engagement through RECOVER, which is important to RECOVER, but also there are a lot of lessons for other research, particularly ME/CFS research, going forward.

Now, recently the RECOVER program solicited and then received a large number of projects aimed at trying to understand the pathobiology underlying Long COVID and 37 grants have been awarded for about 40 million, or maybe 40 grants for 37 million. I think it's the latter. But these are all grants to study why certain problems have occurred in people with Long COVID.

And as you'll see, when I talk to you about them, they're all the kinds of things that we've been worried about in ME/CFS, but never had the large numbers of patients or the natural experiment of being able to see people very shortly after infection to study these things. There are projects looking at what happened to sleep, what happened to the autonomic nervous system, and why did those things happen? Looking in the spinal fluid for abnormalities related to cognitive trouble, looking at immune cells circulating in the body, looking for evidence of immune dysregulation, and experimental models looking at how the virus affects the blood vessels of the brain. Even now we know it's very important acutely, Dr. Nath is the one who discovered that, but also potentially chronically. Looking at metabolic disorders that occur after Long COVID, even in animal models, even in non-human primate animal models that are closest to humans. And some of these projects are focusing on animal experiments, some are looking at patients, and others are targeted at children as a special population of importance.

The next area I wanted to mention is that the RECOVER Initiative has set up a system now to do clinical trials to try and understand what therapies might be helpful in people who are having persistent symptoms of Long COVID. And I would say that the group is instructed by a series of experts, many of whom are picked as people who have expertise in post-viral illnesses. I was just looking at the list and it's 15 people on that list who list their expertise as ME/CFS. And there's another 11 people on that list that list their expertise as postural orthostatic tachycardia syndrome or dysautonomia. So the experts that are involved in the RECOVER Initiative and its work are very closely allied to the ME/CFS researchers as well. The clinical trial steering committee also has people with ME/CFS experience.

And we're looking for clinical trials in two general baskets, the first of which is trials that are looking at intervening in what could be the underlying biological problem, something we've never really quite been able to get to in ME/CFS. But we're looking at things like persistent viral reservoirs and how to get rid of those. Is there evidence for those? And looking for things like alterations in the immune system after COVID. Certainly, COVID disrupts the immune system when you have it acutely, and in some people, it may reset well and others not so well. We're trying to understand that and see if there are interventions that could intervene. Dr. Nath is also running a post-COVID project in the intramural program with similar ideas.

The other area, the other basket is trials that test interventions that attack specific symptoms. So again, in the underlying biology it could be that all the symptoms in an individual could get better. But as we know, that's a long shot. We hope we get there, but we also have to think about things that actually help the symptoms that people are experiencing now. So a number of trials came in which are trying to improve cognition and fatigue in people, and other trials are looking at sleep disorders, how to improve sleep, how to improve autonomic function, tachycardia, drugs that could potentially reduce the tachycardia. And ways in which exercise intolerance can be helped, with special attention to make sure you don't make people worse who are going to develop post-exertional malaise. These are the kinds of symptomatic clinical trials the group is looking at as well.

And all this has been done with patients. So like all the NIH studies, all studies are reviewed by a group of experts. In this case, we actually had two or three patients on the review panels, so patient input was really important in getting the reviews of these clinical trials. We're working on trying to get a post-viral or antiviral trial going quickly and hopefully others to follow in the coming months. So lots of activity, lots of people working on this. I think it's very well coordinated with the ME/CFS research community and patients as well. And so we really look forward to some successes in the near future.

I would say that the other part of RECOVER, which we talked about in the past, was recruiting people to a natural history study, which is going quite well in terms of recruiting people who have symptoms of Long COVID. I think we're upwards at 8000 people now, so it's the largest in-person study of Long COVID in the world. We're still trying to get people who have acute infections so we can study what's the difference between, right from the beginning, someone who is going to make a good recovery versus someone who is going to develop Long COVID. That's been more difficult for a lot of different reasons, recruiting patients. But if people hear about someone who has COVID and if you can get them interested, we're really looking to try to enroll people who have had a recent infection so we can follow them over time.

So that's my update and again, it's an amazing time to try and look at these kind of questions that have been hanging over the ME/CFS community for so long. And with that I would like to turn it to Dr. Nath to give us an update from the intramural program.

Dr. Avindra Nath: Thanks, Dr. Koroshetz. As you mentioned, we've been analyzing the data from the ME/CFS cohort that we recruited here to the intramural program. And so when COVID started, we had to stop that study and we went into data analysis mode. And that's coming along really well. There was a huge amount of data, but I think we've got most of it together now and the manuscript is being written. And so I'm hoping that within the next couple months we'll be able to submit it.

In the meantime, we've also focused our efforts, just as Dr. Koroshetz said, looking at the ME/CFS-like symptoms in COVID patients and we have had over 700 inquiries from patients who want to enroll in one of our studies. We have several of them here. And of those, we had about 361 that we thought would qualify for some of our studies. We initially just put in a huge questionnaire to try and understand all the symptoms and other things that they're experiencing. So we had over 200 individuals who did the baseline questionnaire, 150 who did the three month follow-up, about 100 with the six month follow up, and 83 have had nine month follow-up visits. And then the 12-month follow-up was done in 81 individuals, 56 have had a 15-month follow-up, and 12 have had an 18-month follow-up. Of these seven, we have enrolled in what we call Phase B, where we brought them into the Clinical Center and studied them extensively. There are another five that we're waiting to bring in, we're just waiting on some records.

And then there's a treatment study that has been approved and we're just starting to enroll patients. It will be a three-arm study with placebo control with corticosteroids and IVIG. That's where we stand at the moment, and I'll pass it over to Dr. Breen.

Dr. Joseph Breen: Thank you, Dr. Nath. Hi, my name is Joe Breen and I work very closely with Vicky and others and NINDS to oversee the Collaborative Research Centers. And I wanted to give you a brief update since the last telebriefing on two things. One is the status of the output that we've seen in the literature from the Collaborative Research Centers and then we actually had an annual meeting of the network with significant Community Advisory Committee involvement in June.

The other piece that is part of the Collaborative Research Centers that I want to draw attention to is the Data Management and Coordinating Center which is operated through a cooperative agreement run by NINDS. And they have built mapMECFS that's really growing in the amount of data that is curated and organized, and as the publications in this field increase, both from the CRC's and at large, is becoming increasingly powerful and valuable based on the tools that they've built there to organize the information. So I would encourage anyone who's interested to look at mapMECFS. And actually related is another tool called searchMECFS for samples that that could potentially be used with the proper request, of course. So in terms of productivity, when I prepared for this, now is the largest state of publications that have been available as an output from the research centers, which you would expect over time, but it's still a nice sign, even post-COVID. And I just want to review a few very briefly to give a flavor of the types of studies that were recently published.

Maureen Hanson's group at Cornell, published in May some plasma metabolomics looking at the disrupted response following really intense exercise to try and understand what are the metabolomic changes that are occurring in people with post-exertional malaise. And they saw a number of changes that, of course, will be continued to be analyzed in a number of different ways. But the paper notes some glutamate metabolism differences and I think that is a clue as to how this is occurring, and then of course, how we might disrupt that or potentially treat it. So I think the theme here is that this work is beginning to help us understand the metabolic changes that are occurring, which will hopefully lead to therapeutics, even new therapeutic ideas to help patients with these severe energy issues.

In a related way, the Lipkin Center at Columbia also had a paper published looking at metabolic evidence for peroxisomal dysfunction in ME/CFS, which was consistent with some lipid remodeling and citric acid cycle dysregulation. Again, looking at energy metabolism and pathways. Probably not surprising, but it really is more detailed and is a pathway that's extremely well known and potentially could be impacted. Again, over time, as these results are compiled and put into mapMECFS and cross-validated with each other, we really hope that this helps us move forward and we expect that based on this kind of output.

In addition, I want to point out two other studies, one that was recently published in Proteomes from the Hanson Group looking at anti-pathogen antibodies in ME/CFS patients. It was a small study, but what was really remarkable in this study was that some sex-based differences in humoral antibody response were very evident and really differentiated. I think that is important information, and obviously the authors did too and the journal. So I think that is a theme. We have metabolism differences and sex- and gender-based differences, which is not surprising, but again, it adds pieces to the puzzle.

The last study is how orthostatic challenges also showed distinct symptomatic hemodynamic and cognitive responses in a paper by a combination of different centers but led by Tony Komaroff. In June, in Frontiers in Medicine, where they used the NASA Lean Test, and again, trying to come up with and understand a test that would be able to measure orthostatic differences that are so common in ME/CFS in an office setting. The testing I was mentioning from Dr. Hanson is quite involved and it's a different way, so this is looking at more of a physician-based test to try and understand orthostatic intolerance and autonomic changes. And I think that the differentiation and detailed nature of those studies should also be informative.

These results, which are now public, were part of what was presented in the annual meeting in June, which was a day and a half, and I think this is really just a tip of some of what was presented in that meeting. I'm expecting that more will be published over the next few months based on what we saw. And again, I think we had significant input from the Community Advisory Committee. They were able to see what the results are from this annual meeting, and it was also an opportunity for our Canadian colleagues that we work with as part of the network to present their recent results and to have a discussion. We were very fortunate that we could meet in-person because it happened to be a low in COVID, and with the appropriate spacing. We don't know whether we'll be able to do that again in the short term, but we were very fortunate to be able to do that. I think I'll stop the update here and I'll turn it over to Vicky.

Dr. Vicky Whittemore: Thanks. Great, thank you Joe. Just to let everyone know that the applications for the Centers and the Data Management Coordinating Center have been submitted and will go to review in October or November and the funding plan will go to Council in February of 2023. So we're looking forward to ongoing funding of the work that's going on in the centers and potentially adding new a new center or two.

The other thing, I'll be brief so we can get to Lily's update, the Trans-NIH ME/CFS Working Group continues to meet monthly to talk about various issues related to ME/CFS and Long COVID. At our most recent meeting we looked at the National Plans that were released by HHS for research and for services to look at the potential impact those reports and plans will have on ME/CFS, and I think they were quite broad, and at this point, not a lot of detail provided. So we look forward to getting more information and more details about the plans in both of those plans going forward.

The Trans-NIH Working Group is also planning for several activities in the next year and continuing to look at ways in which we can improve and increase the number of grant applications that come into NINDS and all of us – Joe and I and all the other program directors – continue to meet with investigators to work with them on their grant applications prior to review, after they get reviewed, and we really try to move research on ME/CFS forward. I'm going to stop there so we can give Lily time to present.

As Dr. Koroshetz said, Lily is the Vice President of IACFS/ME, and we're thrilled to have her with us today. She served on multiple federal advisory panels and also has collaborated with Stanford University on some research studies and is going to give us an overview of some of, I'm sure she can't cover the entire IACFS/ME conference in 20 minutes, but I'll turn it over to you now Lily, and thank you very much for being with us today.

Dr. Lily Chu: Thank you, Vicky. Hello everyone. I'm going to share my screen now. My organization IACFS/ME, for the three decades that we've existed, we've regularly held scientific conferences often with the help of the U.S. ľ¹ÏÖ±²¥, NIAID and NINDS. I want to thank them for their support through the years.

This year's conference was virtual, and it was held over three and a half days in late July. We had over 300 attendees from all over the United States and 30% from even outside. There were 58 speakers and 20 plus posters, and because NIH sponsored a conference attendance award, about 20% of those attending were students, trainees, or early career professionals – very important for this field to continue to make progress.

Vicky alluded to, I am not going to be able to cover 60 presentations in 20 minutes, so I'm going to focus on three themes that I think cut across multiple studies and these are: infection, specifically Epstein-Barr virus, immune exhaustion, and imbalance in the autonomic nervous system. And I'm going to give you...I have a biplane here because I'm going to give you the 15,000 foot view. On the one hand, I will give you some details of the studies, but what I really want to focus on is the big picture. What is the context for the study? What questions or issues was it trying to address, and how might the results advance our understanding of ME/CFS or affect clinical care in the future?

Theme number one: infection. As many of you know, a lot of patients say that their ME/CFS started with Epstein-Barr virus mononucleosis, and this figure here illustrates the EBV life cycle. Traditionally, it's understood to be in three phases. So you have this blue phase, which is when the virus first infects the person, and then it shuttles back and forth between the lytic phase, where it's producing baby viruses and they're bursting out of the cell. And that's why it's called the lytic phase – lysine is bursting out of the cell. If someone's immune system is relatively healthy, that infection is controlled pretty quickly, and the virus becomes dormant, and it usually doesn't cause too many problems in this state called the latent phase. And because this is our understanding of Epstein-Barr virus, all the current tests that your doctors order and the antivirals they prescribe, they target these phases.

But what if this picture were wrong? It might explain why when people go to their patients, the doctor says, "I don't think that Epstein-Barr is causing you any problems or that it plays a role in your symptoms" and it might also explain why antivirals don't work for a lot of people, or if it does, it's only temporary or only has mild to moderate effects. Over the last, I would say over a decade, there were several groups that have looked into this question, and they believe there's a fourth state called the EBV abortive lytic state. It's intermediate between the quiet, latent state and the reproductive lytic state.

One group that has been looking at this for many years at Ohio State University is headed by Dr. Maria Arisa and her graduate student Brandon Cox, who presented at our conference. In particular, they focused on an enzyme called the EBV dUTPase, which is involved in not only virus replication but also immune dysfunction. And in a prior study, they showed that 50% of ME/CFS patients had antibodies to the EBV dUTPase versus a much lower 29% in the healthy controls. So their studies are asking questions, do dUTPases cause immune dysfunction and what is the mechanism if it does?

The first study they did was they took blood from healthy controls and ME/CFS patients, and they looked at a number of substances in this blood. One of the substances they found that was significantly different is called Activin A and you can see here in this figure two thirds of the ME/CFS patients had above normal levels versus 14% in the controls. Activin A is interesting because not only is it involved in inflammation and infection, it's also involved in keeping the hormonal balance in people's bodies, and it also affects muscle growth. The next thing they did was they took this group of ME/CFS patients and they split them. So there were some who had antibodies to the dUTPase and some who didn't, and they compared Activin A again and they found, even though this figure isn't the best you can look at the numbers here, that the positive people who had antibodies, they had a much higher level of Activin A versus the people who didn't, about 1300 more picograms.

They then homed in on these people who had positive dUTPase and they exposed naive CD4 T-cells to the serum of these patients. So CD4 T-cells, if you think of it, they're like babies. So a naive T-cell is like a baby, doesn't know what it wants to be when it grows up, and then as it matures, it graduates high school, graduates college, and it starts to specialize in certain activities. This chart, the Y axis shows a marker for more mature T-cells and also the percentage of more mature T-cells. Then down here you see different combinations of media that they exposed the naive T-cells to. So from our prior studies, we know that for the people with ME/CFS, their serum likely has high levels of Activin A and probably EBV dUTPase because they have antibodies to it. I just want to concentrate on the control sera and then on this bar with the ME/CFS sera, and you can tell there's a significant difference in the percentage of cells - here you have around 35% versus maybe 17% in the control sera. And what that implies is there are more mature T-cells in the ME/CFS patients.

To further tack down the role of the different substances involved they also added FST, which is an inhibitor of Activin A. So since after the inhibitor, what you would expect, it's this bar, is when they add it, the number of maturity cells would decline and it did. Basically, this figure, the summary is that Activin A is sufficient to stimulate CD4 T-cell maturation. Now they did about eight different sub-experiments, and I'm not going to get into all of them here, but the bottom line is they showed that despite more mature T-cells in ME/CFS patients, these cells were not functioning normally, they were producing less cytokines, for example.

So what's the upshot of all this? Well, this work and others could redefine what we call an active EBV infection and it could lead to development of tests that look for this particular state because current tests do not cover the state. Secondly, antivirals may be developed that target the abortive lytic state, which not only has implications for ME/CFS, but for a bunch of other EBV-associated conditions like multiple sclerosis and even certain cancers.

Theme number two concerns immune exhaustion, in particular, in CD8 T-cells. The thinking is if you have a chronic viral infection in someone, their immune system is going to be constantly battling it and it's going to become exhausted over time. So a bunch of researchers have looked at this issue, particularly in CD8 T-cells, which are another component of the immune system, because these cells target viruses. We already know that in these T-cells, there are changes in energy production and use, and they also have changes in electrical signals across the mitochondria, which are the factories inside of cells that produce energy. However, are there any other changes that support exhaustion and what can be done when this is seen?

The first set of studies comes from Jessica Maya at Cornell University, and this is a complicated figure, so I'm going to try to simplify it. Basically, she looked at markers on the surface of the cell, like this one, or markers inside of the cell, like these three. And she said, are they more common in ME/CFS patients versus healthy controls? So you can see here that she looked at combinations of different markers and in three out of the four, you can see the star here, there were significantly higher levels of markers of immune exhaustion in the ME/CFS patients versus the controls.

Another way of looking at exhaustion is looking at the function of the cells, and so you have Dr. Lisa Selin and Dr. Anna Gil at the University of Massachusetts looking at this. They took CD8 T-cells, again from healthy people, from people with Long COVID, and people with ME/CFS, and they stimulated them. Then they asked how many cytokines, or what percentage of these cells produce cytokines, which are messengers between the cells. And so the first side looked at was interferon gamma and then the next one was TNF-alpha. And you can see from this figure that in the healthy people, about a third of their CD8 T-cells were producing the cytokines, but less than 10% in the Long COVID and the ME/CFS group were producing the cytokines. So bottom line, CD8 T-cells have markers that indicate exhaustion and function that also indicates exhaustion.

They went a step further and they started looking at a new inhaled medication, a proprietary medication called Inspiritol. I want to point out that these are in very small number of cases, five people in Long COVID and four people in ME/CFS. And so very preliminary results, when these people were given both Inspiritol and I think some of them were given an antiviral because they had evidence of reactivation of viruses, they not only experienced improved symptoms, but also increased function of their CD8 T-cells. They looked at their cytokine levels and found that either an increased percentage of these cells were producing cytokines or that they were coming back closer to the normal level of 30%.

So what's the upshot of this? Well, first, I described immune exhaustion as the egg. It's the consequence of chronic viral infection. But what if it's a chicken? Or what if it is one of several chickens? For example, your ME/CFS might have started with EBV, but now that you're no longer able to control the other microbes in your body, you might be attacked by viruses, bacteria, even parasites. Whatever you've been exposed to in your life. These abnormal CD8 T-cells, they also can increase inflammation and increase the risk of autoimmunity. The markers and the function that these scientists have looked at, they could be combined in different ways, potentially in the future to help diagnose ME/CFS or to help us develop subgroups within ME/CFS.

I also was thinking that for many years, decades, people have been looking for the cause or causes of ME/CFS. Specifically, which virus, which bacteria, etc. But what if instead of trying to find that cause, we looked at improving the environment around that cause? Could it be that we can treat ME/CFS even if we don't know the chicken or the chickens, the starting point? If you look over at the oncology world, they're already looking at ways to reverse T-cell exhaustion. Specifically, there are these medications called checkpoint inhibitors that block surface markers of exhaustion, and some other scientists are also looking into gene editing, where they knockout or silence genes that produce products associated with exhaustion. And finally, if you improve the environment of the body, is it possible that antivirals or other medications might work better in that environment, just like they're looking at both in Inspiritol and antivirals together?

Theme number three is imbalance in the autonomic nervous system. So just very quickly, this is a review of what the autonomic nervous system is. It's the section of the nervous system that controls automatic, involuntary functions of the body. For example, heart rate, blood pressure, breathing, and it's further subdivided into two sections. There's a sympathetic, which is sometimes known as fight or flight, and the parasympathetic, sometimes known as rest and digest. So you have these two sections that push and pull against each other, like Tweedle Dum and Tweedle Dee. The sympathetic dilates the pupils, the parasympathetic constricts them; the sympathetic increases heart rate, the parasympathetic decreases it; the sympathetic it reduces gut motility, movement of the gut, whereas the parasympathetic will stimulate it. So keep that in mind. Also, the sympathetic works through a bundle of nerves that lie along both sides of your spine, called the sympathetic ganglia. In contrast, the parasympathetic works through different nerves, including one called the Vagus nerve. Many scientists have suggested that ME/CFS symptoms could be due to ANS dysfunction and there are some objective findings as well.

For example, there's a group in Germany that have found auto-antibodies to adrenergic and muscarinic receptors in ME/CFS patients at a higher level than in healthy people, and these are receptors involved in the ANS system. There are also several studies that have linked unrefreshing sleep to increased sympathetic activity. So many studies suggest, it seems, that the sympathetic system is predominant in ME/CFS. If you look at this like a seesaw, how do we rebalance it so that these two are no longer one-sided, one way or the other? Well, you can either increase the parasympathetic signal or you can decrease the sympathetic signal, and that is what the next two researchers' studies involve.

The first study comes from Drs. Duricka and Liu at Neuroversion in Alaska, and they reported on five cases of patients that they serendipitously treated with stellate ganglion block. So what is SGB? This is when anesthetic is injected into the stellate ganglion, as I mentioned earlier, that run along both sides of your spine and this is a cross-section, as if you are looking down from someone's head. You can see where they injected it. This is actually a standard procedure for anesthesiologists, and it's been used for many years. It's approved for treatment of various pain syndromes, excessive sweating, Raynauds as well.

The way it works is they think it blocks sympathetic signaling via the stellate ganglia. Here they reported on five cases. I'm just going to show you two to show you how different they are. So these patients were both middle-aged, they had been sick for longer than 15 years. The first patient became ill after an estradiol injection, whereas the second patient became sick after hospitalization for mononucleosis and Hep A. They both had experienced PEM and they both had an approved indication for stellate ganglion block. These are serendipitous discoveries, they didn't set out to treat their ME/CFS.

The first patient had ten sets of injections over 21 days. The second patient had eight sets over four months, and the outcomes were quite different. So even though they both experienced some improvement in multiple symptoms, the first patient recovered their function to 95% or pre-illness for at least nine months, and they're still doing well It sounds like, with no further treatment. But the second patient, when they did respond, it was only after two months, and the response was only for about six weeks. And then about four months into treatment, they relapsed on their ME/CFS with surgery, and I think they're resuming treatment now. Two very different cases. I want to emphasize that these are small case reports, and that Drs. Liu and Duricka also talked about the risks of stellate ganglion block, there are significant risks to doing this procedure.

The second study I wanted to mention concerns transcutaneous auricular vagus nerve stimulation, or taVNS. This was reported by Dr. Nicola Clague-Baker from the University of Liverpool in the UK. This treatment was originally developed for treatment resistant seizures and depression, and basically it stimulates the parasympathetic signaling, it increases it through the vagus nerve. Here is a device. It's like an earbud that's placed in the ear. The vagus nerve runs through the neck and all the way up into the ear, which is why you can stimulate it via the ear. And then there's a device that provides the electrical stimulation. Dr. Clague-Baker interviewed 116 people, 75% of whom lived in Europe and half of whom had been sick for more than 10 years. Only about 10% of them had used it for more than a year. And at this point, 70% of them are still using it but 30% have stopped. The main advantage was that about 40% reported that their PEM and cognition improved, but the main con of the treatment was that 15% reported headaches and 10% reported skin irritation. When she did ask them, would you recommend this to other patients to try, 80% of them said yes, they would suggest it.

There are some cautions here. Coverage of the device. It may not be covered, it may be expensive. There are many different models out there and they're all different in the way they work. It may take people time to find the right dose frequency that works for them with less side effects. And if you read about vagal nerve stimulation, a lot of the studies are about implanted devices which are not equivalent to these ear devices.

So what's next? I think these studies should encourage more exploration of the ANS's role in ME/CFS. Neither of these reports were clinical trials, and they were clear about that. What we really need are clinical trials to test if these procedures actually work. And then after that, they need to be replicated, and then after that, you need refinement. What dose, what frequency? How long should people be treated?

Another thought I had was even if they aren't used specifically for treatment, it could be used as a way to target treatment. So for example, in the future, if there's a medication that works but it has a lot of side effects or is expensive, using these types of procedures might help us pick out which patients would respond better to that medicine. I've been in the ME/CFS field for 15 years now and I'm really optimistic about what I'm seeing. In the past, there were a lot of studies that had contradictory results, but now I'm seeing more studies pointing to the same areas. The results are being replicated, and if they're not being replicated exactly, at least they're reinforcing the results of other studies.

I want to point out it's really important to remember that tests and treatments can be designed and assessed even if we don't know the exact causes and mechanisms. I had a journalist ask me, so what's the cause of ME/CFS? I told her I still don't know, but we have these areas – metabolism, infection, immunity, neurology – that converge. And I think even if we don't know the exact way they interplay or what's the chicken, and what's the egg, we could still make progress.

Now, I've gone through these studies really quickly. So if you wish, you can visit our website, which is iacfsme.org and you can purchase the video recordings of the talks. We've also started posting some of the summaries from writers that are freely available. So that's all I have to say, and I'll try to answer any questions. Thank you.

Ms. Barbara McMakin: Alright, thank you so much Dr. Chu for that great presentation. We will now open the floor for the question and answer session. As a reminder, there are two ways to ask questions today. You can click on the raise hand button at the bottom of the Zoom screen, and we will call on you to unmute. You can also type your question in the Q and A box. We will try to answer as many questions as we can, but we may not be able to get to all of them.

We want to hear from as many people as possible, so we request that everyone ask only one question and just a reminder that this call is open to the public and is recorded. We will start by taking questions for Dr. Lily Chu.

I see as a raised hand, DSA Sacramento, you have your hand raised. Please unmute.

Claire: My name is Claire. I guess my question for Dr. Chu is, my understanding is, a lot of people who are hit with both mono and Long COVID in succession are some of the most severe patients out there. I'm really fortunate to have a primary care provider that's pretty well versed in this stuff.

And so I'm curious if these immune cells in ME/CFS patients are in an abortive lytic state, I believe is what you called it, what happens to an immune system that's already damaged in that way? Whether it's EBV or something else, when there's a secondary infection from Long COVID or any other viral agent for this syndrome or disease?

Dr. Lily Chu: That's a complicated question and I was going to preface my talk by saying I'm a physician who's trained in public health and clinical research, but I'm not a neurologist, virologist, or a immunologist, and I would say that as far as I know, I'm sure there are studies out there that look at when you have two hits, but I'm not that versed in them. It's a complicated picture because if you try to design a study like that, first you have to recruit people who have two hits, then you have to verify, then you have to control for things like what two hits did they experience, what was the timing between the two hits?

So it can be very complicated to study that issue. And I would say that if anyone else in the group right now has an answer to that or has read studies about this, I'd be interested to hear about it.

Dr. Joseph Breen: Lily, this is Joe. I'll say I have read recent reports of the difference in response to SARS-CoV-2 infection with influenza. I know that that's an intense area of research. It's mostly in model systems because with the pandemic, the influenza was less reported in the last two years, and that may be different from this fall.

But I know from influenza meetings that's an intense area of research and I think there is some publicly available data that that could get at this question of a compromised immune system from at least influenza followed by SARS-CoV-2. It's not exactly what the person asked, but I'm not aware of a study yet looking at EBV followed by SARS-CoV-2. I think that's probably being done, but I think the literature right now is available for what I described.

Dr. Lily Chu: The other question too is if you have EBV following SARS, how did they diagnose that person with EBV mononucleosis? Because if the thought is that SARS could cause the immune system to be weakened already, is that actually a reactivation and is that reactivation truly causing the symptoms or is it just based on the lab work?

So there are a lot of questions even if you have EBV mononucleosis following COVID-19 versus if you say you had it before and then you develop COVID.

Ms. Barbara McMakin: Great, thank you. We'll go to one of the questions that was submitted in the Q and A box.

[Question] Is NIH studying the 7300 ME/CFS patients enrolled in the massive NIH All of Us Research Program database, comparing them to the 10,000 plus COVID/long COVID being studied in that program?

Dr. Vicky Whittemore: I can answer that because I just recently had an e-mail exchange with Leslie from the Solve ME/CFS Initiative and they are digging into that data, which I think is really fantastic, that they're looking at those individuals and looking at what data is available both in terms of clinical data, genomic data, and adding that information to the rich data set that they have from their registry. So that's very exciting.

Ms. Barbara McMakin: Great, thank you. We'll go to the raised hands. I see David. You can go ahead and unmute.

David: Yes, thank you all for having this meeting. I appreciate the good work you guys are doing. This is David. I was just curious; I have a question for Dr. Chu or any of you on here. Why hasn't there been more of an effort to look at the role of environmental toxicants like mold and ME/CFS? I'm just curious because you guys have looked a lot at the role of viruses and things that affect immune system overactivity and underactivity. But how come there hasn't been more of an effort to look at mold? Thank you.

Dr. Lily Chu: I can answer that at least from a research design perspective. I looked at this issue briefly several years ago because I conducted a survey based at Stanford. Out of 150 patients, some people said they had exposure, or they thought they had exposure to mold, and that it might have played a role in their illness. Although a lot of that group also said they had an infection kicking off their ME/CFS.

The issue is that anytime you're talking about an environmental factor, it's hard to design a study like that, because you're trying to isolate a particular group of symptoms or symptom to a factor and people are exposed to hundreds, thousands, millions of factors in their lives every day. So how do you control for those factors, and everyone is individually, exposed to different things, and isolate the symptoms or group of symptoms to one factor? That's one major reason I see as why it's difficult.

There's also a paper out there from a few years ago when I was looking at this issue, looking at how do you establish toxicology? How do you link it to a disease? And so, I can share that paper later if there's any emails coming out from NIH and people can read about it, but it's a technical paper that are issues around that.

Ms. Barbara McMakin: Great, thank you. We’ll go to another question that was submitted in the Q and A box.

What studies are looking at long-term ME/CFS patients (5 to 10 years and over) of all ages? Any new studies coming up looking at this group, particularly blood analysis?

Dr. Vicky Whittemore: I can answer that one also. In the center that was funded, Derya Unutmaz, who is the PI at Jackson Laboratories and working very closely with Cindy Bateman at the Bateman Horne Center and Suzanne Vernon. They have studied individuals with ME/CFS who were ill for four years or less and compared them with individuals that were ill for 10 years or more. I hope I got those right, Cindy, I think I saw you on here.

But they are seeing differences in when you divide those two populations. So I think they're working on finalizing all of that data analysis and putting out the publications. And I would expect that there will be additional follow on studies like that from that center and from other centers, where we begin to really separate out the individuals with ME/CFS depending, on as Joe mentioned, both male/female and versus length of illness.

I think those studies are still to come and as far as I'm aware none of them are recruiting at this current time. But as soon as those new centers are funded and are beginning to recruit, we'll certainly circulate information about how to get involved in those studies.

Ms. Barbara McMakin: Great, thank you. I see a number of people have their hands raised. Rivka Solomon, feel free to unmute.

Rivka Solomon: Hi, thank you. First of all, Lily Chu, thank you so much for reporting. That was really wonderful, and I happened to be texting right now with Luke Liu, the stellate ganglion block M.D. and he asked me to say to you, please tell them that this, that stellate ganglion block is more of a proof-of-concept of physiological manipulation and neuromodulation effect on ME. He's not advocating for widespread use. And the other thing to mention is that the two patients that he treated that Dr. Chu just talked about were being specifically treated for their ME.

Separate from that, I just wanted to ask Dr. Koroshetz. Dr. Koroshetz, I think you mentioned that there was going to be a clinical trial for post-viral patients. Was that going to include ME?

Dr. Walter Koroshetz: Thank you for that. The issue in Long COVID is whether the SARS-CoV-2 virus is persistent, and that's somewhere hiding in a tissue somewhere. And we've seen some evidence that it might be the case, but it's not definite yet. The first trial we're thinking of, in fact, as part of the RECOVER Initiative, is to look at an antiviral for the SARS-CoV-2 virus itself.

So that's the kind of low hanging fruit, swinging for the fences type of idea that we're looking at first. Because if it's true, it could have widespread, major implications.

Ms. Barbara McMakin: Alright, thank you.

Dr. Lily Chu: I also wanted to just point out that I asked Dr. Liu and Dr. Duricka about the risk of SGB. I think it's important to mention them just very quickly. So the neck has a bunch of different organs and nerves running through it and you have the thyroid which leads a lot, and you also have these nerves that control breathing and speech and you have this huge carotid artery that takes blood up to your brain.

Dr. Liu is very careful about saying that he has a lot of experience doing this and they do it under guidance with an ultrasound. So they're not just poking around. I've done this before when I was a resident putting in catheters. They now have an ultrasound that can visualize what that area is before they put in the needle. But yes, he was very careful about not advocating for that as a treatment right now.

Ms. Barbara McMakin: Great. Thank you. We have time for one more question. Please send any additional questions to braininfo@ninds.nih.gov or go to the NIH ME/CFS website and click on contact us to submit those questions. Nancy Matthews, you can unmute.

Nancy Matthews: Hi, this is very interesting. I just wanted to follow up with a question to Dr. Chu about retraining the sympathetic balance to the autonomic nervous system. I was wondering how you felt about using biofeedback as a method to do this?

Dr. Lily Chu: If you start looking in the literature, there are different suggestions for trying to, in particular, increase the parasympathetic signal, especially in the athletic literature where you have a lot of athletes who are trying to recover from a hard day of exercising and they have things including meditation, yoga, cold water, showers, there are suggestions like that. In terms of feedback, I don't know if there are any studies that have looked at this.

One thought is, what the risks and what are the expenses? With ME/CFS and with Long COVID, when you're talking about a disease that doesn't have a disease modifying treatment, if something is relatively inexpensive or you can afford it and it doesn't have much risk, then I think you can talk to your doctors and your healthcare providers, and it might be worth trying. The real problem is when you're talking about treatments that have a lot of risk, side effects, and are very expensive. If you have tried neural feedback, what was your experience, Miss Matthews or anyone else in the audience?

Nancy Matthews: I used to be a biofeedback therapist years ago, before I came down with chronic fatigue. And I did a lot of training when I was sick and I do think it was one of the things that put me into a shift. And I regained about 80% of my health. There are no risks with biofeedback equipment. There are hundreds and hundreds of studies because this was done by psychologists and they'd love to study everything, and the device that I used is not expensive, it was $60.

Dr. Lily Chu: One question is when people talk about recovery with various modalities, again, this points to the need for clinical trials because we know... I remember in my survey I found large numbers of people, their symptoms would fluctuate up and down. And in fact, some people had remissions of up to several years even, and so the question is, when you're doing a treatment with those fluctuations and with people who even have remissions that can last for a while, are you seeing a natural fluctuation or remission, or is it truly a treatment? Only with clinical trials can you really get at that answer.

The other issue is how much gain are you going to get? In your case it's great that you had that huge gain from where you were previously, but a lot of these treatments, they might do enough. I mean mild or moderate changes could mean a significant increase in the function or quality of life for someone from their baseline. But you might need more than just those treatments. You might need a combination and an actual medication that gets at the disease.

Barbara McMakin: Great. Thank you. Well, we are at time. We'll go ahead and close out the webinar. A recording and transcript of the webinar will be posted to the NIH ME/CFS website soon and that’s .

I'd also like to remind you about our listserv for updates from NIH. To be added to the listserv please visit the NIH ME/CFS website and click on join our listserv. Thank you all for an informative and thoughtful discussion. Have a good afternoon and a great weekend.