Chronic Overlapping Pain Conditions in ME/CFS, new insights

Emily Kate Stephens (0:07): Welcome to Episode 12, following a short hiatus where I was focusing on maintaining my health and travelling to gather some fantastic interviews that we have upcoming. This week I am bringing you a conversation I had with members of the US Centers for Disease Control, the CDC. I had the pleasure of talking to Dr Beth Unger, who has been researching ME/CFS for several decades, and with Yang Chen and Elizabeth Fall, who are all part of the ME/CFS program there. And our conversation focused on their recent paper looking at chronic overlapping pain conditions that occur in ME/CFS. There are quite a few factions that probably need explaining, and I don't know if we might actually just take it back slightly from the study about which I approached you, because we should probably talk about the CDC's CFS program, and the MCAM, which was initiated in 2012 I believe, and ran the actual study, ran through until 2020. I think you've all been involved in MCAM almost since its inception. Could you just give me a little overview for our audience of what MCAM was set up to do, and the way in which it's worked. Yang.

Yang Chen (2:18): Sure. Of course. So let me talk about the MCAM study. The full name is the Multi Site Clinical Assessment of myalgic encephalomyelitis / chronic fatigue syndrome, short for MCAM study. This study was conducted across seven specialized clinics in the United States, from you mentioned from 2012 to 2020. This project enhanced our understanding of ME/CFS. And by using the expertise from leading clinicians in this field. MCAM study relied on those ME/CFS clinical expertise to decide who were qualified for ME/CFS groups based on their clinical expertise with this illness. We did not use any specific case definition, so our study population includes people diagnosed with CFS, ME or post-infectious fatigue, and also some who were managed like other ME/CFS patients. So we published the details of those study designs in 2017. Since then we also published nine papers from the MCAM Study, including the one we are talking today later - the chronic overlapping pain conditions. So we also have more than 17 data sets, and our specimen from MCAM study right now available for some website that include mapMECFS and the searchMECFS. If anyone or any investigators who are very interested in using our data and biospecimens from MCAM study, they can apply and get use through those data-use agreement for the study.

Emily Kate Stephens (4:06): I see, that's fascinating, so your study, which was retrospective and prospective, people can still go back and use that data for new studies in the future, via application to you.

Yang Chen (4:19): That is correct,

Emily Kate Stephens (4:19): Beth.

Elizabeth Unger (4:20): I would say it's not really a retrospective study. I mean, we did use the medical records from the past, but it was the baseline data is what's available right now. And so that's a cross-sectional view. We are going to be adding the longitudinal data which we're looking at. So most of the study, most of the data that we've published so far has been from the first look that we call the baseline, as people were enrolled, and the design was for a rolling enrollment, so people's baseline could occur at different times as they were eligible for enrollment.

Emily Kate Stephens (4:52): Which is quite important with this -

Elizabeth Unger (4:52): Right.

Emily Kate Stephens (4:55): Because you're watching them from the time that for the time...

Elizabeth Unger (4:57): The time that they enrolled. Yes, and that is one of the features of using these specialty clinics. They're very well defined patients. These are experts in the illness, but the patients, by the time they get to them, have all been ill, or a lot of them have been ill for many years, and so the average duration of illness in our patients is significant. It's on the order of seven years. We made a special effort in some of the phases of the study to try to enroll newly diagnosed patients with an onset of illness less than three years but those numbers are relatively small.

Emily Kate Stephens (5:37): Is that to do with the nature of ME/CFS and its diagnosis? So it's almost those people have been going through years of not necessarily having a diagnosis or being treated for the COPCs that we will talk about without actually necessarily having a concrete diagnosis of ME/CFS

Elizabeth Unger (5:58): That's one of the problems that patients with ME/CFS have faced for years, is the ability to get diagnosed. And many patients go years without a diagnosis. And, of course, in order to get to a tertiary care clinic, which all of these are that had participated in a study, it takes a number of years and referrals and many other clinicians to get there, so...

Emily Kate Stephens (6:23): And it's also I think, that people can't underestimate how involved that process for people with complex chronic illness, with conditions such as ME/CFS. On a daily basis, even just trying to use your general practitioner or your local health care provider before you even get down the road to going to a specialist clinic, which might be some distance away. I think you have all been involved in a study as well that looked at the cognitive impact, cognitive assessment of actually going through those processes. You were all three involved in that study were you?

Elizabeth Unger (7:01): Yes, and Yang and Liz may want to comment on their educational initiatives for clinicians that we've worked on, because we are trying to target the primary care physicians.

Emily Kate Stephens (7:12): So let's talk about that now, and that is one of the things behind the CDC's ME/CFS program. One of your primary focuses is the education of primary healthcare providers. Liz, do you want to talk about how you do that and how you make that happen?

Elizabeth Fall (7:36): Yeah, of course. So CDC has a number of different initiatives aimed at providing healthcare education. One in particular, and we have a collaboration with Medscape, we offer continuing medical education courses specifically tailored toward primary care physicians, nurses, nurse practitioners, pharmacists, other healthcare professionals. And these continuing medical education courses have information specifically on diagnosing ME/CFS, managing clinical care for patients with ME/CFS, among other important information that healthcare providers should take a look at.

Emily Kate Stephens (8:21): And is that your primary route into educating healthcare providers? Obviously, you are part of the CDC. You are visible. Are you able to influence policy or government in other ways, or is the primary route through that primary health care?

Elizabeth Fall (8:40): I would probably let Beth answer that one, it's a little complicated.

Elizabeth Unger (8:46): Yeah, I would say there isn't a specific policy, but CDC does advocate and raises the issue of ME/CFS at every possible opportunity. And I would say our web pages that we've spent a lot of time and a lot of collaboration with our persons with lived experience to get into really good shape, is really another important outreach. And the web page has sections for healthcare providers as well as for medical students. They have a special section on ME/CFS in a pediatric population, also some tool kits for patients as they go to attend their clinical visit to help them ask some questions and provide guidance. So our web page is really, I think, one of our primary outreaches. We continue to update that. Yeah, and so, you know, the whole government. I mean, it's not just CDC, NIH is involved in addressing ME/CFS through their research component, and we collaborate very or in, you know, try to integrate our programs and have very close quote communication.

Emily Kate Stephens (9:55): So and in terms of the funding model for such a large project as the MCAM project. Is that something that you have had to fund independently, or have to seek funding for and for its continuation? Or was that something that, from initiation, was guaranteed funding?

Elizabeth Unger (10:19): CDC’s ME/CFS program is funded through congressional appropriations, there's a special line item for ME/CFS, and that is determined each year. So it's a year by year determination. And the MCAM study was funded through CDC funding law that Congress approved,

Emily Kate Stephens (10:40): All right, and just while we are sort of talking about an overview of the CDC's ME/CFS program, Beth, you are chief of the chronic viral diseases branch, so you don't only look at ME/CFS. You have a broader remit. Am I right in that?

Elizabeth Unger (11:02): Well, you know, it's really interesting how things are organized at CDC and the two major focuses of our branch are ME/CFS and HPV. We have an HPV laboratory, we're very active in supporting monitoring of HPV vaccine impact, as well as pathogenesis of HPV. And of course, HPV is a chronic virus that has a very different kind of chronic outcome in that it can result in cancer. And with coming of the Covid-19 pandemic, we were already alerted to the fact that there was likely to be a long term outcome of this. And so while we are not responsible for Long Covid, we have been very active in working with cross center groups to establish a working group on infection associated chronic conditions and illnesses, that includes ME/CFS, as well as Long Covid and post-treatment Lyme disease and the other post-infection conditions that have been following dengue or, you know, any of the pathogens that CDC is studying, and that's why we have a cross Center working group. Progress in all of these illnesses, post-infection, conditions and illnesses has been, I think, limited by the small numbers of people involved and the kind of siloed approach each organism's group, you know, kind of looking at it in isolation, and the huge number of people affected by Covid kind of changed that and helped everyone recognize that it's very important to look at all of these conditions together, to understand the similarities differences and try to understand the underlying pathogenesis.

Emily Kate Stephens (12:49): Yeah, absolutely. And I think that's one of the fascinating things, if we look at something like your paper into chronic overlapping pain conditions, and actually looking at some of your work, historically, you can see this huge overlap between some of these chronic overlapping pain conditions and ME, but also many of the other post-infectious conditions, and in that, I mean Long Covid, of course, but there's also chronic Lyme, I think also there's possibly conditions that don't necessarily have any kind of specific definition within one or all of them, And it's for all of us to work out this, where we overlap, where we don't, right? Let's talk about this paper you wrote with some of the people who have always been involved in your MCAM study, but some of the biggest researchers and people who are most visible on ME/CFS. So I've spoken to this Lucinda Bateman, and I've previously spoken to Benjamin Natelson and Nancy Klimas. These people who have been working for decades, collaborated with you, looking at the chronic overlapping pain conditions. Liz, would you first of all like to tell me the definition of those chronic overlapping pain conditions?

Elizabeth Fall (14:22): Yeah, so chronic overlapping pain conditions or COPCs, for short, they're a group of pain related conditions that frequently occur together in the same person. These conditions include chronic low back pain, chronic migraine headache, fibromyalgia, irritable bowel syndrome, interstitial cystitis, which causes pain in the bladder, and pelvic area, temporomandibular disorder, which affects the jaw joint and can lead to pain, difficulty with jaw movement, and also two female specific conditions, endometriosis and vulvodynia. And vulvodynia, for those who are unfamiliar, is a condition that leads to chronic pain in the vulva area. ME/CFS is actually considered a chronic overlapping pain condition as well, because those affected with ME/CFS often experience pain as a symptom. And just overall, these conditions are frequently seen in ME/CFS, and having one of these conditions can increase the likelihood of experiencing others.

Emily Kate Stephens (15:30): I think that you found that almost 75% of the people involved in your study did have a COPC. Is that the correct figure?

Elizabeth Fall (15:39): Yes, that's right.

Emily Kate Stephens (15:42): The questions that this raises is, what comes first, or how these things interrelate? Is it that people with the propensity, for example, for migraine, therefore have a propensity to move into ME/CFS, if they have a viral insult. Or do you believe that the ME/CFS leaves you open to a lower pain threshold? Or I think that's a really negative way of putting it - a difference in pain perception?

Elizabeth Fall (16:17): I think the term that's commonly used is central sensitization, so it's this over-activity in the central nervous system that leads to pain amplification. That's one of the theories, anyway, that may, you know, be common among these chronic overlapping pain conditions, that there is this overactive pain response, in response to pain stimuli.

Emily Kate Stephens (16:44): But to be clear, you're not saying these people are somehow making this up, generating it.

Elizabeth Fall (16:52): No, not at all.

Emily Kate Stephens (16:54): So, so in terms of the order of things, do you have any idea whether people had an underlying condition, underlying pain condition prior to the ME/CFS, or whether it came in after?

Elizabeth Fall (17:08): That's a good question. I think in most cases, it's not always easy to tease out the timing of, you know, which condition came first. I think in a lot of cases, having one condition may lead to complications later on. But I would say research in this area is still emerging. So there's a lot more information that we need to figure out about these conditions for sure.

Emily Kate Stephens (17:35): I think one of the interesting things to come out of the paper is this idea that if you treat some of these things for which they already have some kind of management, so if you are able to provide some kind of pain relief or treat migraine... If we treat the symptoms of the COPCs, you actually alleviate some of the symptoms of ME/CFS. Is that something that you found in this study?

Elizabeth Fall (18:07): Well, it's not something that we directly studied in this particular analysis. But I would say that given that the chronic overlapping pain conditions did exacerbate certain symptoms in people with ME/CFS. It would be possible that by treating these chronic overlapping pain conditions, we may be able to alleviate different symptoms, like pain, for instance. And I just want to point out that a lot of these chronic overlapping pain conditions do have their own FDA approved treatments. So that's one thing that healthcare providers should you know, understand is that there may be options to help improve quality of life for patients with ME/CFS by treating these other conditions.

Emily Kate Stephens (19:02): Okay, I think that we could say that all of the COPCs, along with the ME/CFS, have inflammation in common. Is that one of the things that is driving all of this?

Elizabeth Unger (19:23): We did not get mechanisms in this particular study.

Elizabeth Fall (19:26): Yeah, it's a little bit outside the scope of what we were looking at specifically.

Emily Kate Stephens (19:31): Okay,

Elizabeth Unger (19:32): There has been a lot of research in the chronic overlapping pain field about what the mechanisms may be, and so there's a lot of questions. And understanding the role of the immune system in ME/CFS and all the post acute infection syndromes is really basic. It's central. Inflammation and autoimmune and all of that is just still a very big question, and very much an area that's likely to yield answers, but very complicated, and it's not something we examined in this study. We just looked at conditions. Yeah.

Emily Kate Stephens (20:09): Okay, Yang, tell me about what you found from the study and looking at these COPCs with ME/CFS.

Yang Chen (20:17): Yeah, sure. Of course, the first one we found, as you mentioned, we found that the COPCs are very, extremely common among the people with ME/CFS, much more than those healthy controls. From our study, we found over 75 percentage of ME/CFS reported at least one COPCs, but only 17 percentage of control reported. And when we look at each COPC, we found that the chronic migraine headache was the most common COPC reported from the ME/CFS patient - 48%, close to half, ME/CFS patients had the chronic migraine headache. And fibromyalgia, chronic lower back pain and irritable bowel syndrome are also very common with the rate 30 to 40 percentage of ME/CFS patients reported having this one. People with one COPC are more likely to have another one. So as Liz mentioned earlier, that is from some literature. Also, our study also found the most common combination of two COPCs, there are chronic migraine headache and fibromyalgia. And from the impact we found, the people with those additional pain conditions, those tend to have worse pain, and that can reduce the physical function and the lower quality of life. So this suggests the overlapping conditions may contribute to the very higher level of pain among the people with ME/CFS. That is why we said that is important to identify and manage the COPCs, that could happen to improve the health outcomes among ME/CFS patients.

Emily Kate Stephens (21:59): It's interesting, isn't it, because they are all completely different regions of the body - localized, the majority of them, not fibromyalgia, and some people might say migraine is not just in the head. But several of them are localized, whereas ME/CFS tends to be a full body condition. Is it easy to separate each of them out from the ME/CFS to identify it as a COPC instead of a symptom of the ME/CFS?

Yang Chen (22:33): For our study, we use the medical history form, so have those patients reported if they have a pain on their head, have a pain on their lower back? And we also use the brief pain inventory body map, to ask them to identify which their pain area. You know if they in the shoulder, head or lower back. And we also ask how long of those pains lasted. We only selected those that lasted more than three months. That is the definition for chronic pain. So in this way, we can identify those chronic pain, different kind of location on their body. And for those chronic pain conditions.

Emily Kate Stephens (23:10): Okay.

Elizabeth Unger (23:10): And I will say we, you know, we relied on the clinicians to make the distinction. And there are case definitions for each of the chronic overlapping pain conditions, and sometimes it takes the clinician to be able to try to distinguish and separate. And so I think that what's important is to look for them and to recognize those that may be amenable to some therapies.

Emily Kate Stephens (23:36): Yeah, some kind of treatment. Are there other COPCs that are not concurrent with ME/CFS, or do majority of COPCs appear in ME/CFS patients?

Elizabeth Fall (23:53): In our study, we did find that at least one patient had each of the chronic overlapping pain conditions, although, as Yang mentioned, there were certain COPCs that were represented, yeah, more prevalent than others. So...

Emily Kate Stephens (24:11): But are there any other COPCs that are not included in here in terms of the definition of COPCs?

Elizabeth Fall (24:19): So I think that the field of chronic, overlapping pain conditions is kind of evolving over time, and new conditions are being considered COPCs. So it is possible that there are additional conditions since the time that we conducted this study, so that would definitely be an area for future research, is to include any additional conditions that have emerged as part of the definition.

Emily Kate Stephens (24:48): Okay, I wasn't sure if you had taken all of them and tried to assess whether they were concurrent with ME/CFS or if you had just looked at various conditions, that were appearing in an ME/CFS patient. I didn't know which way round it was.

Elizabeth Unger (25:02): It's the first way. We had the list and we looked for them in the patients.

Elizabeth Fall (25:07): Yeah, that's right,

Emily Kate Stephens (25:08): The endometriosis, that is female condition, Beth that's an area that you've been looking at for a long time, and I think in 2015 you published a paper about the menopause and gynecological changes in ME/CFS. Can you tell me a little bit more about that, because I don't think it's something that has very much been discussed in relation to some of these conditions? One, possibly because it is a female only condition. But two, also, I just think it's one of those things that is not necessarily as easily discussed. I think people talk about migraine headache, because it's one of those things that is more commonly discussed. But can you tell me a bit about endometriosis?

Elizabeth Unger (26:00): Sure, and actually, endometriosis is, in and of itself, is a very challenging diagnosis for clinicians to make. It causes a lot of symptoms and sometimes infertility in women. And what it is, it's just implantation of the endometrium outside of the endometrial cavity, and so you have these little implants of tissue kind of growing that can cause severe pain in this cyclic manner. And there are treatments and approaches for it, sometimes some hormonal therapies, and sometimes people even have surgery. Now, what we found, there's so many things about ME/CFS that not every study can go into detail in every possible connection and medical condition, and most of these don't take a detailed gynecologic history for some reason, and that's what it takes in order to really find out if a patient has had endometriosis. And what we found was combination of endometriosis, heavy menstrual bleeding and fibroids, often led to surgery when the uterus and the ovaries were removed, and that contributed to early menopause, and this was much more common in women with ME/CFS than those that did not have ME/CFS. But again, it takes looking at a very careful gynecologic history in order to tease out that information and in both the patients and the comparison group, and in this particular case, we looked at endometriosis, we didn't look at menopause at all, because that wasn't sort of the focus of the paper. And then, because we wanted to look at all of the patients together, we ended up not focusing as much on endometriosis, because we were just trying to overall look at those that could have affected all the patients, males and females.

Emily Kate Stephens (28:05): I don't know very much about endometriosis, but a lot of the COPCs seem to be primarily pain, although the mechanism or the root is not necessarily apparent, or there's nothing necessarily physical, whereas endometriosis does that always have some kind of change in the physicality of the endometrium?

Elizabeth Unger (28:28): Right? In order to make a diagnosis of endometriosis, there has to be some evidence of this implantation of endometrium outside of the uterus.

Emily Kate Stephens (28:41): So it's not just the pain?

Elizabeth Unger (28:43): It's not just the pain, although sometimes pain and imaging, they can kind of put the two together in evaluating women for this. This is a gynecologic condition really needs experts to look at.

Emily Kate Stephens (29:01): And in terms of your data on ME/CFS, what is the prevalence of male versus female? And do you have data on the age ranges and that sort of demographic data from the studies that you've been doing? That's not necessarily related to this paper, but I just thought it's relevant because of the female only conditions that you have included in the COPCs paper.

Elizabeth Unger (29:27): And there's a difference between the population that we have in our study and the population that estimates that we have for the United States

Emily Kate Stephens (29:37): Right.

Elizabeth Unger (29:37): Right? So you want to pull in those. I mean, you would, you, is your question about who was in our study, or what we think ME/CFS is in the United States.

Emily Kate Stephens (29:50): It was both because I thought, well, your study has pulled up two female only COPCs that are quite prevalent. But I think it's interesting when you say that those things are not necessarily so heavily studied, and I just ask the female only group, because obviously there are a lot of concerns historically about some kind of patriarchal medical system that possibly we are missing things that are only related to women. So I think some of these gynecological things possibly fall within that, like we say that a detailed gynecological history was not necessarily taken over every patient. I'm interested to find out whether that is symptomatic of the number of people who have ME/CFS, whether it's symptomatic of our medical systems.

Elizabeth Unger (30:47): So in general, what I meant was a lot of studies of ME/CFS don't focus on the gynecologic conditions. And the NIH did a whole series of trying to come up with what are the current research questions, and they had a series of webinars covering various topics. And the gynecologic question came up in a webinar series that was called lesser studied pathologies, because it just doesn't come up. There are so many things to address about ME/CFS. I'm just saying that it happens that the... Including the gynecologic history, doesn't come up. Right? If you're focusing on cognition, you might not be collecting a gynecologic study and a lot of studies to focus on one thing or focusing on exercise, you may not take that detailed gynecologic history. So it's not, I'm not saying that women didn't have appropriate care or diagnosis. I'm saying the studies didn't necessarily collect the information. Now, the whole question about how ME/CFS has been a female predominant condition, and whether that's contributed to the under diagnosis, I think it could agree that's likely, just like migraines, the same thing, all of these conditions that are difficult to localize or identify in a routine, simple test that shows its presence, when women complain of it's very easy to write it off as anxiety or depression or whatever. So.

Emily Kate Stephens (32:25): Which is interesting in itself, though, because, you know, I would say that the thing that we all have in common women is the gynecological element, so and the hormonal element of that obviously has a - in my understanding - has huge impact in things such as the migraine and in pain perception,

Elizabeth Unger (32:54): Right, and you think of patients when what they're dealing with and living with ME/CFS, thinking about their gynecologic issues might not be top of the mind, right? We have not actually looked at, you know, how women keep up with their screening and all of the things that should happen if you're a healthy person, mammography and regular pelvic examinations. But if you're having trouble just even getting out of bed, that's not first of mind, right? Sort of deal with the priority, you know, what you "have to" that's another factor that can kind of contribute to the problems. I mean, this is a very, very, very challenging illness.

Emily Kate Stephens (33:42): Yeah. I mean, that is so true that you especially the way that the healthcare systems are set up, that you tend to focus on what is the absolute most important thing that I need to address. And I imagine for a lot of people, that is simply, how am I getting out of bed to have some kind of functional existence? Obviously, there are hugely varying degrees in terms of people's severity, but it comes down to that, doesn't it? What's the most important right now? And yeah, you're right. So the things that fall by the wayside will be the thing that you don't necessarily think about on a daily basis. Yang, did you have some data on the demographics?

Yang Chen (34:37): Yes, I just found some, and for the sex difference for all the COPC conditions are higher - with higher rate among the female than male. And if we're

Emily Kate Stephens (34:54): With all of the COPCs, not just the ME/CFS?

Yang Chen (34:58): With all the COPCs among the ME/CFS females, they have higher rate than those ME/CFS in males. So if we only look at those non-female only conditions, you know, other COPC, not include endometriosis and vulvodynia, we found that 87% of ME/CFS females has at least one COPC, but where only 65% of ME/CFS males have at least one COPC, that is a big difference over the 20% difference.

Emily Kate Stephens (35:34): Yes, that's a huge difference. To put that into perspective, in terms of ME/CFS figures in general, what is the prevalence in male versus female?

Elizabeth Unger (35:46): I think she's asking in the US, what is our estimate of males versus females? Is that? Am I correct? That's what you're asking?

Emily Kate Stephens (35:54): Yeah. I'm just interested to know, like, if we then compare that against the COPC figures, the ME/CFS prevalence in female versus male.

Elizabeth Unger (36:06): Now it varies on the approach that's used to come up with the estimate, and is usually on the order of three to one or two to one.

Emily Kate Stephens (36:19): So that is not dissimilar from the Long Covid prevalence female to male ratio is it?

Elizabeth Unger (36:28): No, and actually, I think that is kind of a characteristic of a lot of the infection associated chronic conditions and illnesses, seems to be a female predominance. And that has raised a lot of questions about why. And autoimmune conditions, again, are much more predominantly female. Yeah, predominantly female. So, so, yes, coming back to the whole question about inflammation and immunity playing a central role in this condition. I mean, that's why people have looked again and again at this. What is triggering it? Could be different in different situations, but it does something. It's a good place to look right,

Emily Kate Stephens (37:08): Beth I know that historically that you've done studies in so many different things, but one study that came up that I was reading was a study in 2014 that you did into the basal ganglia that suggested this dopamine dysfunction in ME/CFS just related to what we were just saying, Is there a difference in dopamine production or receptors in male versus female?

Elizabeth Unger (37:37): I don't know that's been documented. And this raises, there are a lot of really intriguing studies. It raises this question and that question and this abnormality, and I think we're just starting to get pieces of the puzzle to try to see how these things all interface, you know, yeah. You ask about which came first, and that's one of the most intriguing things. Is it the inflammation, or genetics about your inflammatory response that primes you for something, or is it the environment? As far as the data on the dopamine receptors, I am not up to date on male versus female differences.

Emily Kate Stephens (38:26): Not everything that we have we discussed has to be male versus female that. But I just thought that was an interesting point, that there are two female only conditions included on your COPCs paper. But in terms of the design and implementation of the MCAM Study, one of the things that I wanted to ask about is that in your principal objectives, it says to collect biospecimens for future hypothesis testing and for evaluation of morning cortisol profiles. What is the relevance of cortisol, morning cortisol profiles in ME/CFS?

Elizabeth Unger (39:08): So cortisol changes cyclically with time, and the morning profile is one of the best ways to get sort of a snapshot of a person's usual cycle of cortisol. And there have been prior studies that indicate that ME/CFS patients have kind of a flattened cortisol profile, and that may be an indication of how they respond to stress and interaction with the immune system. So we, in prior studies, used salivary... Salivettes to actually collect at different time points, right as a person wakes up. So they're mailed, the kit is mailed to them, and then they kind of stick this little cotton plug in their cheek for a certain amount of time, and allow it to collect saliva every ten minutes, I think, spaced out over up to two hours, approximately. And then you can sort of plot, you know, how the cortisol... It should. It should show a change with time. And we are still analyzing that data.

Emily Kate Stephens (40:18): Okay, okay, I just thought that was because it's one of the things that has been looked into within they've started to look into it in Long Covid as well. I was curious as to what a person's cortisol is supposed to be doing first thing in the morning, versus what changes there might be in people with ME/CFS?

Elizabeth Unger (40:41): The hypothesis is there may at least be a subgroup with a flattened cortisol response, so less cortisol being produced.

Emily Kate Stephens (40:49): And that, in turn, does what? Less cortisol?

Elizabeth Unger (40:53): Yeah, so cortisol does influence the immune system in very complex ways. It's not like you can say, boom, it's going to do this, but it's an indication of that there could be a less modulating effect of cortisol on the inflammatory and immune response.

Emily Kate Stephens (41:13): Okay, does it also have an impact on the stress response?

Elizabeth Unger (41:13): Oh, yes.

Emily Kate Stephens (41:18): Sort of fight or flight, right? So that idea that possibly people are shunted into some kind of freeze mechanism, that their immune system can't fight.

Elizabeth Unger (41:27): The cortisol is part of the stress response interacts with hypothalamic pituitary axis, and there's, in one sense, you would think maybe that people would have a heightened cortisol response, because we know that there's evidence for some increased epinephrine and sympathetic activities, but with chronic stress, there actually can be sort of a flattening of that whole response. So again, it's a very complicated picture. It won't be a straightforward "this is the answer", kind of a thing, because there's a spectrum of people's responses, and that's part of the challenge of analyzing that data.

Emily Kate Stephens (42:12): Well, in terms of what is coming up for the three of you, for your program, I'm excited about hearing about this cortisol. Can you each tell me what you're excited about in terms of research, in terms of the data that you're either analyzing, driving or hoping to gather? I'd love to hear what you're looking forward to and excited about in terms of this research in this space. Liz, do you want to go first?

Elizabeth Fall (42:42): Yeah, sure. As Beth mentioned earlier, you know, a lot of the studies that we have published to this point have been using the baseline data, so in the future, I'm really looking forward to delving more into the longitudinal data from the MCAM study, the multi site clinical assessment of ME/CFS, just so we can, you know, get a sense of the illness over time, as that is really important to look at, given all the fluctuations that are common with ME/CFS, so understanding more the time course of the illness, I think, will be very insightful.

Emily Kate Stephens (43:18): And that must be something that is not data that's accessible to any other study. The majority of people certainly to have that longitudinal data, something that's fairly unique to your center

Elizabeth Fall (43:33): That's right.

Emily Kate Stephens (43:34): So very exciting. Yang what? Tell me what you're excited about.

Yang Chen (43:38): Yes, some similar with Liz mentioned, we continue to get the longitudinal data ready, and we can use another release for any other investigators use, and we can use this data to compare other studying or other illness - Long Covid you mentioned earlier. And we also can look at some time relationship, as you mentioned, which comes first, which condition, which chronic condition comes first, which comes later is also a good way to use longitudinal study data to explore. Additionally, the MCAM study collected so many information. Currently, we just explore some part, we can use our data to continue explore other part, other instruments, like the sleep part and sleep impact for the ME/CFS. And as you mentioned for the cortisol, so we're also working on that and link some biospecimen data with our clinical data and look at their relationship. Of course, release all our information for public health use, and maybe we can compare with other conditions.

Emily Kate Stephens (44:45): Beth.

Elizabeth Unger (44:45): I'm excited about subgrouping of these patients to identify biologic basis, because I think that's been one of the big problems with ME/CFS. There's so much heterogeneity in the illness. And we're seeing the same thing with Long Covid where we know there's one infection and it's such a pleomorphic illness. So there are different pathways, I think, involved. They could be different kinds of the illness that all appear the same clinically. So I think identifying biologic sub-groups that are going to be responsive to therapies, that's the thing that's most exciting to me. And I don't see that as unique to CDC. I see CDC contributing to the broader field that's going to advance this kind of work.

Emily Kate Stephens (45:34): That’s amazing. Thank you so much. Thank you so much for your collaboration with all of these people who hopefully are the people together with you that can make a difference for patients. I really appreciate your time.

Elizabeth Fall (45:45): Thank you.

Emily Kate Stephens (45:53): I look forward to hearing more from the team at the CDC as they explore that longitudinal data and start to drill down into some of the aspects that have arisen from looking at these chronic overlapping pain conditions. There are conversations to be had and research to be done around whether it is that ME/CFS changes pain perception, or is it indicative of inflammatory response, increasing the likelihood of further inflammatory response. More broadly, what is the mechanism behind those chronic overlapping pain conditions, and what is the mechanism that is driving this heterogeneous collection of symptoms that form ME/CFS and other post viral conditions? I hope that, like me, you are learning as we go through these interviews and, as ever, we would love to hear what you're taking from the conversations and what you're still wanting to hear more about. I assure you, every single request that is sent in to me, I add to my list, and I am slowly working through them one by one. I really, really appreciate all of your feedback, and I'm striving to bring you more of what you need. Wishing you a lovely week. Thank you for listening to Make Visible. Please do like, follow or subscribe to listen to our next episode where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how Visible could help you, visit our website at makevisible.com.

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