NIH ME/CFS Advocacy Call - March 28, 2022

Ms. Barbara McMakin: Good afternoon everyone and thank you for standing by. My name is Barbara McMakin and I'm from the NINDS Office of Neurosciece 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. Vicky Whittemore, Program Director at 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 Q and A box at the bottom of the Zoom screen. We will try to make our remarks brief so that we can answer as many questions as possible in the time available to us this afternoon.

I also wanted to mention that we are exploring different formats for these telebriefings going forward. For our next telebriefing we plan to include live oral questions during the question and answer session. That telebriefing has not yet been scheduled, but once we have those details we will send out a message to the listserv and post the call information on the ME/CFS website. Now, I would like to hand the call over to Dr. Whittemore.

Dr. Vicky Whittemore: Thank you very much Barbara and apologies for the delay in getting started. We've been waiting for Dr. Koroshetz to join us, who I see is now here. I will turn it over to Walter for some opening remarks.

Dr. Walter Koroshetz: Again, sorry to be late. I've been working on a COVID project, which is relevant, and we'll talk about that. I want to welcome everyone to our first telebriefing of 2022. We have several developments to talk about.

Dr. Joe Breen from NIAID will let us know what's happening in the consortium and Dr. Vicky Whittemore will talk about the Trans-NIH ME/CFS Working Group. Dr. Avi Nath has a conflict as well this afternoon, so he may be able to join later to talk about analysis going on in the intramural study and we're really gratified to have a wonderful guest speaker this afternoon, Dr. Benjamin Natelson from the Neurology Department at the Icahn School of Medicine at Mount Sinai where he leads the Pain and Fatigue Study Center and has several grants from NIH. He'll talk to us about his current and planned research studies. We're always eager to hear from you, so we'll keep our own remarks very brief before answering your questions.

We did receive a number of different questions about the RECOVER Initiative, which is actually where I was just a second ago. It's NIH's large-scale effort to understand why some people do not fully recover from infection by the SARS CoV-2 virus. Many people experience long-term symptoms, and a large number of these symptoms overlap with ME/CFS, and the expectation is that many of these people, after the six-month period, will actually meet criteria that have been established for ME/CFS. Unfortunately, the COVID pandemic is looking to really worsen the problem of suffering due to ME/CFS.

In the RECOVER program, we're concentrating on trying to understand this post-infectious persistence of symptoms and of all the symptoms, fatigue is the most prominent. ME/CFS investigators and clinicians are involved in the research and collaborating with the RECOVER investigators. They're also involved in the oversight committees and working groups of the RECOVER Initiative, of which there are many. We're going to have an upcoming RECOVER webinar for the RECOVER investigators and people who are interested and it's going to focus entirely on ME/CFS, and the lessons learned there.

RECOVER is a special situation; it's an ability to closely study a large number of people as they recover from the same virus at the same time. It's unfortunately a natural experiment that we've never been able to do in ME/CFS, but one of the silver linings of the horrible pandemic is that we can examine the transition from an acute infection to the chronic condition, look for clues as to why some people develop long COVID and others do not, and it's likely that we will find in these individuals biological drivers that are relevant to ME/CFS.

We're also hoping to start clinical trials on people with long COVID and if anything works in that large homogeneous population I think one of the first things is to try and see if it generalizes to the greater ME/CFS population where we don't actually know what the virus is, in some people it's not clear if it is a virus, for some people it does seem to be a virus. It's very heterogeneous, ME/CFS compared to COVID. And also, the COVID situation is fairly new; we're looking at people who are just months or mostly a year or two out, but with ME/CFS the heterogeneity is such that unfortunately many people have been suffering for decades, so COVID is a much more pure way of trying to get at the bottom of these problems that ME/CFS has been trying to get at, but hopefully we'll have better success because of the advantages of this natural experiment.

I see I have a couple of questions. Barbara, did you want me to continue with the questions or will we do those later?

Ms. Barbara McMakin: We'll do questions following everyone's opening remarks.

Dr. Walter Koroshetz: Okay, thank you.

Dr. Joseph Breenz: My name is Joe Breen. I'm a Program Official and I work closely with Dr. Koroshetz and Dr. Whittemore and I just wanted to give you a few introductory comments about the status of the Collaborative Research Centers for ME/CFS, an NIH-funded effort.

Suffice to say, there has been vigorous activity across the three research Centers and the Data Management and Coordinating Center. They're really hard at work in year five of their funding and there were some slowdowns due to the pandemic of course, and I think that now they're really working hard and at full function and that is reflected in some of the output, including a number of pre-prints that I just wanted to make you aware of as an example of the productivity that I think we'll expect to see in the next few months.

The Columbia Center has a January medRxiv paper noting some peroxisomal dysfunction and dysregulation of a choline pathway in ME/CFS, which is a novel finding. The Jackson Labs Center led by Derya Unutmaz has a bioRxiv pre-print about multiomics of host microbiome interactions utilizing some of their really groundbreaking and leadership in terms of microbiome studies that are occurring there at Jackson, in this case applied to ME/CFS. The Cornell Center led by Dr. Maureen Hanson has continued to be productive. They have a number of papers, the most recent of which is a plasma proteome study as well as some interesting recent reviews that I would encourage folks to look at.

And the Data Management Coordinating Center has really two things that we've mentioned before that I think are really going to be, or are already, assets to the community and the research community, and I think they'll be increasingly so. For the mapMECFS data management structure, there's a pre-print available on the website. If you go to mapMECFS you can find that to really see all the powerful things that the mapMECFS organization can do and with the organization of research to eventually allow cross-study comparisons and the kind of things that we weren't able to do before in this field, which I think will be a big advantage.

So I don't want to spend too much time, I want to leave time for others on this. But suffice to say that there are a lot of projects that are reaching the stage where they'll be peer-reviewed and available to the public in these areas, including from our Canadian collaborator, the lab of Dr. Alain Moreau, who isn't NIH funded but works very closely with us. So I'll stop there, and I believe Vicky you're up next.

Dr. Vicky Whittemore: Thank you, Dr. Breen. I'm Vicky Whittemore, Program Director at NINDS, and I just wanted to tell you what the Trans-NIH ME/CFS Working Group has been up to.

As most of you know, we released the Request for Applications for funding of the Centers as well as the Data Management Coordinating Center. Those were delayed a bit and we're working on their release and the deadline for applications is in May and they'll be reviewed this Fall. And Dr. Breen and I are working closely with all of the investigators to make sure that they can get through that gap period in funding with either continuing their work with no cost extensions, which means using funding that they still have available to them, just extending the year of their award, or providing supplements so that their research will not come to a halt at the end of their funding period, but they'll be able to continue with their data analysis and writing papers and continuing their work.

We got a question in advance from Cort Johnson about the funding for these Centers and as I explained in the newsletter, our first newsletter that we sent out recently, when Congress appropriates money to NIH, each Institute receives a budget and within that budget are funds for what we call intramural research, which is where Dr. Nath works, and those are the labs that are actually on the NIH campus. And then there's the extramural budget, which is research funding that goes to investigators outside of NIH like Dr. Natelson, like funding for the Centers, and it's funding that is out of that extramural budget that is designated for the Center, so it's not a mysterious place where this money comes from, it's money from that extramural budget that gets designated for those requests for applications. It's been exciting, I've been contacted by several new groups who are interested in submitting applications and so we'll see who competes for the three Centers this Summer and Fall.

With that I would now like to turn it over to Dr. Benjamin Natelson, who it's our pleasure to have with us this afternoon. I'm the Program Director for Dr. Natelson's grants and have really enjoyed interacting and interfacing with him over the years and so we'll turn it over to Benjamin to talk about his recent and ongoing research. Dr. Natelson?

Dr. Benjamin Natelson: Hi, thank you very much. Do you see my slides Vicky?

Dr. Vicky Whittemore: Yes, they look great.

Dr. Benjamin Natelson: Thank you, great okay. Well first, let me thank you and Dr. Koroshetz for honoring me to update you about where we are here at Mount Sinai. I need to thank Michelle Blate, our Center Nurse Practitioner and Tiffany Soto, our Study Coordinator, for making the Pain and Study Center research work and certainly I need to thank all of you patients who have been or will be in the work that I'll review in this talk.

So the first funded study I'd like to present to you has to do with our belief that CFS is a brain disease. And for me, ME is myalgic encephalopathy and if you want to know why you can ask me that in the question period, but our plan is to collect spinal fluid from CFS patients, I'm going to say CFS just for brevity, and to identify every protein in spinal fluid to identify biomarkers that are specific for this disease, and this will allow a lab-based diagnosis. If you look at the figure on the right, that's the results of our first study which was very exciting because that red part of the figure indicates that there are 738 proteins in spinal fluid that differentiated from patients that have fatigue after Lyme or healthy controls.

But there's a problem with this early study and that is that the technology available then required us to pool spinal fluids, so we essentially had 43 patients and we had to pool them all to be able to do the analysis. And so the problem was that since we had to pool, it's possible that many of the results, many of the differences may have been just a few subjects exerting those differences due to our need to pool. So then because of that we moved to request additional funding for a new method not requiring pooling and there we received funding from NINDS, and we have a new set of spinal fluids from chronic fatigue and from sedentary healthy controls.

We're going to get more spinal fluids from our colleagues Dr. Dan Peterson or Avi Nath and in order to factor out proteins that are not specific to the fatigue of CFS, we're going to add samples from patients with multiple sclerosis and other neurological diseases that do not have CFS and the team we put together to do this is, I think, fabulous. Besides me there's Steve Schutzer, my colleague at Rutgers New Jersey Medical School, Dr. Smith is the person who now has been involved in developing these new proteomic methods that let you identify the protein in a single sample of spinal fluid, and our partner Tao Liu, who is actually working to make the analyses happen. I'm having trouble getting the next slide.

Our second funded study has to do with the fact that my postdoctoral fellow identified a new way of looking at sleep. He looked at every change among sleep stages, so when you go from wake to light sleep, and to deeper sleep, each of those is a transition and he did this transition analysis which found differences between patients who had CFS alone and others who had CFS with coexisting FM and so the question that we wanted to look at in this study is: are these two illnesses the same or are they different disease processes, because some say they are the same but that's just a belief. So here's the data on the right from our sleep study. What this figure shows you is that patients with CFS alone have different sleep transition patterns than those who have CFS with FM. The CFS alone transitioned from REM to wake (the red arrow) whereas the patients with CFS plus FM transitioned from wake to deeper sleep and then are aroused going from N3 (which is deep sleep) back to lighter sleep.

And then we found the paper that indicated that if you sleep on a rocking bed it improves all that stuff on the left. That is, all that disrupted sleep gets better if you sleep on a rocking bed. So Dave Rapoport, my colleague who's the head of sleep research here at the medical school and I went to the New Jersey Institute of Technology, enlisted some senior biomedical education students and invented a rocking bed.

Now before I show you the rocking bed, briefly, I need to tell you that COVID has really disrupted recruitment for this study and so we need you. If you have CFS and are taking no brain active meds, that means no sleep, no pain, and no antidepressants, please call our research line 212-844-6665 we really, really need you to participate if you live within 50 miles from New York City. So here's the rocking bed and we compare sleep on this rocking bed to when it's stable and that's the whole research protocol.

Then I want to move on to our third funded study which is of course the first in our part of the medical school that's going to compare COVID CFS to classical CFS, and as Dr. Koroshetz said and as I was worried about, COVID has produced an epidemic of chronic fatigue syndrome and so the research question is to determine if CFS unassociated with COVID is the same as what we're calling PASC-CFS. We received funding from NINDS, me and a brilliant biomedical engineer Xiang Xu who is a neuro-imager here at Mount Sinai, and this is what we propose to do. We're going to look at three sets of patients: PASC-CFS, classical CFS, and age-matched healthy sedentary controls. We're going to put them in the 3T magnet and we're going to look at their anatomy, we're going to study perfusion to see if there are differences in blood flow across the brain, and then in a whole different step we're going to look at brain metabolism via venous oxygen extraction and each of these should provide very important data, the anatomic to show whether there are any structural abnormalities, the perfusion, are we going to be able to replicate our prior work showing reduced blood flow and I'm very excited to see if there are global energy deficits, and each of these we then will link with the patient's self-report of symptom severity to see what the relation is between these brain dysfunctions and CFS.

So the last funded study has to do with a hypothesis that data from two consecutive cardiopulmonary exercise tests or stress tests inform us about PEM. To test that idea we are doing these 2-CPETS along with something called ecological momentary assessment of symptoms, and I'll explain what that is in a second, and that will allow us to look at the relation between cardiac work and PEM. We received funding from NINDS, and I am a co-PI with a brilliant exercise physiologist Dr. Donna Mancini, a cardiologist here at Mount Sinai, and here's the protocol: individuals will be sent a wrist-mounted computer which records activity and allows the subject to respond to how he or she is feeling across a number of symptoms several times a day and they'll do this for eight days and then they'll come into the lab where we will determine their blood volume and do the first CPET.

Why are we doing blood volume? Because reduced blood volume may be a predictor of PEM and during the exercise we use echocardiography which allows us to assess heart size and heart work stroke volume. Patients then come back the next day to do the second CPET and if the blood volume was reduced on day one, we randomize the patient to receive a saline infusion or a sham saline infusion, and the reason we're doing this is to determine if increasing blood volume improves cardiac work and reduces PEM and again we're using the echocardiography to assess cardiac work, and the patient continues to use the wrist mounted computer to report activity and it also records symptoms and symptom severity and it also records activity and now we'll be able to track PEM, and then we have the cardiopulmonary and metabolic data to look at the relation between the two.

So now I want to move on to some recent published results that have come from our lab. The first of these is a collaboration with CDC on orthostatic intolerance and chronic fatigue syndrome and we did the NASA Lean Test on 63 CFS patients. I guess the first most important thing to report to you is that the majority of the tests were abnormal and the most common was POSH.

What's POSH? Well what POSH is, is postural orthostatic syndrome of hypocapnia or hyperventilation. We decided to use POSH because it was sort of the same as POTS, postural orthostatic tachycardia syndrome, and here you see POSH in a group of patients during a lean test where we look at end-tidal CO2 via nasal cannula and what you can see is during the lean, the end-tidal CO2 falls beneath 30 which is indicative of over breathing, so this is either hypocapnia or hyperventilation, the same thing. So this is POSH.

So as I said, 32 showed abnormal results out of the 63 and the great majority had POSH and they had abnormal respiratory rates, so we infer that they're not breathing quickly but they're breathing deeply, that's what hyperpnea is. Some had POTS alone, some had POTS and POSH together and importantly a subgroup were hyperventilating before exercise at all, and I'll explain why that's important in a second. But the bottom line is the majority of patients in this paper had abnormalities, they were mostly respiratory, so if you were unable to look at their end-tidal CO2 via capnography you would have missed it, so capnography really is necessary when evaluating a patient for complaints of feeling horrible while standing still.

Then the next study looked at PASC patients before and during exercise, so we did cardiopulmonary stress tests on a group of PASC patients who averaged nine months after their acute COVID infection and we really found three major findings: many had chronic fatigue syndrome, many hyperventilated before exercise in the baseline condition, and many had odd looking abnormal breathing patterns during exercise. So nearly half the patients had CFS and if we had not excluded for BMIs over 30 it would have been about 56 percent, half had hyperventilation during baseline and the non-overlapping half had what we call dysfunctional breathing. So on the left this is normal breathing during exercise, and you see it's quite smooth the patient or subject just breathes more deeper and more across time but that's not what happens in dysfunctional breathing, actually we see a little dysfunctional breathing before the exercise but then with exercise we see sighs, deep breaths, less breathing, and this odd dysfunctional breathing. Now these Venn figures show which patients had what, CFS group on the left, (these are PASC patients) no CFS on the right, and the first thing to see is that both groups had the same rate of dysfunctional breathing.

This is a small preliminary study, there's a hint of evidence that the CFS patients had more hyperventilation but as I'm going to show you we need to do more and we're embarking on that. Here's our planned research; question number one, what happens to hyperventilation and dysfunctional breathing seen in PASC? What we're doing now is we've just submitted paperwork to the IRB to allow us to do CPET testing on PASC patients, we expect that will again provide us with patients that either hyperventilate or have dysfunctional breathing and we're going to do sleep studies on them because sleep is a metabolic tranquilizer, if you will. That is, if there's anything going on that's not metabolic then that will disappear during sleep and so we're going to use sleep to see what happens to dysfunctional breathing and hyperventilation. We'll also be able to determine what the differences are between PASC patients that do not have chronic fatigue syndrome and PASC-CFS.

Our next study that we're just submitting is going to use oxaloacetate supplement to see if it reduces or increases the reduced glutathione that we have reported to occur in the cortex of patients with chronic fatigue syndrome. So these patients would be neuroimaged before and after taking six weeks of oxaloacetate.

And the last study is one that I'm going to do all on my own because really I care for PASC patients and while I can use the same approach I use in ME/CFS we really need more tools and I found a paper that vagus nerve stimulation improves the symptoms of PASC and we have done prior work with vagus nerve stimulation but it required implantation which was a very expensive and surgical procedure, and now we're proposing to be able to stimulate the auricular branch of the vagus which will allow us to deliver relatively long periods of vagus nerve stimulation to see if that improves PASC.

And finally, I need your help for all these studies so patients with ME/CFS alone or ME/CFS following COVID you'll get a free workup, you'll be reimbursed for your time, you have to live relatively close to New York to do this but if you're at all interested you can get more detail about these studies if you Google Natelson lab at Mount Sinai or call our research line 212-844-6665. Thank you for the honor of letting me speak to you.

Dr. Vicky Whittemore: Thank you very much Benjamin, we'll come back with some questions that I see both in the chat and that we've received in advance. But I see that Dr. Nath has joined us, so can we go over to you Dr. Nath to give us an update?

Dr. Avindra Nath: Yeah sure, first of all let me just say that I've enjoyed your presentation, you're doing a lot of really nice work. Congratulations.

So as you know our ME/CFS study had to stop enrollment at the beginning of COVID because we weren't allowed to bring anybody so then we went ahead, and we collected a lot of samples and we started analyzing all the samples. It's best to do it at the end of the study where you don't have variability between assays. So now a lot of the data has been collected and analyzed, we're in the process of writing up our first manuscript and it has a lot of moving parts, but nonetheless it's coming along well, and our hope is to get it into at least a review process maybe within the next couple months or so. Then I think subsequently there will be a number of other manuscripts that will come out on various other parts of the data so there should be a series of them coming out in a short while.

Then as Dr. Natelson said we're doing the exact same thing that is to look at the PASC conditions, and bring them in and compare them with what we've done with the ME/CFS patients and do the exact same testing that we did on them as well so that way we could compare the two cohorts and see where there are similarities and differences. So that's where we stand at the moment.

Dr. Vicky Whittemore: Great, thank you very much Dr. Nath. We'll move to some questions, and I'll start with some questions for Dr. Natelson first. I have a question first about the rocking bed study, if you're involved in that study is it a one night study or is it like over multiple nights that you would have to participate in that study?

Dr. Benjamin Natelson: Well, Vicky it's two naps, 200 minute naps during the day. What we do in that very briefly is we give patients an actigraph to wear on their wrist for eight days, so we have some idea from their activity, some information about their sleep and then before we study them they wear a home device to make sure they don't have sleep apnea. Once they've been through that elementary, that introductory part they come into the sleep lab for a 100 minute nap that has to be separated from the last nap by at least one day, so it's every other day.

The other thing is that this is a fussy study, for menstruating women we can only study them in the first half of their menstrual cycle because the first half and the second half of their menstrual cycle are different in sleep so if the woman is menstruating that adds another sort of not limitation but requirement, so sometimes we have to study them a week apart but we try to do the two naps within one week, Vicky.

Dr. Vicky Whittemore: Okay thank you. A question that came in from the audience is, in your study on PASC-CFS versus CFS, how are PASC-CFS and CFS defined, how are you defining that?

Dr. Benjamin Natelson: We are going to use the IOM criteria for both groups. I think instead of inventing a new case definition for PASC I am a big adherent of using published case definitions, so we will identify the group of patients who fulfill the IOM criteria for chronic fatigue, I mean chronic ME/CFS, and then we'll look at the ones that don't.

Why don't they fulfill the criteria? What about them? If they're very similar well that's one thing, but if they have very different symptoms, because besides asking the IOM questions we ask them the questions from way back in 1988, all the symptoms that were initially thought to reflect CFS and that's 10 symptoms so we have information about 10 CFS-related symptoms and can use that to block out diagnosis.

Dr. Vicky Whittemore: Okay thank you, and another question is in your studies how will you measure blood volume?

Dr. Benjamin Natelson: Well it used to be pretty complicated, but a company invented a device called the daxor or D-A-X-O-R and that allows us to have the patient come in and we inject a tiny bit of radioactive isotope, less radioactivity than a regular chest x-ray, and then we take four or five blood samples, and the machine tells us their blood volume. It's actually quite wonderful because the old method used to require several isotopes and it was much more unwieldy.

Dr. Vicky Whittemore: Thanks. We’ll just see if any of the panelists have any questions for Dr. Natelson.

Dr. Walter Koroshetz: Hi, it's Walter, thanks very much. I was wondering what you've seen in terms of post-exertional malaise in the COVID patients.

Dr. Benjamin Natelson: Plenty of it, plenty of it. To me the only difference Dr. Koroshetz is that the PASC-CFS, that's what I'm calling them, the PASC-CFS patients have more chest palpitation, they have more chest pain, they may even have more shortness of breath, although that's hard because classical CFS patients complain of shortness of breath on exertion but some of that of course is due to the fact that their ailment makes them rest and they get deconditioning. But the two ailments overlap except for those cardiac symptoms, I think those are more common.

Dr. Walter Koroshetz: Thank you.

Dr. Vicky Whittemore: Any other questions from the panel? If not there's a question why do you use the term CFS and not ME, and I know that there are other questions from people about the terminology for the disease. Dr. Natelson, do you want to respond to that?

Dr. Benjamin Natelson: Well I call it chronic fatigue syndrome because I'm old and I've been calling it that since 1988 when I first started studying this illness and ME, myalgic encephalomyelitis, is a term that came out of the Iceland mini-epidemic many years ago and those patients indeed did have myalgic encephalomyelitis; they were left with neurologic abnormalities and signs. I do not believe patients with ME have encephalomyelitis, thank goodness, and that's why I call it myalgic encephalopathy. They certainly have achy muscles, and they certainly have brain dysfunction.

Dr. Vicky Whittemore: Great thank you. We got some questions before, and I think from people who submitted questions in advance and several of the questions really focused on how will the NIH utilize the information coming out of the RECOVER studies to advance research on ME/CFS? Who wants to take that question?

Dr. Walter Koroshetz: This is Walter, you know as I said in my opening remarks we've kind of been stymied in ME/CFS because we haven't had, well thank god, until now we haven't had thousands of people coming down with the illness all at the same time with a known virus. So the goal we have is to understand the chronic fatigue, ME/CFS that comes from COVID and as soon as we have clues from that we can see if those clues generalize to ME/CFS or at least subgroups of ME/CFS, so I see the RECOVER Initiative as getting at the biological drivers that we've never been able to nail down before. I think that this is really an opportunity to understand the fundamental nature of ME/CFS. Now Dr. Natelson am I naïve here or what do you think?

Dr. Benjamin Natelson: I totally agree Walter. When COVID hit the first thing I did was read about the SARS mini-epidemic in Canada and 25 percent of those patients fulfilled criteria 1994 case definition for chronic fatigue syndrome four years out. I was afraid there was going to be an epidemic of CFS, and we are seeing it now. And we're going to learn from it.

This horrible epidemic of CFS is going to do two important things for us; first of all doctors want to dismiss CFS, they often stigmatize the patient, they did the same thing in fibromyalgia and then there were three FDA-approved drugs for fibromyalgia and when there were FDA approved drugs for fibromyalgia, the practicing community changed its mind and started believing in FM. This epidemic of CFS has to make the practitioner understand that this is a post-viral syndrome, and these patients are devastated by this, and they can't be dismissed as quote "all in your head". That was why I wrote a book about this 12 years ago. It's not all in your head, it may be in your head because it's neurological, but not psychological.

So yes Walter, we really are seeing a lot of it more than even I was worried about, and RECOVER should help, and then individual scientists and physicians like myself need to be applying with their own ideas because RECOVER is going to give ideas to a group of investigators that are going to come from the top down. Our scientific progress is always helped when investigators around the water fountain talk and come up with ideas, sit down and write the grant and that's what I did with Xiang Xu, she and I talked about chronic fatigue syndrome and PASC and we put together an application which was just awarded by your Institute funding about a month ago, sir. We were grateful and that's the first that's going to look directly at PASC versus classic CFS.

Dr. Walter Koroshetz: I think also there was a question about stigma and so hopefully I can make it absolutely clear that NIH believes that stigma is a horrible thing, particularly for people with ME/CFS.

They're suffering enough and then they have to deal with stigma, but I think that what you're getting at Benjamin is that potentially this will decrease the stigma associated with ME/CFS because people are seeing all the post-COVID patients and as you said now that it's right in front of everyone that this is a major public health issue hopefully that will decrease stigma. But I want to make perfectly clear NIH is always trying to get rid of stigma for all our diseases.

Dr. Benjamin Natelson: There's no question that that's the mission and that's what your funding does, Walter. Your funding brings data and there's nothing like data to make the point that chronic fatigue syndrome is a brain disease, and we need to understand that's why you're funding it at NINDS because it is a brain disease and we are, I am committed to understanding this illness and to helping the patient cope with the disability that's inherent in just receiving the diagnosis.

Dr. Vicky Whittemore: I'd like to apologize to Robert Goldsmith. I'm not trying to censor your questions I'm just simply trying to get through as many questions as we can. So my apologies and your original question I assume was what you were referring to that I censored was, let me go back up here, when will Dr. Koroshetz stop publicly calling the disease chronic fatigue, a symptom, or CFS and be uniformly respectful and call it ME/CFS or ME?

Dr. Walter Koroshetz: I apologize for going back and forth like that. I should stick with ME/CFS and will do so. Thanks, good point.

Dr. Vicky Whittemore: There's a question from Cort, many new findings are going to come out of RECOVER, how will NIH ensure funding is available to generalize them to ME/CFS?

I first can say that currently under RECOVER there are funding announcements that have gone out for administrative supplements and there are ME/CFS investigators who have submitted applications for supplemental funds where they will be able to add cohorts of PASC or long COVID, individuals with long COVID, to their ongoing ME/CFS studies for very direct comparison utilizing funds from the RECOVER Initiative.

In addition, in two of the Centers currently funded the Columbia Center under Ian Lipkin, as well as the Jax Center, the PI is Derya Unutmaz, we approved pilot projects for both of those Centers to be able to collect biospecimens and clinical data from individuals with PASC again to be able to very directly compare those results with the results they have from individuals with ME/CFS.

In addition, in the new RFAs the focus continues to be on ME/CFS, however if an investigator and their team would like to have a comparator group of individuals with PASC or long COVID they'll be allowed to write that into their grant application and I'm certain that there will be additional funding announcements coming out of the RECOVER Initiative that will be open to individual investigators including investigators who are currently doing research on ME/CFS to do those comparator studies.

Dr. Walter Koroshetz: I can also see questions about us showing leadership and reputing the false matters that ME/CFS is psychological. Why does there seem to be apprehension to defend this patient population?

I mean it should be really clear to everybody that NIH is all about trying to understand the biology underneath ME/CFS and never say that it's all psychological, so people should know that it's not an issue. NIH is not saying this is psychological. Benjamin, in his talk he mentioned it, I've mentioned it hundreds of times, let's put it behind us and let's try and work together to find out what's the cause of the problem and what we can do to treat it. But we're all together and we all agree on this, absolutely.

Same thing with the stigma question, we all agree that stigma is horrible for people who are suffering with ME/CFS, and the same problem with epilepsy, stigma is horrible for people with epilepsies. This stigma is a real threat to people's health and that's our position on this. Any other questions?

Dr. Vicky Whittemore: Yeah, another question, do you see a link between EBV (Epstein-Barr virus) and ME/CFS? Benjamin or Dr. Nath?

Dr. Benjamin Natelson: Let me try. First of all we heard recently that if you're sick with COVID and you have active EBV that's a risk factor for long COVID so that's one thing, but that doesn't tell us anything about EBV in long COVID. There was a paper, I don't believe it's been replicated, showing that having high titers of EBV early antigen in survivors but they were soon after acute COVID. We know that titers of EBV are significantly elevated compared to healthy controls but there is a huge overlap.

In my practice, whenever I suspect it I look at the one antibody that tells you about reactivation and that's EBV early antigen and if it's elevated I do PCR and I have to tell you in 30 years of practice I personally have not had a positive, but I know my colleague Dan Peterson who sees many patients has found positive PCR and so there are a small number who do but it's still a research question.

What about if you have elevated levels of EBV early antigen? Is that somehow involved in long COVID? We don't know.

Ms. Barbara McMakin: Okay, we have time for one more question.

Dr. Walter Koroshetz: We're funding a project in Chicago looking at EBV, infectious mono, and chronic fatigue syndrome, and the problem with EBV is that it's with you all the time you never get rid of it and as Dr. Natelson said, in acute COVID you get a reactivation of EBV but as Dr. Nath taught me that's true about almost all infectious diseases, so it's not unexpected. But it is a sign from this paper that came out that the higher the EBV titers from the RNA, I'm not sure?

Dr. Benjamin Natelson: No, I think it may have been VCA, I'm not sure.

Dr. Walter Koroshetz: Yeah so anyway the higher the levels the higher your chance of getting PASC and that could be because the higher levels are in the more severe patients and more severe patients are more likely to get PASC. It's not clear what's cause and effect, I guess.

Dr. Vicky Whittemore: Yeah, the grant that Dr. Koroshetz is referring to is a grant from NINDS to Leonard Jason who also received a supplement to add a long COVID or PASC cohort to that study looking at individuals who have mono and now have developed COVID, had mono, got COVID, and now have symptoms of PASC.

The last question, which is a tough one I think but I'll ask it anyway, someone was asking how does mitochondrial dysfunction fit into the whole picture and the question actually, how does mitochondrial dysfunction fit in with CFS research? Anyone want to take that one?

Dr. Joseph Breen: I'll take it Vicky because I think that line of research is being addressed in several of the Collaborative Research Centers because they are basically trying to correlate things like post-exertional malaise and overall energy metabolism, and so given the role of mitochondria I think that's been a natural place to look for clues. Dr. Nath may have done this in his intramural study, but the extramural community is certainly focusing on that because it's a natural place to look with regard to energy metabolism and I think there are some preliminary results that are intriguing, and I expect we'll see more. And there's also been some clues from work that's now in the published milieu from Norway and other places, so I think it's emerging.

Dr. Nath, you have your hand up, maybe you want to answer that?

Dr. Avindra Nath: You're absolutely right, mitochondria produces energy so you have low energy you think okay there must be some mitochondrial dysfunction. But mitochondria is very different than other parts of the cell, you know the mitochondrial abnormalities you see in the muscle you won't find in the brain, what you find in the brain you won't find in the heart.

Or the PBMCs can be very different in different parts of the body. That's why in many cases if you want to look at mitochondrial DNA and RNA you have to go to the source, so it's not easy to study. You have to first decide okay this is a muscle problem then you go after the muscle mitochondria, you think this is a problem in the lymphocytes and lymphocytes functions are impaired then you got to look over there, so it should be studied but I'm not sure how easy it's going to be and how easy it's going to be to figure it out.

Then the other thing about mitochondria is that most of, or a number of the proteins in the mitochondria come from the nucleus and there's some that are specific to the mitochondria, now you got to figure out which one is which.

Dr. Vicky Whittemore: Thank you, well thanks to all of our panelists and thanks to our audience for excellent questions and I'll turn it back to Barbara.

Ms. Barbara McMakin: All right, thank you Dr. Whittemore. A recording and transcript of the call will be posted to the NIH ME/CFS website soon. In closing today's call I'd like to remind you about our listserv for updates from NIH. To be added to the listserv please visit the NIH ME/CFS website at and click on join our listserv at the bottom of the left sidebar.

Thank you for an informative and thoughtful discussion and have a great rest of your day.

This page last reviewed on August 1, 2022