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NIH ME/CFS Advocacy Call March 30, 2021

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 answer your questions. If you have a question for our speakers, we invite you to submit it through the chat 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, Dr. Koroshetz.

Dr. Walter Koroshetz: Well thank you very much Barbara, and thanks for those who are calling in. I want to start by saying that I'm kind of representing the work of many different people here at NIH, across multiple different institutes and Dr. Joe Breen is here from the NIAID institute and many of the folks here are from NINDS, which is the neurologic institute. We are all acutely aware of the lack of progress in delivering therapies for people who are suffering from ME/CFS.

And please know we're as frustrated as you are and we are working as hard as we can to try to change that and to develop science that would inform treatments for people who are suffering with ME/CFS. Since our last call there have been several developments here at NIH which are related to ME/CFS and we want to update you about those. As you know NIH is still in the midst of trying to fight the COVID-19 pandemic. We are hopeful that the vaccines, now three available, will help get the virus under control.

Although there is still serious concern that until we can stamp out this virus, that we may have to be dealing with multiple different mutants of the virus and that this could be a more continuous battle. Although there is a lot of hope that if we can really get it under control now as the vaccines are coming out that we can get control over the mutant virus as well. So we do encourage everyone to continue social distancing, wearing masks, and get your vaccine as soon as it is available.

We have not heard of any adverse reactions to the virus that are more common in people who have ME/CFS but everyone who gets the vaccine, or many people who get the vaccine anyway, will have some side effects that last about two days, with severe fatigue, muscle ache, sore throat, headache, and so those I'm sure exacerbate the problems that people with ME/CFS are having but they should be short-lived.

Now the issue that seems to be most relevant to ME/CFS and COVID-19 is the emergence of continuous symptoms in people who suffered an acute infection with COVID-19. Some of the people who have persistent symptoms were hospitalized in the intensive care unit and developed acute respiratory distress syndrome. People who have developed acute respiratory distress syndrome even without COVID are expected to have a fairly long recovery stretching out six months to a year.

What is more surprising after COVID-19 is that people have developed persistent symptoms even if they only had quote unquote a mild case which was treated at home. So with the viral infection like many others one would get fatigue, aches, pain syndromes, cough, this shortness of breath, and they may last a week to three weeks at home and then they start to get better. But unfortunately there are a significant number of people in whom the symptoms have not dissipated and there have been reports now with people who are out even past six months and according to our definitions of ME/CFS, many of those would probably qualify for the diagnosis of ME/CFS now after COVID-19. This is of course unfortunate.

There are millions of people who have been infected with the virus and so even if a small percentage quote-unquote small, one to five percent, have these post-acute sequelae of COVID, that is a serious public health problem. The potential silver lining is that one of the major stumbling barriers to understanding ME/CFS has been that, although there was suspicion that it occurred due to a viral infection or some other infection, there was never the natural experiment that we have now to actually look and see knowing when the infection occurred and knowing exactly what the infection is and being able to follow people after they're infected trying to understand why some people develop persistent symptoms and others do not.

And that actually is the subject of a major initiative coming out of NIH. We call it the post-acute sequelae of COVID Initiative and it has received over 1 billion dollars of funding from the Congress to understand this condition. We now have plans that are underway, we have calls out for grants. Some of them have already come in and those grants fit into three major categories. One is, as I just explained, to try to understand what is the natural recovery after COVID-19 infection and what differentiates those people who recover quickly, those people who recover slowly, and those who may have symptoms, even sick more than six months later.

So we can do that now unfortunately because there are still a number of active infections. We have to do this now hoping that if the vaccine takes effect we will no longer have the acute infections and we'll lose that opportunity to study the recovery process in large numbers of patients. The second group is to study people who are persistently symptomatic after COVID months after the initial infection and to try and understand the underlying biology in those folks. And these strategies will be, it's very similar to those that have been used to try to study ME/CFS but we're now able to focus particularly on COVID-19 and its effects whereas in ME/CFS in general we did not have that ability to focus on a virus and its ensuing pathology.

The third part of this project will be to set up cohorts that can be followed over many number of years potentially using electronic health record data to try to understand the incidence and prevalence but also to set up infrastructure that would enable us to know whether COVID-19 increases one's risk for common diseases, say atherosclerosis or dementia for instance, occurring five or six years from now. We don't have any suspicion of that now but because of the large number of people infected we feel it's really important to set up to check on this in the future. So this is the research that's going on in the post-acute sequelae of COVID space.

As I mentioned its incredibly relevant, we think to ME/CFS. It has significant resources, there'll be data centers where all the data will come in, there'll be sample repositories where samples can come in for future study, there's an autopsy component to try to see if someone dies with post-acute sequelae of COVID, we don't expect them to die of it, but they may die for other reasons with the condition. We can try to see if there is a continued pathology with, and this has been a real stumbling block in trying to understand ME/CFS.

I think a lot of the research that's coming out now has a chance to really help ME/CFS. In addition physicians will be taking care of people with post-acute sequelae of COVID and the symptoms, and trying to help those folks. We're hopeful that will actually also spill over and help us better take care of people with ME/CFS, even if it's not due to COVID. This has been a big problem in the past but there are now many more physicians who have been recruited in now to take care of the type of symptoms that people with ME/CFS have in these post-COVID groups.

You'll be hearing from Dr. Nath about an intramural study looking at both ME/CFS and a study now looking at the post-acute sequelae of COVID. And Dr. Breen will also let us know what's been happening in the consortium we have for ME/CFS research. And Dr. Vicky Whittemore will discuss the activities of the Working Group. And as always we're very eager to hear from you, so we'll keep our remarks very brief. With that I'd like to turn the call over to Dr. Avi Nath.

Dr. Avi Nath: Thank you Dr. Koroshetz. So I'm going to tell you three things. One is I'll tell you where we stand currently with the ME/CFS study that we were doing. Second thing I want to tell you is what we've been doing with COVID and the third thing I'm going to tell you is the overlap between COVID and ME/CFS and what we're doing about that.

So first of all with the current ME/CFS intramural study that we were conducting, it came to a grinding halt when the COVID outbreak occurred but we took that opportunity to look at the data that we have collected on these patients. And we have a huge amount of data and so what we did was, we formed working groups, several different working groups, one for immunology, one for the virology, one for the physiology that we've done, and so on and so forth. All those people have started looking at the data, analyzing it and when you analyze data it leads sometimes to more questions than answers, which is the way science works, but I think that's perfectly fine. So now we're doing some follow-up experiments to answer those things, trying to make correlations between each of these working groups. So anyhow that's where we stand with that. I think we have some really interesting findings that are coming out of this stuff and so our hope is to get this out as soon as we can.

The second thing is when COVID hit, I mean my area of expertise is infections of the nervous system, so as you can imagine we got very heavily involved and with Dr. Koroshetz' help we were able to send messages around to all over the country to collect brain samples from patients who were dying of COVID and we were fortunate to be able to get some samples because these autopsies had to be done in BSL3 labs. We didn't have a BSL3 functioning lab here in the intramural NIH at that time that we could take our brains from and there were very few that were available around the country and even some places who had it they didn't have PPE to actually do these things. So multiple challenges but we overcame all of them.

And what we did was we accessed the brains and we studied the pathology. We found that actually there is a fair bit of inflammation in the brain, there was damage to the blood vessels in the brain, and these were very unique individuals because they were individuals we got from the New York medical examiner's office. Some of them had died in bed, or in a subway, and so they did not have much respiratory symptoms. They were not critically ill individuals but they still had pathology in their brain, so my suspicion is that had these individuals survived they would have had these long-haul COVID symptoms for sure. That gives us an opportunity to understand the brain pathology of long-haul COVID patients.

And I think that brings me to the relevance for ME/CFS because we suspect that there's overlap between the two syndromes and so what we learned from these patients is applicable to ME/CFS. What we've done now is, we are very eager to bring in patients with so-called long-haul COVID who look exactly like ME/CFS, they meet all the criteria for ME/CFS. We bring them to NIH, study them exactly the same way as we've done for the ME/CFS patients and try to see if we can determine what the similarities and differences might be. For that there's no intramural funding currently available, so we wrote a grant like everybody else and we've submitted it and if the grant gets funded we plan to bring in about 50 individuals with ME/CFS-like symptoms and another 50 who had COVID and got better completely, so we can compare the two. So that's where we stand. We're waiting to see if the funds arrive, we'll initiate the studies. So I'll stop over here.

Dr. Walter Koroshetz: Thank you very much Avi. I think next we'd like to ask Dr. Joe Breen to give an update on the consortium.

Dr. Joseph Breen: Thank you Dr. Koroshetz. Hi my name is Joseph Breen. I work closely with Vicky Whittemore and others in the Trans-NIH ME/CFS Working Group and I want to tell you a little bit about some of the progress in the Collaborative Research Centers that are currently supported. As I've mentioned on this call before there's three research centers and one data management coordinating center.

The three research centers all have independent projects. The one that is at the Jackson Labs actually is very immunology and microbiome focused and I'm going to highlight some of the things that are the result of work between the last time we had a teleconference in November and today. In that period of time the Jackson Labs has put a paper in the bioarchive, which is publicly available, where they're really looking at the immunological differences between ME/CFS patients and healthy controls and they see some differences that are notable in T-cell subsets, part of the response to how presumably they're developing ME/CFS.

And so looking for differences is a way to try and understand the mechanism, which will hopefully give us ideas about improved therapeutics, for example. There are some CD8 T-cell differences that are noted and Dr. Unutmaz who is in the center, is continuing to follow that up and I'm sure that this paper which is available in bioarchive will be in a peer-reviewed published journal soon. Another one of the centers is at Columbia, led by Ian Lipkin and colleagues, and last time on this call actually I talked about a proteomics paper that they had recently published and they're continuing to follow up on that work, and how the proteomics that they found and how it may relate to metabolomics might help understand some of the energy differences that are clearly evident in the patient population and the healthy controls, again which I think would be really exciting and important if those can be better understood because that energy metabolism actually there tends to be therapeutics available since those pathways tend to be quite conserved. There's no publication but I'm sure very soon we'll hopefully get to read about that in the public.

The third research center is led by Dr. Maureen Hanson at Cornell and this center has two particular papers that I wanted to highlight. One is looking at metabolites in females, actually ME/CFS suffers versus controls, and they saw very clear differences in some fatty acid metabolism which hadn't really been implicated before so that's exciting to think about a new way that there may be differences and again understanding what's driving ME/CFS. That was a small sample of 52 cases and controls and they're going to continue to work on that and that work was published since we last spoke and also another project which was recently published, a pilot study where again they're looking at plasma proteomics. This time looking at controls versus ME/CFS sufferers and they saw very clear differences in extracellular vesicles and looking at some neural proteins, axon guiding proteins called the ephrin family which have been well described in other literature but hadn't really been investigated for ME/CFS before. So those are three findings and there's a report from the Hanson group in Proteomes and also Metabolites, those two journals.

And the last thing I wanted to mention was something that actually Dr. Koroshetz described in his recent blog post in the very beginning of February. The Data Management Coordinating Center has launched two tools, which are, we think they're going to be very useful to the community. One is called mapMECFS, just the way it sounds, where people can share data and folks in the community are already joining this resource to see what's available and what can be shared.

And in fact two of the proteomics studies are already being compared in this platform and we hope in the future that will be even more useful. So you can do cross-comparison across published studies using this tool, again that's developed at the Data Management Coordinating Center, which is run by RTI under the management of Linda Brown and Matt Schu. And finally the last tool was called searchMECFS, which is a really a very nice and powerful search engine to find biospecimens that can be utilized, so there's a way to go in, see what's in there. There's a fair number of specimens available if you have a research question and you can actually see what's available and then make a request, which will then you know go through an approval process, but there is a repository that is run and managed by NINDS for those samples.

So those are two things I think, are exciting developments in the last month or two which should really give benefit to the community for increasingly so in the future and I think I'll stop there. Thanks.

Dr. Walter Koroshetz: Thank you very much, Joe. And let's turn now to Dr. Vicky Whittemore to talk to you a little bit about our Trans-NIH Working Group and Interagency Working Group.

Dr. Vicky Whittemore: Sorry, thank you Dr. Koroshetz. The Trans-NIH Working Group as many of you know, is composed of representatives from 23 different Institutes and Centers across NIH. The two things we're working on now is that, in early February, the NINDS Advisory Council approved the concept for us to reissue the funding announcements for the Collaborative Research Centers for ME/CFS as well as the Data Management Coordinating Center, so we're currently working on writing those funding announcements to be released to the public this spring.

And in addition to that we're also working very hard to put together a workshop to talk about clinical trials and clinical trial readiness for ME/CFS because this is a huge area of need. We understand that from the community and need to talk through many of the significant barriers and challenges that are in the way in terms of who would do the clinical trials, what are objective outcome measures, et cetera et cetera, so we're putting those things in place for that workshop.

The Interagency ME/CFS Working Group, the last meeting was coordinated by the CDC and was held at the end of February. And from that we're working on continuing to have discussions around workforce development, understanding also the severe lack of clinicians in the area or across the United States who see individuals with ME/CFS, and really the barriers and challenges to accessing care. That is really outside the NINDS mission but we're actively participating with the CDC and thinking through those issues.

And the other thing that was addressed at the last meeting was an update on long COVID, in other words, the Post-Acute Sequelae of SARS-CoV-2, or PASC, Initiative and as Dr. Koroshetz pointed out those applications have come in now. There's rapid review. I in fact served as a reviewer for the first round and will for the second round as well. We had a week to review the first round of applications so these are not grants, these grants are not being reviewed in the Special Emphasis Panel, they're being reviewed by a whole large, very large, group of reviewers and so the second round is in now and those second round of grants will be reviewed very soon and very quickly as well.

So I think with that, we will end our comments and move to the Q & A. And I'll try to field these questions, there are many questions that have come in through the chat. I see Dr. Koroshetz has already started to answer some of them. I'm going to go all the way back up to the top and talk about grant submissions and review.

We were just recently informed that we are allowed to tell the public the number of grants reviewed in a given study section. The ME/CFS SEP met last week I believe and 11 grants were reviewed and what I want to make clear is that every grant that gets submitted and is accepted by NIH is reviewed. Not all grants necessarily are discussed in the study section, so if a grant does not score well in the preliminary scoring by the reviewers then it's not discussed in the study section, but there were 11 grants submitted and reviewed in the last round.

The NIH policy has always been that members of the Special Emphasis Panels are, that the names are listed in aggregate for all of the Special Emphasis Panels, and it's my understanding that, actually before I joined NIH in 2011, that there were death threats made to some of these reviewers and that's in large part why that, plus many of the Special Emphasis Panels review very small numbers of grants that it would be very obvious to investigators who reviewed their grants and NIH peer review policy is to keep the review anonymous.* So for those reasons the actual identity of the reviewers is not released for each individual Special Emphasis Panel but is released in aggregate.

So moving down the list here. There was the article that was published in the Wall Street Journal, on STAT News, by doctors asserting that long COVID and ME/CFS are psychosomatic. I saw those articles and was shocked that they were published. So do you agree with this? No and I think the fact that NINDS is committing 1.15 billion dollars now towards studying post-COVID shows that we do not agree that this is pseudoscience. I don't know if Dr. Nath or Dr. Breen or Dr. Koroshetz want to comment further on that article?

Dr. Avi Nath: It requires no comment. I mean it's absolutely crazy for anybody to you know in this day and age so that's not what we subscribe to and you know that. Otherwise we wouldn’t be spending our time and effort on it.

Dr. Walter Koroshetz: I agree with that. You know I think people with ME/CFS have been stigmatized but the fact that now you have tens of thousands of people who had very similar symptoms after the virus, I hope that that will reduce the stigma because as Avi said, you know it's clear this is due to a virus and it's a biological abnormality that's causing these symptoms. We don't know what the abnormality is yet but it's pretty clear it's a biological abnormality due to the virus and I think that's you know similarly what happened in ME/CFS. So I'm hoping that reduction in stigma due to the fact that there's so many people with post-acute COVID symptoms that that will reduce stigma for ME/CFS as well.

Dr. Vicky Whittemore: Thank you. So there's questions about including ME/CFS as a major focus of the post-acute COVID syndrome program. Why isn't it highlighted? And I think as we explained in the Interagency Working Group meeting, the way the Initiative is working is they've taken in applications and once the sites are selected for who will carry out the studies, those investigators will be brought together and a common protocol will be discussed. Clearly there will be, part of those protocols will be looking at the symptoms of ME/CFS and as Dr. Nath described, really looking at what is the overlap and what is different about individuals who have post-acute COVID syndrome. So I think although it's not called out, it's clearly going to be part of the protocols going forward.

There's a study or a question here, I'm sorry, about the amount, so in Reporter, which is the NIH public way to report the amount of funding for individual diseases, so you can go to categorical spending within Reporter and see the total amount of grant funding going toward ME/CFS or epilepsy or any of the other diseases that are supported by NIH research and there were instances in the past where for example Dr. Nath's lab, say he gets 10 million dollars for his lab, all 10 million of those dollars were included in the funding for ME/CFS. Once those numbers in Reporter are finalized and sent to Congress, they cannot be changed. So we worked very hard last year to have discussions with the individuals who do the coding and determine what these numbers are to try to work with them to make sure that going forward there's accurate numbers that are being reported. So if a fifth of what Dr. Nath's lab is doing is ME/CFS then a fifth of his total budget for example would be included. We're working very hard to correct that problem within Reporter and within the reports for ME/CFS funding.

Dr. Joseph Breen: Vicky, there was a question about how are we advertising mapMECFS and searchMECFS? I'll just say that you know Dr. Koroshetz promoted that on his blog, we sent it out to the listserv, and then I know that the Data Management Coordinating Center staff is actually planning to attend and present that tool and the utility of it at upcoming scientific meetings, certainly at ME/CFS centered meetings, but hopefully we can broaden that so that we can bring others, perhaps at like immunology meetings and other infectious disease meetings. So it is being, the tool is being broadcast but we'll have to keep working at it, I admit that. Over.

Dr. Vicky Whittemore: Right, thank you Joe. We're also planning an update email that will go out to all ME/CFS investigators and more broadly, we can send emails out directly to investigators from our NIH systems. All right so let's see, let me scroll down here. Sorry it's sort of hard to do this off the chat, there are so many questions. So there's a lot of questions here about clinical trials. I don't know if Dr. Koroshetz, do you want to address this also, but clinical trials are expensive endeavors and we really need to have very good scientific rationale going into a clinical trial that also includes very objective measures so that you can identify who has responded to the treatment or not.

And so these are some of the things that we're looking into as to how to really put these things in place. Also you need to have individuals preferably in academic centers that have the support and infrastructure to perform clinical trials, so building out sort of those academic partners also will be critically important to being able to do clinical trials for ME/CFS. I don't know if anyone else would like to comment on that?

Dr. Walter Koroshetz: I agree Vicky, that you know, clinical trials, you always have some risk and you always want to run a clinical trial that you think is going to work, something that that has a strong chance of actually helping people. And unfortunately in ME/CFS it's been really difficult to get that kind of evidence but that's exactly what we're trying to do, that's what we're trying to get at. In the post-acute sequelae of COVID initiative you know, again, we don't really know enough about the condition to fund clinical trials with the funding that we have at this point in time but the plan is to investigate the causes and then identify potential treatments and then do trials in the post-acute sequelae of COVID so we're kind of in that same boat where we don't have any evidence for what to try at this current time but the whole idea of the initiative is to get the kind of data that would inform what might work.

The other thing that the post-acute sequelae of COVID initiative has going for it is that people who have COVID, who had COVID, have received a whole bunch of different treatments and so we'll actually be able to look and see if people getting one treatment or another during the acute event had any effect on them developing the post-acute sequelae of COVID. That's something that only this COVID pandemic allows you to do and that might also give some clues as to what might be a good treatment for people who have the symptoms of ME/CFS due to post-COVID and maybe even people who have ME/CFS that's unrelated to COVID.

Dr. Vicky Whittemore: Right and there was I think a good point made and question about that not all ME/CFS is acute onset. How will we track that? The studies that are being put in place for developing these cohorts of long COVID patients will track them over three to four years so hopefully within that timeframe individuals who have somewhat later onset of ME/CFS symptoms who are post-COVID will be identified through the study.

Let's see, so some of these are repeat questions about the article. Let's see. Are we looking into special studies related to age and ME/CFS? So for example children or the elderly. Joe do you want to take that question based on the PASC initiative?

Dr. Joseph Breen: Actually I was going to mention that in the Jackson Lab they have also found some age-related discrimination and immune cell response to ME/CFS. I think those are important. Well there's almost certainly differences in the immune response in, they looked over 50 and under 50 but it was a very clear distinction so I think that will tell. That's a good point and that I think it will tell us about the response to ME/CFS and so it looks like age and gender based responses may be quite different, at least in terms of immune dysregulation. That's really important for us to know, but how it relates to long COVID Vicky maybe you could say something about that?

Dr. Vicky Whittemore: I know that in the call for grants to develop cohorts they are looking at all ages as well as looking at developing a cohort of pregnant women who have COVID and long COVID to follow them as well, but I'm sorry you're right this question was specific to ME/CFS, and I'll just add that we are encouraging investigators to submit grants to focus on the more pediatric ages and working with our colleagues at the National Institute of Child Health and Human Development to help support studies that are in younger children.

We also recently together with the National Heart Lung and Blood Institute released a Notice of Special Interest indicating interest to support research on POTS, postural orthostatic tachycardia syndrome, which as you know is comorbid with many individuals with ME/CFS and also is very prevalent in young adults, adolescents and young adults, so we are definitely encouraging research in those areas.

So when will, there's a question about when can further guidance be given to doctors on specific symptom management? This person's indicating that doctors won't prescribe medicine for symptom management because there's no recommendations. As we heard from the CDC at the Interagency Working Group meeting, they had done a new literature review looking at evidence for treatment for ME/CFS and really found no evidence for any and no scientific evidence published for any new treatment recommendations. We recognize that this is a serious concern and the reason why we do need to move into doing clinical trials and rigorous studies to really identify and gain this evidence that we need to make better recommendations.

There's a question Dr. Nath about testing ME/CFS patients and long-COVID patients with immune biomarker tests, so looking at CD4, CD8, those kinds of things. Can you comment on if those kinds of studies are included in the things that you're working on?

Dr. Avi Nath: CD4 and CD8, everybody does that, that's not going to tell you much. So when we look at the immune system we do a very detailed analysis. These days what you want to do is single cell analysis, you can look at thousands of transcripts, you can look at multiple different cell types and just CD4 CD8 is not going to get you very far. We have a very exhaustive panel that we look at cytokine production, multiple different cell types. I think that's the best of the best way to look at it and we've got that in place.

Dr. Vicky Whittemore: Maybe Dr. Nath would you like to address this as well? There's a question about potential overlap of symptoms between lymphoma and ME and brain cancer and ME. Do you want to address any kind of overlapping?

Dr. Avi Nath: Dealing with a lot of different diseases, that's not my area of expertise. I'm not a lymphoma expert. My area of expertise is infections and so that's why we've established a cohort of ME/CFS patients who clearly had an infectious process and then developed that and the COVID patients again very clearly, they had an infectious process and now they're developing symptoms that look like ME/CFS. So for me that makes the most sense to use my expertise to study those kinds of patients. Lymphoma patients other people should study if they have that kind of expertise.

Dr. Joseph Breen: Vicky, there seems to be a lot of questions about the diagnostics and why It isn't a priority? I guess my answer to that would be that you know that's part of the reason that the work going on in the centers as well as few funded grants, other grants outside of the centers, are trying to identify biomarkers that have very, you know, statistically meaningful differences, both because that helps us understand a little bit about the mechanism but also if it's repeatable and statistically significant then it could be, you know, then it could be at least a surrogate biomarker for disease, which could turn into a diagnostic test.

I think we're definitely interested in that. There are some candidates out there which I'm guessing that's what this is really asking and we if someone had a proposal to look at that, I think it would be evaluated but again the community has to look at that and it has to be validated and that's one thing that could happen through sharing of cohorts for example through the mapMECFS tool as we move along in time. I don't know if you have any thoughts about the diagnostic piece, Vicky?

Dr. Vicky Whittemore: I know Dr. Ron Davis developed the test and I've had discussions with him about expanding that research because what they looked at were 20 individuals with ME/CFS and 20 controls and what needs to be done is that needs to be expanded to larger numbers to make sure that it maintains the rigorous findings that he had from those 20 and 20 patients and healthy controls as well as look at specificity. So how specific is that test or if you tested someone say with multiple sclerosis or with fibromyalgia, would you also see the same thing? So in order for a diagnostic test to be both sensitive and specific, you need to ask those different questions. I think it's very promising and I think that those findings are very interesting but need to be expanded to really flesh out the sensitivity and specificity.

There are questions here about vaccine, the long COVID vaccine and response in individuals with ME/CFS and non-response to the COVID vaccine. I don't know if anyone wants to comment on that here. I anecdotally know from three different people with ME/CFS who have had the vaccine who actually had a milder response than their spouse but did have a response and so likely will be immunized against long COVID. Dr. Nath do you want to comment on that?

Dr. Avi Nath: Yeah sure. Now we were very fascinated by that observation and I've commented on it in the news media as well. So it is interesting that some patients with ME/CFS or sorry long haul COVID with the COVID vaccine have experienced improvement in their symptoms. The question really is how long does it last and I think one of the people in the Q&A has mentioned their own experience that it didn't last very long. I think that's the major concern.

What it means is that yes you activate the immune system, you activate a lot of different immune parameters and they are leading to some improvement. Now there are two possibilities. One is the immune system is dysregulated in these patients and you're providing some regulation for a certain period of time and that's helping, so suggesting clearly that the immune system is key to the symptoms of these patients.

The second possibility is maybe there's restrictive viral replication, there's persistent virus that they never got rid of in the first place and now with the vaccine you cranked up the immune system. It suppressed it for some period of time and their symptoms got better so there are these two possibilities and we are very eager to look at it and the long-haul COVID patients that we bring in over here to study those two possibilities.

Dr. Vicky Whittemore: Let's see, sorry, this is challenging. There are so many questions, I'm doing my best here and my dog is helping. Let's see. If anyone sees other questions, anyone else on the panel, please jump in. I'm trying to sort of scroll through here and pick up questions.

Dr. Joseph Breen: I saw a question, I think it was for Dr. Nath, whether he would be able to finish his original protocol with the post ME/CFS?

Dr. Avi Nath: Yeah so currently the thing is that we are now analyzing the data, so I think it makes more sense for us to publish whatever we have right now, because otherwise we will be enrolling more patients or delayed another few years and we want to get the findings out into the community so people can benefit from it. It's true there may be some certain findings we may not have you know robust statistics because the sample size is small, but we will have trends.

There's lots of data so I think the best thing for us to do is to get it out in the public domain and then the second paper would be to compare the long haulers with ME/CFS, we'll have a second paper that would follow, I think that's the approach that we want to take.

Dr. Vicky Whittemore: Great thank you. There's a question here about working on an ME/CFS research plan that was recommended within the report from the NINDS Advisory Council Working Group. We had begun planning for that last year when the pandemic hit and as you can well imagine we've just been totally swamped and so our planning for this clinical workshop is the first step toward that.

We likely will also have a workshop or a think tank bringing together some of the basic scientists who are now coming forward with some pretty initial preliminary findings to think through on different levels what strategies we need to approach. So it's not that we've abandoned it, it's very critical and important, but we understand the frustration, but it's just really I think had to take a backseat at this point in time until we can sort of, we're now somewhat beyond the heavy burden of the pandemic and can begin to really focus on developing a research plan.

Dr. Joseph Breen: Barbara directed a question to me. Will the NIH be doing any genetic analysis of ME and long COVID patients to see if there are any underlying genetic predispositions developing in either? For long COVID we'll have to see what proposals come in and get supported under the PASC Initiative. I would guess they'd be very well characterized although we'll have to see.

For ME patients actually there are, there's a very large project underway in the UK to, I believe they're genotyping. I don't think they're going to do whole genome sequence but it's a very large number of, a very large cohort. It's a very ambitious plan, it's just starting and I know there are also some privately funded efforts in the U.S. doing both genotyping and whole genome sequencing and hopefully that work will be published soon.

For acute COVID patients there are longitudinal studies certainly of severe patients taking them out 12 to 24 months, that are being extensively characterized genetically and so that's something you can do with a severe patient. That may not be the best model for long COVID but at least it's a SARS-CoV-2 infection and so those people are, it's a study called IMPACT that's actually available on clinicaltrials.gov as an observational study.

They are being deep phenotyped, some of the tests are different than what Dr. Nath is doing but I think that might be interesting to people who are here so I think that might be valuable. It might basically catch some of those people who have more like long COVID symptoms and even ME/CFS, in a cohort that large, that remains to be seen. Actually we don't know, so that's some answers to those questions. Vicky I don't know if you want to supplement that or not.

Dr. Vicky Whittemore: No, I think that's a good answer. A couple questions I've seen, are there studies being done on individuals who have had ME/CFS for 10 years or more? I don't remember the specifics but I would think that the majority of individuals who are being studied as part of the Collaborative Research Centers are individuals that have been ill for five or ten or even longer. We can get that specific information for you but most of those individuals are people who have been ill for quite some time.

And then another interesting question, does the NIH believe that ME/CFS can have a non-immune trigger? That's a very interesting question and I'm not sure about, I'll maybe turn this over to Dr. Nath to address as well but there is evidence coming out about dysfunction, mitochondrial dysfunction, energetics inability for the body and cells to use energy which is not part of necessarily the immune system, but whether that is a trigger or a response to the illness is an interesting question. Dr. Nath do you want to comment?

Dr. Avi Nath: Yeah so I think you're absolutely right Vicky. And this question is very appropriate. There may be more than one way to get ME/CFS and infections and the immune system may be only one subset of patients and there could be other subsets that are triggered by other kinds of things and yes a mitochondrial dysfunction, we're seeing mitochondrial dysfunction in the cohort that we are seeing right now so we know that it was triggered by an infectious and immune process but those things can also be triggered by non-immune mediated phenomenon. For example the Gulf War syndrome is a good example. They have symptoms that look like ME/CFS, there was no infection that anybody could identify or they never complained of any symptoms of it but so that's a cohort that could be non-immunity but the end result could be the same.

Dr. Walter Koroshetz: Avi, do you want to say anything about autoimmune?

Dr. Avi Nath: Autoimmune phenomenon? People have looked at it and really the findings for autoimmune phenomenon haven't really been, at least in my mind, the way I've looked at the literature, it's not a major finding in these patients. And the Norwegians even did a clinical trial with rituximab and that didn't do much of anything so I don't think if you look at the auto antibodies that people reported there are very low titers, so I don't think that's the major driver of this disease. I think there's more to it than that.

Dr. Walter Koroshetz: What about in COVID?

Dr. Avi Nath: COVID is interesting. So there are a subset of individuals who definitely have auto antibodies, that is very fascinating. Whether these patients are also the same that have the long-haul ME/CFS and that I don't know but yes, you're absolutely right, so there's definitely auto antibodies to do multiple different antigens and new antigens that we had not recognized before so there's definitely the case there. You're absolutely right.

Dr. Vicky Whittemore: Thank you. So there's a question here about what, in terms of programmatic shifts, have been most helpful to stimulate ME/CFS extramural research and increase applications, increasing the number of applications coming in? I think a couple of things are that I and Dr. Breen and other program directors across NIH have been working very closely with grantees and investigators who are interested in doing research on ME/CFS.

So this round as I said we had 11 applications, last round there were 14 and the majority, no I shouldn't say that, not the majority, a large number, I'm sorry I'm not clear on the numbers at the moment, but a large number of the applications are from individuals who it was the first time that they're submitting grants to NIH on ME/CFS which is exciting, that we're both expanding the numbers and expanding the number of different investigators interested in doing research on ME/CFS. I don't know Joe if you want to comment on that question also?

Dr. Joseph Breen: Yeah so I think we have seen generally, a few more applications each round after we published the notices that we were trying to emphasize that we still need a lot of work in this area and the other thing that's been productive I think is our communication and collaboration with some of the advocacy organizations that fund pilot research. And that has worked well. Some, like Solve ME/CFS, has supported two folks with their pilot grant program who ended up getting NIH funding for an R01 in one case and R21 in another, so I think that's a success story.

Actually, somebody mentioned a project about T-cell exhaustion that was one of the examples. So I think that's a good collaboration. I think as part of our Trans-NIH effort we try and coordinate it as much as we can with all other organizations that support research so that's, those are some of the things that seem to be working and we'll have to keep, keep working on it to increase the number of supported applications.

Ms. Barbara McMakin: Great, so we are almost at three o'clock. To close out the call we wanted to let you know that a recording and transcript of this call will be posted on the NIH ME/CFS website soon. 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 at the bottom of the left sidebar.

Thank you for an informative and thoughtful discussion. Have a great afternoon.

*After the telebriefing, Dr. Whittemore issued the following statement:

“I am truly sorry for the hurt and harm I have caused the ME/CFS community by raising the issue of death threats in my comments during the NIH telebriefing. Since the telebriefing, I have heard from several individuals with ME/CFS who have expressed to me how hurtful my comments were. That was certainly not my intent and I sincerely apologize for making those remarks. I was wrong to have said those things.

NIH works to maintain the confidentiality of peer review of grant applications reviewed in all standing study sections, and in the Special Emphasis Panels that often review very small numbers of applications. The main driving factor for the aggregate listing of members of the SEPs is to keep the identity of the reviewers confidential.

For everyone’s information, the reviewers who participated in the most recent ME/CFS SEP were posted: ”

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