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Transcript of Solve ME/CFS webinar with Dr Unger, Sept 2016

Discussion in 'General ME/CFS News' started by AndyPR, Sep 22, 2016.

  1. AndyPR

    AndyPR Senior Member

    Hi all,

    Usual caveats apply, majority of text is supplied by the Youtube automatic subtitling which is then edited by myself - I have no science training of any sort so if there are any errors of any sort in the text assume they are mine first until you can check back to the source video.

    All paragraph headings are taken from the slides used in the webinar.

    Hope this is of use.

    @znahle Let me know if you spot any issues with this :)
    Last edited: Sep 22, 2016
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  2. AndyPR

    AndyPR Senior Member

    Page 1

    Dr. Nahle
    Greetings, this is Zaher Nahle from the Solve ME/CFS Initiative welcoming you to our webinar series. We have a special guest with us today, we have Dr. Elizabeth Unger MD PhD from the Centers for Disease Control and Prevention or the CDC. Dr. Unger will teach us about the ongoing research on ME/CFS at the CDC, Dr. Unger is currently the Chief of the Chronic Viral Diseases Branch in the Division of High Consequence Pathogens and Pathology at the CDC.

    She has an impressive body of work and scholarly accomplishments in the field of Public Health. Dr. Unger is the author or co-author of more than 142 peer-reviewed publications, 24 book chapters and she serves on the editorial board of six scientific journals. In 2008, for her work on human papillomavirus research accomplishments, she received the Health and Human Services career achievement award, which is a high distinction. Dr. Unger did her undergrad in Chemistry at Lebanon Valley College in Pennsylvania, she then earned her PhD and MD from the University of Chicago, where she also began a residency in pathology but completed that residency, in addition to a fellowship, at Pennsylvania State University Medical Center. Dr. Unger has initiated and is leading many important initiatives at the CDC on ME/CFS and we will hear that from her directly, in fact we will hear all about that right now.

    So Dr. Unger, we are thrilled to welcome you to this webinar series, thank you for doing this, I know that many in our community are eager to hear from you, the floor is yours.

    Dr. Unger
    Thank you very much, I really appreciate the opportunity to talk to you.

    Update on CDC's Public Health Approach to ME/CFS
    And so the topic that I chose was basically just to call this an Update on CDC's Public Health approach to ME/CFS. And I am speaking about the program that's at CDC but I just want to remind everyone that what I'm presenting is my view of the situation and it doesn't represent the official position of CDC.

    What is Public Health
    And I'm emphasizing public health in this talk because that does frame how CDC approaches basically everything it does and, despite the fact that I went to medical school before I went to CDC, I really didn't have a good idea of what public health was, I had a really vague notion.

    So I'm going to take a few minutes to share with you what public health is and basically it differs from clinical care, I think just about everybody has seen a physician, and they're used to the kind of healthcare system that we have but rather than clinical care, which addresses the needs of the individual, public health addresses the well-being of the community as a whole and it's oriented to towards the prevention of disease and promoting health through the organized efforts of society and government and because of that, because it uses sort of joint resources, it needs to include considerations of social justice, things that are done need to benefit the population.

    Modern Public Health Practice
    Modern public health practice really emphasizes prevention, and I think everybody's familiar with the the phrase
    “an ounce of prevention is worth a pound of cure” and that is really true and to give you an idea of how this works we
    can talk about lung cancer interventions, approaching lung cancer from a public health perspective. You can start at one
    end of the spectrum where the patient already has lung cancer, you need to do something to ensure that the patients have access to care and have the best care possible. However if you could detect cancer at an earlier stage through screening that would reduce the burden and preventing cancer from occurring by stopping smoking through cessation programs would be an even earlier intervention and, finally, even preventing people from starting to smoke through changing social acceptance of smoking is another mechanism. You could throw into this the public policy considerations that go into decisions about taxes on cigarettes and things like that, but this just gives you an idea that while all of those
    activities are part of Public Health the most benefit comes from the earliest that we can intervene on the problem. Modern public health practice is grounded in science and medicine and all fields of academic inquiry are involved,
    and, to me, this is good news because anybody with any training could want to join in the public health battles and
    there's a home for them at CDC, in some aspects of what is being done.

    Steps in Public Health Planning Process
    The public health planning process is a lot like pretty much every other planning process, you have to have decisions to ensure that the resources are most efficiently used, it kind of follows a cycle of planning, implementation of whatever the intervention is that you have planned and then evaluation of how effective that intervention is. It kind of goes around and around with each each phase of work.

    Objectives of ME/CFS Program
    And if we map CDC's ME/CFS program to these various activities, sometimes they don't fit precisely into one or the other, but the overall goal is that we are trying to establish control and prevention strategies for ME/CFS. Now of course we can't prevent it when we don't understand the causes but, as part of our planning process, one of the very first steps that CDC did was try to understand the epidemiology of it, we conducted surveillance to determine the economic burden, who is affected by ME/CFS, what healthcare utilization and needs are there. We shared what we've learned through provider outreach and continuing medical education, our webpage, and we are searching for risk factors and biologic subgroups. We're trying to evaluate what we've done through monitoring trends in knowledge, attitudes and beliefs of healthcare professionals. We use the results of pre and post-tests to evaluate our educational materials and we have an ongoing communication with the advocacy community.
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  3. AndyPR

    AndyPR Senior Member

    Page 2

    Organizational Location of CDC's ME/CFS Program & Unique Features of CDC's ME/CFS Work
    Now, as Dr. Nahle indicated the program is located in the Chronic Viral Diseases branch, which is in the division of High Consequence Pathogens and Pathology in the National Center for Emerging and Zoonotic Diseases, and that is in the Office of Infectious Diseases and so, just like any government, we have our little hierarchy of where the boxes fit and then to emphasize, once again, the unique features of CDC's work is that we focus on the public health questions of the burden of disease, risk factors and causes, and intervention.

    Approaching ME/CFS – Current understanding that guides our work
    So part of approaching ME/CFS is that CDC needs to have a current understanding of the illness that guides our work and this diagram is one that most investigators in ME/CFS could endorse, at least at some level, too it emphasizes the multi-system nature of this illness. To this we could add the GI tract sitting in through diet and lifestyle and contributing to inflammation and changes in the CNS and as more data is incorporated this is added into the model, so that we can pick areas where we want to focus and develop studies that would address one hypothesis or another.

    Complexity of ME/CFS
    In short, we agree and we understand from other workers in the field that CFS is very complex. It likely results from alterations in the systems that maintain the body's homeostasis. Homeostasis refers to the ability of the body to adapt to changes and, because it is so important that the internal environment of the body is maintained constant, there's a lot of
    redundancies in these systems that are built in and they connect one in with the other, so it's very hard to just look at one system in isolation.

    It is likely that this illness is not the result of a single mutation or a single environmental factor, it could be the combined actions of many genes, environment, infections, trauma and understanding the pathophysiology of ME/CFS may very well uncover novel mechanisms that are important in other illnesses. So it's clear that a multi-disciplinary approach is necessary. The field has found that studies of “ME/CFS in motion” and by that I mean ME/CFS not just at rest but in response to a challenge such as exercise or stress are most informative in demonstrating the differences between patients with ME/CFS and patients with other conditions or healthy persons.

    ME/CFS Complexity and Case Definition Issues
    So the very complexity of ME/CFS leads, in a way, to the case definition issues and the problems that people have had with case definitions and questions about case definition. Case definition alone is very unlikely to be sufficient to fully describe patients for studies or clinical practice and we're kind of learning this, I would say, the hard way after years of starting off papers by saying the patient's met a so-and-so case definition, we're realizing that the very heterogeneity of the patients that were studying is very important, in things like age and race and sex and socioeconomics known to be factors in many many illnesses are important, as well as duration of illness, the presence of other illnesses that we call comorbid conditions, the medications that patients are on and the severity of symptoms, and the specific array of
    symptoms that an individual has all would make potential differences in one patient study versus another.

    Need for Improved Measures of ME/CFS
    And so this brings us to the need for improved measures of ME/CFS. These measures would be very important to describe the natural history of the illness, as well as to identify and measure change in response to treatment, and one of the findings of the FDA's workshop on drug discovery for ME/CFS is that there really needs to be better documentation of measures that could be used to track response to treatment. Improved measures of ME/CFS could also help identify
    patient populations with similar characteristics for research and for clinical trials and as well as potentially identify sub groups with different biological basis for their illness. This leads to questions such as what parts of the illness need to be measured, what questionnaires will measure these better than others and how should the scores be calculated and used.

    Major Illness Domains in ME/CFS
    Now the major domains in ME/CFS are fairly constant in many case definitions and that is there's more agreement then
    there is disagreement. This array of circles lists some of the major domains and the ones that are shown in blue are more or less specific for ME/CFS, but the ones in gray are shared in common with many many illnesses, fatigue and pain and function and sleep and cognition, and there are measures for these conditions, for these problems, that have been used in other illnesses and they could very well be applicable for ME/CFS, but for some of the other ME/CFS specific domains we may need new measures. In any event standardized ways to measure each domain of illness is really an important step to allow scientists and clinicians to share their results

    Multi-site clinical assessment of ME/CFS (MCAM)
    And so, the need to improve measures of ME/CFS really led to the multi-site clinical assessment of ME/CFS study that CDC has undertaken. Now the objectives of our study were to collect standardized data on as many of the ME/CFS illness domains as possible, using recognized patient reported outcome measures, these are often called PROMs, PROMs, but are probably more familiar to everyone as questionnaires.

    We wanted to be sure that the patients were diagnosed by experts in ME/CFS and we wanted the patients to come from
    multiple clinics and to include a large number of patients. Now the the idea of multi-site investigations of illness is not new but there's only a few studies to date that have used this approach for ME/CFS. Other rare illnesses definitely make progress when clinicians merge together, pool their cases and come up with unified plans for research and testing, and so we adopted this concept from other illnesses. We thought that this study would provide data about the patients with ME/CFS to inform case definition questions, to learn if the patients are different between clinics and to identify patient subgroups.

    Now the question about learning if the patients are different between clinics arose because so many studies find very important and interesting results and then the findings are not reproduced when the next investigator studies them, and this could be for any number of reasons but one of them could be differences in patients between clinics so we wanted to see how similar patients were. We also felt that the information that we collect from the study would tell us something about how well the questionnaires work at measuring the parts of the illness that we are studying.
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  4. AndyPR

    AndyPR Senior Member

    Page 3

    Request for Proposals – Mechanism to start
    So the way that CDC approach this was we issued a request for proposals through FedBiz Opps, this is a public site, it lists a lot of government contract needs, the process is that the request includes a general description of the questions to be answered, the qualifications of the contractors and what CDC will provide. It requires a full and open competition and it was posted and then we encourage qualified clinicians to apply.

    It wasn't necessarily an easy process so this, the clinicians, really had to go out of their way to really provide the information we needed in order to make the awards, and indeed we were able to make three contract awards that involved a total of seven clinics and the target enrollment based on the proposals was 450 patients with ME/CFS which meets all of our goals of a large number, and multiple clinics, and clinics from experts.

    Participating Clinics
    And the participating clinics include many of the experts in the field and I think that the stars on the map showing where those clinics are located and you see we're kind of East Coast & West Coast biased but we include Dr. Nancy Klimas, Dr. Benjamin Natelson, Dr. Lucinda Bateman, Dr. Charles Lapp, Dr. Andreas Kogelnik, Dr. Richard Podell and Dr. Daniel Peterson and we are so pleased that we are able to work with these experts.

    Beginning the study
    We started off by inviting all of the contractors and their staff to a kickoff meeting at CDC in November of 2011. At that time we agreed on the study protocol and the idea was that we wanted it to fit into the clinical routine as much as possible so as to minimize the patient burden. The enrollment criteria was any person diagnosed with ME/CFS in
    the participating clinic between the ages 18 and 70 years, the only exclusions that the clinicians recommended that we add were that the patient's not be HIV+ and that anybody that was diagnosed at age older than 62 would not be a good candidate.

    The key feature of this is that enrollment relies solely on the clinical judgment of these experts rather than on any one case definition. We submitted the first protocol for ethics review at that time and the protocol included a physical examination, medical record abstraction by clinical staff and quite a few questionnaires measuring those domains of illness.

    Next steps
    So we extended and broaden the goals of this study through a multi-year contract and this was used a sole source
    recommendation because we wanted to be able to follow-up the enrolled patients, we had a baseline year in 2012 and four option periods. We made additions to the study through protocol amendments or new protocols and, through discussions with the clinicians and comments through sip sack(?), we included a component of pediatric and adolescent patients, we added healthy and ill comparison groups, we added patients with new-onset and severely ill patients and this last group are really very understudied for quite a few reasons. We added biologic sampling, which I'm going to talk about a little bit more, and we added a combined exercise and cognition protocol. Now because this is all under the rubric of the MCAM study it gets a little confusing, one part versus another part, but I just wanted to walk you through how the different parts relate to each other.

    Benefits of MCAM Study
    Now the benefits of this study have been a lot from our point of view, not the least of which was it provided a mechanism to work with ME/CFS clinical experts and we definitely built relationships through collaboration, they were kind enough to open their clinics to us, and the patients in their clinics welcomed our visits, and many of them talked with us. We also found that this reassured our stakeholders that CDC is studying a relevant population.

    What we didn't expect was that this also benefited the clinicians and that they had a forum to exchange ideas with each other that wasn't really there in other ways. We share data from the first year of study with the Institute of Medicine committee that that was addressing the clinical case definition for ME/CFS and our data was unique because we did not enroll by any one case definition and so it allowed the IOM report to use the data to inform exactly how they put their case definition together.
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  5. AndyPR

    AndyPR Senior Member

    Page 4

    Limitations of MCAM Study
    However no study is perfect, and there are limitations to the approach that we've taken. Patients in specialty clinics may
    not represent ME/CFS patients in primary care health settings, all of the patients were highly educated, they had excellent social and economic support and nearly all had health insurance. In addition, they were a referral population, most of the patients have been seen and evaluated by more than one physician and this made it difficult to identify patients with new onset of disease.

    Outcomes to date
    So our outcomes to date. We shared information with the FDA Scientific Drug Development Workshop, it was sort of preliminary data, in April of 2013. We shared our findings with the IOM committee in January of 2014. We presented this information to the NIH Pathways to Prevention in December of 2014 and some of this information was included in CDC's Public Health Grand Rounds in February of 2016. I think in each forum(?), we tried to emphasize the importance of the multi-site study design and emphasize the advantages that increased standardization for measures of ME/CFS could give to the field, and then finally the data clearly showed that ME/CFS results in substantial functional impairment and that more research is needed.

    Functional Impact: Shown in SF36 Scores
    Now as an example of functional impact, as well as the heterogeneity of the illness, I'm going to show this SF-36 score. The SF-36 is a measure of function and it has several subscales that are used, the lower the score the worse the function, the plot is shown is called a bar graph or a box plot and the bottom, the full range is shown, the bottom of the box is the 25th percentile, the top is the 75th percentile, the bar in the middle is the mean and the triangle is the average or median or mean sorry, so median was the bar, triangle is the average or mean and the red bars are the average for the healthy comparison group.

    And it shows very clearly that the dramatic impairment in the physical goal functioning as well as in vitality, and the relative sparing on the sub scales measuring Mental Health and Emotional Role Functioning. Given that the range of scores basically are from zero to a hundred and in essentially every scale you can see that there is a wide range in patients, patients are not, one is not like the other.

    Comparing measurement tools
    We have looked at how well measurement tools compared to each other and we've added an instrument called the PROMIS instrument, these instruments were supported by an NIH development to create and validate scales for use across a wide variety of chronic diseases and conditions in the general population, specifically to allow comparisons to be directly made, that means scores for ME/CFS patients can be compared to illnesses that are better understood by clinicians, and again it gives another window onto the illness for clinicians that are not familiar with this illness. So MCAM uses PROMIS measures for pain, fatigue and sleep and we found that there was a good correlation with other validated measures of these domains and it demonstrated illness severity as shown in the next table.

    PROMIS T-Scores [Mean (SD)]
    This shows the PROMIS T-Scores and T-Scores are 0 to 100. The top row gives the values for Fatigue, Sleep Disturbance, Sleep Related Impairment, Pain Interference and Pain Behavior related to for the MCAM study, and then the measures found in other studies of Chronic Pelvic Pain, Spinal Cord Injury, Muscular Dystrophy, Post-Polio Syndrome and Multiple Sclerosis are shown, and you can see that the scores for ME/CFS patients are the same or higher than those in other illnesses.

    Patient Heterogeneity Shown in Measures
    So again going back to the heterogeneity, I want to emphasize this is shows the symptom scores for the CDC Symptom Inventory and the worse the the scores the lower the numbers, no backwards, higher, higher scores, so the Post Exertional Malaise and Unrefreshing Sleep are the highest scores here, that indicates that most patients have higher severity and frequency in those particular symptoms than in Sore Throat for example which is much lower.

    Again there's a large range but what we found is that there were no significant differences between clinics on nearly
    all of the measures that we looked at, so each clinic had patients that differed in their scores or in their characteristics that we looked at.

    Lessons Learned
    One of the lessons that we learned was about the physical examination, in that parts of the physical examination perhaps could be better standardized. We noted that the clinicians differed in how they describe the Romberg test and in the frequency in which they noted abnormalities and so, at one of our meetings at CDC, we discussed exactly how the test was done and how it should be scored. We came up with this standardized approach and it's not unique but it is at least standardized.

    Now the Romberg test, for those of you that might not know what that is, you've probably been asked to do it by a physician. It's a neurologic test of the body sense of position. You are standing with your eyes closed and your arms folded across your body, and you need to maintain this position without moving your arms or stepping out for at least 10 seconds, and patients need to be monitored closely to avoid the falls.

    Now there's two different versions, and they differ in where you place your feet, and Standard Romberg, the feet are placed together and in the Tandem Romberg one foot is placed in front of the other. Now it happens that the Tandem Romberg is much more difficult to perform, and you can try it out yourself as long as you've got a friend with you to make sure that you don't get hurt in the process. So we introduced the process where Standard Romberg would be performed followed by the Tandem Romberg and the standard protocol, we're just getting the data back from this, it also included how to score it and note the changes are the patient's movements.
    Last edited: Sep 23, 2016
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  6. AndyPR

    AndyPR Senior Member

    Page 5

    Introduction of NASA Lean Test to Physical Exam
    We also found that introducing the NASA Lean Test could be helpful in the physical examination. Now NASA is the space group and their lean test is a standardised method to evaluate postural hypotension and some people have described this kind of as a Poor Man's Tilt Table Test, it's certainly much more simple to perform and it involves serial measures of heart rate and blood pressure.

    The first one is done after the patient is lying down for five minutes, then the patient is asked to stand up, move to a
    wall that's convenient in the examining room place, place their heels six to eight inches from the wall and lean back on the wall with their shoulders and then the blood pressure and pulse is recorded at two-minute intervals for 10 minutes.
    Now the examiner must monitor the patient closely for lightheadedness or impending fainting and the test is stopped if the patient has difficulty maintaining position. Now the lean test is better than just a simple standing up because, when you're standing, you can use leg muscles to help maintain blood pressure and so, when you lean against the wall, you take away that additional crutch and it allows uncovering of additional abnormalities that could be missed by another method. In addition to standardizing the length of time and the intervals for recording the blood pressure and pulse, we believe that we will get results that will be easier to interpret, and this could be a real important tool to recommend to the healthcare community when evaluating any CFS patients, and we're looking forward to completing our data analysis on this.

    Collection of Biologic Specimens
    So we did add collection of biologic specimens, and these are definitely required for any biomarker evaluation and for correlating potential patient subgroups to test results from these kind of samples. We didn't do it initially because it does add a significant burden to the clinic's and to the patients, it also adds to the cost of the study as sample collection, shipping and storage is really more expensive than you would anticipate, and finally it's difficult to standardize collection and processing, and this has to be done if the biospecimens are going to generate reliable results. And so we got in our choice of samples to optimize simplicity for collection, that was important in maintaining quality, and in maximizing utility that is the different types of potential test that could be done on the samples that we collected.

    MCAM Biospecimens – Why Saliva
    And so one of the samples we collected is saliva, and I can imagine people would say well why saliva? And it happens that many compounds can be measured in saliva, unbound hormones in the blood move directly into the saliva. The sample can be collected noninvasively and that means there's no needles or anything that that hurts and CDC's experience with prior studies indicated that study participants could collect these samples at home. Now the collection involves a Salivette, which is this little white plug of cottony material that goes under the tongue, and it passively allows the saliva to be soaked up for two minutes and then the patients just put it back in this tube for storage and collection into the clinic.

    Salivary Cortisol – Measure of Cortisol Production
    Salivary cortisol is our primary measure, it's the first one that we're actually going to be, that we are assaying, and it is a measure of cortisol production. Low cortisol has been associated with ME/CFS and but it's not clear if this is true for all patients or subset of patients and so again, by studying as many patients as possible from our multi-site study, we will get a good idea of how the morning cortisol profile changes, and in addition, as we conduct follow-up, we will have an idea if this profile is constant or if it changes with time in an individual patient. Now cortisol levels do vary with time and that's why a single measure is just about impossible to interpret, and so you have a choice of studying the diurnal profile, that is collecting samples throughout the day, or an awakening profile, which is just within the first 60 minutes of awakening, and for our study we selected the awakening profile for convenience. These samples are assayed by Salimetrics, and then the residual saliva is returned to CDC, and we form an archive of these samples for testing, for additional compounds, if needed.

    Additional Biospecimens
    The other specimens that we've collected include whole blood into tubes with special preservatives, the advantages of these preservatives is that the chemicals rapidly break open the cells and stabilize the DNA and RNA, we have Paxgene tubes for DNA that, they're specially for DNA, and Tempus tubes for RNA isolation. They're pretty simple to handle for the clinic personnel, it involves just shaking the tubes and then freezing them, and then these are shipped to CDC on dry ice following biosafety guidelines, the Salivettes are also shipped the same way, and this is a little harder than it sounds but it certainly is doable. These samples will form the basis for a biorepository for future hypothesis testing and we're currently developing the governance structure and process for making these samples available.
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  7. AndyPR

    AndyPR Senior Member

    Page 6

    Testing Natural Killer Cell Function
    I want to talk about our Natural Killer (NK) Cell function pilot. Impaired NK function is one of the most consistent findings in ME/CFS but this test was very challenging to introduce into our study. There is no routine clinical tests available for NK cell function and same day testing has been used by most laboratories that have published on these findings. Same day testing at laboratories and at sites that don't have a lab is basically impossible and so we needed to evaluate whether next day testing would give us the answers that we could rely on. So our pilot study evaluated whether next day testing at one laboratory compared with same-day testing and next day testing at our established laboratory, and we relied on Dr. Mary-Anne Fletcher and Dr. Klimas' laboratory which they've been the pioneers in this area.

    Results of Pilot Study of NK Cell Function
    What we found is that NK cell counts are stable but they don't reflect the function, this was expected, same day versus next day in between laboratories were all really reliable, however it's the function that we need not just counts. And NK cell function same day versus next day was best assayed on isolated mononuclear cells sometimes called PBMCs. Whole blood assayed the next day resulted in dramatically decreased activity and NK cell function was really impaired by freezing the cells even when they were frozen for viability, and so next day testing results on the isolated cells are comparable between the two laboratories and we're moving forward to adding NK cell function testing in the next round of visits for those enrolled in the MCAM study. We estimate at least 400 tests are going to be performed and this will be between a mixture of cases in our comparison groups.

    Publication plans
    Our publication plans, I'm really happy to let you know that the manuscript describing the study design and detail has been accepted by the American Journal of Epidemiology. Now it doesn't sound too exciting that we published the methods, but it's exciting to me because I think having standardized methods and sharing how researchers approach collecting data on this field is really important to, again, move toward standardization and all of the study forms that were used will be available for use by others.

    Unfortunately the American Journal of Epidemiology has undergone some changes in their typesetting company and they have a backlog, so it will be four to five months until this actually is viewable, but at least it's our first publication and we're going to rely on this publication so that our other publications can refer to it.

    We have submitted abstracts on preliminary results of the studies on cortisol, cognition, exercise, the NK cell pilot in the biorepository to the 2016 International Association of ME/CFS meeting in October.

    The next papers that we are working on are to describe the clinical attributes of ME/CFS by clinic and overall, and we also are planning to describe the clinical practices of ME/CFS experts to compare in detail ME/CFS with illness controls and evaluate the performance of questionnaires.

    Now I should have mentioned before that the comparison of ME/CFS with other illness controls is a step that is often left out, investigators spend a lot of time trying to show how ME/CFS differs from healthy controls and I would wager that every clinician would be able to tell the difference between an ME/CFS patient and a healthy control. However it's the other illnesses that may mimic ME/CFS that we really need to have measures on so that we can identify those that are most specific for ME/CFS.

    Impact of Institute of Medicine Report

    Institute of Medicine Report – Strong message to the clinical community
    And so I'm going to move on to CDC's roles in disseminating information, and particularly the Institute of Medicine report. The IOM report really gave a strong message to the clinical community about the significance and importance of this illness, it included a case definition that has core features of ME/CFS that was streamlined so that clinicians could use it and recognize it, the prestige of the Institute of Medicine leads credibility to the recommendations, however the HHS CFS advisory committee work group, while they cautiously endorsed it, had concerns about the potential for misinterpretation over simplification, questions about when the findings should be revisited, and so since the IOM report charged CDC with disseminating findings on the webpage and other educational materials, we felt that this could be best done by convening, by getting input from all of the stakeholders that are in involved, broad stakeholder collaboration, and this includes the patient advocates, as well as the medical professional organizations, medical educational organizations and clinicians with expertise in ME/CFS, as well as the government.

    Developing Educational Materials with Broad Stakeholder Collaboration
    We felt that this would provide a mechanism to improve communications among the stakeholders so that patients concerns about what might be misinterpreted positions, concerns about complexity or what they're looking for in case definition, educational materials, we could get input on all of those factors. We're going to use this as we incorporate recommendations of the Institute of Medicine report on webpage and other educational materials. Other government agencies are participating in this process and we initiated it with small group calls conducted by a non CDC facilitator and we will be having a face-to-face meeting in Atlanta at the end of the month
    Last edited: Sep 23, 2016
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  8. AndyPR

    AndyPR Senior Member

    Page 7

    Final Comments
    Progress is slow but steady

    And so some final comments and looking forward, I would like to echo the message that's on the Solve ME/CFS Initiative web page, it's on some of the pictures they have down at the bottom, over and over again, they have this tagline “We will move forward, we will move forward”. That is exactly correct, progress is slow but it is steady. I think the convergence of the IOM report, NIH's pathways to prevention and increased interagency dialogue has really given impetus to this field. There's exciting new findings as has been shown by the speakers in this webinar series, and the first PNAS paper which just appeared. And I want to emphasize that data is really essential for progress and standardization of data methods is advancing, CDC has a collaboration with the NIH, National Institute of Neurological Disorders and Stroke, to produce common data elements for ME/CFS and then NINDS, on their website, has a whole lot of common data elements for other illnesses and it will be absolutely fantastic to have ME/CFS join this group, and I think this will help in data sharing and moving the field forward.

    And finally I want to thank the MCAM Study Group and Study Participants, and my Division, and the Branch colleagues for helping me and being the reason that this program exists.

    Q & A Section

    Dr. Nahle
    Thank you, thank you, Dr. Unger, I appreciate this overview, you summarized a lot of things for us today. You started framing the conversation in the public health format, and then you told us about the control and prevention
    strategies at the CDC for ME/CFS, you also summarized the complexity analysis diagrams of ME/CFS and then discussed the multi clinic site, its inception and some updates, mainly the Cortisol Project and the Natural Killer Cell Function Project, and then you ended up with the publication plan and the role of the CDC in the dissemination of the
    Institute of Medicine report so I appreciate all that.

    We received many questions, as you can imagine, so I will try to summarize them here. I prioritize the questions from our audience over mine although I have a couple myself and I'm itching to ask you, let me do this one because it's representative of probably 10 questions and I felt, I'm going to ask it exactly the way it is it came. It's about the elephant in the room, really one of the elephants, the Cognitive Behavioral Therapy and the Graded Exercise Therapy, that I'm going to ask it exactly as it came, it was measured and it encapsulates whats on people's mind

    Here's the question, citing the CDC, the Mayo Clinic website lists Cognitive Behavioral Therapy and Graded Exercise
    as treatment for CFS, since we know this doesn't work and may hurt is CDC doing anything to reeducate institutions such as the Mayo Clinic.

    Dr. Unger
    OK yes, there have been a lot of discussion about therapy and, let me just say that first of all our education, our stakeholder meeting, is about the IOM recommendations which, unfortunately, have not gotten to treatment recommendations for treatment guidelines or management approaches. Much more needs to be published and studied about this in order for there to be a literature to refer to. We definitely understand the limitations of the data that is present and, as part of our website production, we will need to consider how to approach this, and we are discussing this at CDC, and we will be discussing it with the stakeholders, so I think one of the things to be, to keep in mind is that none, there's probably, there's no medication, there's no management approach or way of of handling illness that's going to help everyone, and one of the things that may be most helpful is if we divide our recommendations into degrees of severity, and I think where the problem comes is that when patients are very very severely ill, some of the things that may benefit people with less severe impairment either appears condescending or is actually harmful and so we're going to have to do a better job of explaining this.

    Dr. Nahle
    So I'll follow up on this Dr. Unger, how do you frame this in the context of the AHRQ(?) recommendations or or that opinion recently on finding these type of treatments inefficient.

    Dr. Unger
    Well they certainly are inefficient and they actually aren't treatments. Cognitive Behavioral Therapy, is what's called a management tool, that doesn't mean that, it's it's not a negative thing, it's just a way of helping people get a little bit more control over their illness. It doesn't change the illness, and so it's really inappropriate to call it a treatment and we did move it from our, we did move the way we describe it into a, under the idea of something that may help some people and I think that is the way to keep it in mind. It is nothing, is in all, its (not) gonna be for everyone.

    Dr. Nahle
    Absolutely, and I have to acknowledge that you have made some changes, but as the questioners ask the question, the institutions like the Mayo Clinic are citing the CDC for this type of information to educate physicians and that is an important element. Now let me move on to, Dr. Unger, to another question here that I have, in what you described as the complexity analysis of ME/CFS, you showed some overlap between other diseases, another fatigue etc as well as Post-Exertional Malaise, now when we talk about the fatigue in the context of ME/CFS can you make the distinction to
    us about what we mean by that fatigue because it's very different, clearly, from the fatigue that we see in depression, for example, exercise helps in that context, however in in in the case of ME/CFS patient's you have Post-Exertional Malaise as if you exercise you crash, so when we try to I identify the similarities and the differences between ME/CFS and other diseases, how do we distinguish fatigue? Is there a qualifier that should be there?

    Dr. Unger
    Well I think, if I'm not sure, I'm going to see if I can go back to that, to that diagram, and one of the domains is Fatigue but another domain that was listed was Post Exertional Malaise because I do, all that it is, it is a different part of fatigue, and it actually is sort of the $65,000 question, is there a difference in fatigue between different kinds of illnesses, and what we can do is use the same instruments and measure the amount of fatigue that a patient is experiencing. I think one of the most important lessons that we have is that it's, fatigue might not be the best measure of this illness, and maybe not even Post Exertional Malaise, rather where they're at in their functioning, and that's because patients are so anxious to do more and more that they, when they are better they will exercise or work up to their level of fatigue, and that they've had that, they had before and so what changes is their function and not their fatigue and so that's one of the questions, and that's why you need to measure all of these things together, no one measure is going to be unique for ME/CFS.

    Dr. Nahle
    Yes, thank you, I'd like to move on to other questions, is ME/CFS tracked at all for prevalence in the U.S.?

    Dr. Unger
    There is not a systematic way to track it, we have added a question, an optional question, to some of the states that wanted to do it, basically just asking have you been diagnosed with ME/CFS by a physician, that is in the Behavioral Risk Factor Surveillance Survey and it would be just self-report.

    Dr. Nahle
    And is it the CDC in charge of tracking disease, demographics about diseases in the United States and perhaps in the world?

    Dr. Unger
    Well, yes I guess, I guess we are. If you're asking is ME/CFS a reportable condition? No it is not one of the reportable conditions and that has, people have asked about that, why isn't it a reportable condition and the process for making a condition reportable is a very very complex, and it requires agreements with states, and I don't think we're there yet with ME/CFS. It could be that we'll get there at some point but were just not there yet. And I really feel like the data that CDC and others have produced about the the burden of this illness is sufficient to justify more work, and getting more numbers on, you know, who's affected isn't gonna give us any more impetus than we already have.
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  9. AndyPR

    AndyPR Senior Member

    Page 8

    Dr. Nahle
    Thank you Dr. Unger for this explanation, and can you just elaborate very briefly on what is reportable, what's the definition of reportable.

    Dr. Unger
    I'm sorry, I didn't, I didn't look that up, so I don't, you know, that that's the correct answer for that, but there is, there is a process by which states have to report, or are required to report on specific, and they're usually infectious organism, infectious diseases and then, there's been, they've been tracked and it's reported in MMWR.

    Dr. Nahle
    Yes, thank you, thank you. This question is, I believe, is insightful, should it be called Post-Exertional, Post-Stressful Malaise? I believe that the question is asking not only about the exertion but the stress in general.

    Dr. Unger
    I use the term Post-Exertional Malaise, that is the one that's most commonly used but when you go right after the word its talked about our response to exercise or cognitive challenge or anything, and so I guess you need to think of exertion in terms of both physical, mental and emotional, all of those things are part of getting through the day, and anybody with ME/CFS recognizes, or experiences, relapses if they've gone beyond what they can manage.

    Dr. Nahle
    Yes, thank you, Dr. Unger there's a question on the Epstein-Barr Virus and pregnancy, understanding that many ME/CFS patient's have EBVs, do you care to comment on that? I thought this is a different kind of question.

    Dr. Unger
    Right I don't have anything specific to to comment about that, certainly Epstein-Barr Virus is one of several infectious diseases that have a long-term prolonged fatiguing illness associated with them and when the infectious illness like Epstein-Barr Virus is recognized, it's often termed a post-infectious fatigue, and this is different from patients that have Epstein-Barr Virus that's normally fatiguing but the recovery phase is much longer.

    Dr. Nahle
    Yes, thank you, thank you, there's a question here on geographic equity and you alluded to that before, regarding the MCAM study, is there anything that the CDC is doing now, to the questioner is from the great state of Missouri and I think that is on point, is there anything in the plan to provide geographic equity on this.

    Dr. Unger
    Right, where we definitely are aware of it and I think more than geographic equity what this highlights is the need for more physicians that are really expert in ME/CFS and the clinicians and where they're located seem to be largely on
    the coast, and we definitely need more physicians that can care for patients and that is one of the biggest questions CDC
    gets, we can't refer people to to any clinic but we are aware that patients have great difficulty identifying physicians that know about this illness.

    Dr. Nahle
    Yes, thank you. We promised folks that we will stop at the top of the hour but I have a question here that I hope you
    know, if you cannot give us just a brief synopsis about it we can answer it after this, it's a long question I'm going to read it just so that you hear it, that's the objective of these forums, this is the question. Regarding improved measures, are you saying that researchers need to use both standardized measures and also case definitions for ME/CFS research that require the presence of hallmark criteria such as post-exertional malaise and cognitive dysfunction

    Dr. Unger
    Absolutely, and so what I'm saying is that people need to meet the case definition but then more than that they, each of the criteria need to be measured, so that that's because you can meet the case definition and, in no matter what case definition use, in multiple ways and with multiple degrees of severity, and so adding measures, it's it's not a replacement for a case definition, but what you can do with measures is you can say okay this level of fatigue or this level of function, you need to have at least that in order to meet you know, impaired function, you can set your scores rather than asking just the question, are you know does your fatigue impair your ability to under go activities of daily living, it gives a little bit more reproducibility to the measures if it's a good questionnaire, and so yes both case definitions and measures.

    Dr. Nahle
    Thank you Dr. Unger, thank you. I appreciate this, again we we have to stop now, many of our listeners in would like us to do that at the top of the hour, so thank you so much for giving this webinar, for sharing the information and the status at the CDC, of all the work you're doing on ME/CFS, as you can see and as you can tell, us and others have high expectations of the CDC, and we appreciate your work on on the subject, and we will keep asking you these questions and again I appreciate your professionalism in coming and answering this with no frills directly to our audience and our patients.

    Thank you so much.

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  10. shannah

    shannah Senior Member


    and thank you!
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  11. mango

    mango Senior Member

    Brilliant job, well done @AndyPR! Thank you so soo much! Much appreciated! :thumbsup::hug:
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  12. aimossy

    aimossy Senior Member

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  13. gretac


    First, thanks for all of this, Andy!
    From p. 4, Functional Impact: Shown in SF36 Scores, 2nd paragraph:
    I think she says "relative sparing" - i.e., Mental Health and Emotional Role Functioning are spared by this disease - as can be seen clearly by the graph --- hooray, great finding! Do you think now they'll stop wasting resources on including CBT in their research????? (I'll read and listen on to see!)
    AndyPR likes this.
  14. AndyPR

    AndyPR Senior Member

    Ah, yeah, I think you are right. My brain couldn't make the connection from the use of the word sparing to what was being talked about but that makes sense now.

    ETA: I have now edited my transcript to read this now, thank you.
    Last edited: Sep 23, 2016
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  15. Nielk


    It still clearly appears on CDC's website under treatments and managements - http://www.cdc.gov/cfs/management/index.html

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  16. gretac


    Yes. She fumbled in response to this question (if you listen to the audio), and was at best less than clear and transparent in her response, as you pointed out. Claimed we need more "studies." Kudos to Dr Nahle for pushing her a bit on that.
    If CBT could help me "control my illness," guess what, I wouldn't be sick! The only way it can help with that is by increasing my mindfulness of how I'm doing so I can stop activities sooner - and there are better ways of improving that than CBT. (Psychologist speaking, here.)
    Why is it so hard to let go of that and GET?? "Developing an activity program"?? "Modifying exercises for extremely ill...:?? And "most disruptive symptoms" still does not include post-exertional collapse! And she used the patient demand for input on the response to the IOM to justify why they haven't changed it - that seemed very disingenuous to me.
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  17. Simon


    Monmouth, UK
    My favourite bits

    New-onset and severely-ill are both understudied, so hats off to the CDC for making effort to include them. More on those healthy and sick control groups below.

    The biologics include saliva, blood (inc DNA, and RNA for gene expression) and specifically Natural Killer cell function. I was impressed by the lengths they went to in order to find tests that would work well, and cope with collection in a clinic and testing at a lab elsewhere next day, eg for NK cell function, where they tried testing in many different ways, most of which didn't work well. Finally:
    That will be interesting.

    Never mind a trained doc, my nieces could have spotted the difference between a mecfs patient and a healthy bod when they were still quite young. It's so important, and NK cell function might be an example - I think @Jonathan Edwards has argued before that NK cell problems might well be more marker's of poor health than specific to mecfs. With the sick control groups, we'll be able to tell, for NK cell function and everything else too.

    Finally, thanks, @AndyPR, great work.
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  18. Laurie P

    Laurie P

    New England, USA
    AndyPR transcript of what Dr. Unger said:
    Dr. Unger said:
    I wonder how many more years/decades this is going to take?!

    Patients are bedridden and worse because of the; as Dr. Unger herself put it, "actually harmful" information that the CDC puts out. How many more lives are they going to destroy before they put out accurate information?

    Dr. Unger avoided discussing GET, so I'll post what the CDC website http://www.cdc.gov/cfs/management/managing-activities.html says:

    Last edited: Sep 24, 2016
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  19. alex3619

    alex3619 Senior Member

    Logan, Queensland, Australia
    Thanks for this. Would that be PBMCs, or peripheral blood mononuclear cells?
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  20. alex3619

    alex3619 Senior Member

    Logan, Queensland, Australia
    On CBT, it is a management technique, and has failed everywhere to show actual physical changes to disease. However the issue that was not addressed is the use of therapies that are different to regular CBT but still use the term, as in PACE.
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