Wednesday, March 9, 2016

CDC Grand Rounds: Chronic Fatigue Syndrome: Advancing Research and Clinical Education, Part II

This post first appeared on ProHealth.

Transcript by Erica Verrillo

On February 16, 2016, the CDC hosted a one-hour session on ME/CFS. Featured speakers included Dr. Charles Lapp, Dr. Beth Unger, Dr. Anthony Komaroff, and Dr. Avi Nath. The session was introduced by Dr. Harold Jaffe, CDC Associate Director for Science.

This second part of the session consists of a presentation by Dr. Avi Nath, the neuroimmunologist who is heading the NIH study on ME/CFS. The last 10 minutes of the session was opened to questions from the floor, during which Dr. Nath supplied more details about the study.

Main points in Dr. Nath's presentation:

Phase I of the trial will involve 40 patients. This will be an in-depth study, and will take about a year. NIH hopes to discover the pathophysiology of ME/CFS during this period and discover biomarkers. Tests will include an exercise test to induce PEM, MRIs, cerebrospinal fluid tests, including a screen for autoantibodies to neural antigens, and an exploration of the gut and oral microbiome applying proteomics and metabolomics approaches.

Phase II of the trial will be open to a larger group of participants. This phase will validate biomarkers found in Phase I.

Phase III of the trial will focus on immunomodulatory agent, such as Ampligen, which can target the biomarkers found in Phase I.

Some questions raised by the audience concerned how NIH would incorporate patient input, what steps were being taken to educate physicians and medical students, and what kind of immune tests would be performed.

You can watch a video of the entire session HERE.

You can see the slides that accompanied the four presentations HERE.

You can read FAQs about the study HERE.

You can read about the Grand Rounds' first three presentations hereCDC Grand Rounds: Chronic Fatigue Syndrome: Advancing Research and Clinical Education, Part I

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Dr. Avi Nath [42:38]: As some of you know, the National Institutes of Health has had a long-standing interest in chronic fatigue syndrome. In December of 2014, NIH sponsored a Pathways to Prevention workshop to advance research on ME/CFS.  In September of 2015, Dr. Francis Colllins, the director of NIH, tasked the intramural program to develop a research protocol to study the illness using the unique resources that are available at the intramural program.

The relationship to infections to the onset or ME/CFS and the large body of literature identifying a variety of interesting but inconsistent immune abnormalities in these patients provide a rationale for further studies of immune regulation. For example, two studies from a group in Norway showed delayed clinical improvement in patients following treatment with rituximab, which is a monoclonal antibody that depletes B cells. However, these studies were small, and the immune profiles were not measured in these patients.

Patients with ME/CFS can be associated with a variety of precipitating factors. Our studies will be focused on a defined subset of patients who have a viral illness at onset of their illness. These patients are likely to have quite similar immune profiles. Our hypothesis is that post-infectious ME/CFS is triggered by a viral illness that results in immune-mediated brain dysfunction. To address this we have proposed a three-phase study.

The first phase is a cross-sectional study which will define the phenotype and pathophysiology of the disease. Phase two will validate the biomarkers in a longitudinal study. And phase three will be an early intervention trial to target the biomarkers identified in phase two.

The first aim of the phase one study is to define the clinical phenotype using in-depth assessments of all domains of the illness. [slide] Aim two of the study is to define the physiological basis of fatigue using functional MRI scan of the brain to define the brain circuits involved; do detailed metabolic studies in a metabolic chamber, and so transcranial magnetic stimulation as well as very detailed autonomic testing. Each of these tests will be performed before and after exercise.



The third aim of the study is to conduct a detailed immunological study in blood as well as cerebrospinal fluid, including a screen for autoantibodies to neural antigens. We will also fully explore the gut and oral microbiome and apply proteomics and metabolomics approaches to the cerebrospinal fluid.

The fourth aim of the study will utilize a variety of novel approaches to explore whether cells or serum from patients can be used to experimentally reproduce some of the features of the illness. We will determine if there is an inherent metabolic abnormality in neurons derived from stem cells and culture from these patients and if exposure of spinal fluid will induce the functional abnormalities in these cells.

We will also generate humanized mice using blood cells and determine if the clinical phenotype can be reproduced in these animals.  If these experimental systems are able to reproduce the clinical or biologic abnormalities seen in these patients, it would be a major step towards identifying the cause and the pathophysiology of the illness, and for developing a variety of treatment approaches to these patients.

For the purpose of our phase one study, we plan to recruit patients primarily from well-characterized cohorts, particularly the CDC’s MCAM study.  Selection criteria will include documentation of the acute onset and duration of fatiguing illness for more than six months but less than five years. All patients will have post-exertional malaise and full criteria of the 1994 research case definition and the Canadian Consensus Criteria. The study population will include 40 post-infectious ME/CFS patients, 20 healthy controls, 20 post-Lyme patients who are asymptomatic, that means they do not have fatigue, and 20 patients with functional movement disorders.

These studies are still being refined and rely on the talent and expertise of a large number of investigators listed here. I would particularly like to thank Dr. Brian Walitt, who is the lead clinical investigator of this study at NIH and Drs. Unger and Lipkin as members of the executive committee for their valuable advice.

Q&A [49:36]

Q: Why isn’t the CDC/NIH as a whole bringing pressure to bear on researchers and educating treating physicians to use far more extensive and detailed survey instruments and be far more precise in their description of the symptom presentation and pathogenesis?

Unger: I think that we are publicizing the importance of using instruments to precisely characterize the illness and we are in the process of publishing the baseline results of the MCAM study which will absolutely specify the instruments we are using and how they can help in other studies. And I believe we have been working with NIH and we are going to be sharing a lot of the same instruments and approaches.

Nath: We are delighted to be able to share whatever information we have and to work very closely with the CDC as Dr. Unger mentioned to achieve those goals.

Q: Another of our viewers would like to know all the specific steps that are being taken to educate medical students in medical schools using the latest information from that 2015 Institute of Medicine ME/CFS report.

Unger: Okay, well, we are… we have just started our medical student curriculum, as I mentioned through the MedEdPORTAL. This incorporates … so we started it before the 2015 but the educational curriculum that goes along with it gives the references from the IOM – the IOM report. In addition we have our collaborative process ongoing … or it’s just being started where we are trying to work with medical educators to find out what kind of materials they want and can easily incorporate into their classes. The advantage of the MedEdPORTAL is that it is online and it is free for faculty and actually medical students actually can have access to it as well. So we think that will be a useful start.  The collaborative work group is what we hope will also be giving us advice as to what would be most helpful.

Q[Wilhemina Jenkins]: Dr. Nath, could I ask you to be a little more detailed about the patient advisory committee, how you intend to incorporate patient input into the NIH study? And could I also ask, I don’t know if you have the answer to this, about external funding from NIH to other researchers on the outside, possibly through RFAs that might be developed.

Nath: So, firstly I think input from the patients is absolutely critical for any disease that you want to study. They are ones who really experience the symptoms and live it – live it from day to day. As physicians whatever input we can get from patients is very important to whatever mechanism it is. Any physician will tell you that you learn a lot more from talking to patients than you do from reading any kind of textbook, journal, or whatever medical literature that is available. Careful listening to patients is absolutely critical. What that in mind, I grew up in the early AIDS epidemic , and I saw interactive with Act Up, and other patient forums whereby they had a great impact on the way the disease was handled, treated and moved the Federal government to make changes at every level. And so, we understand the importance of it, and there are efforts under way to put that advisory group together. So, you know, people who are senior to myself want to look at it from all perspectives and put together a proper group that will address both intramural and extramural teams. I think those efforts are under way and we are looking forward to that input.

With regards to external funding, again, that is beyond my area of authority and so I know there is a lot of interest in being able to make that happen. A lot of advocacy groups have approached NIH with that effort. I think the heart is in the right place and all those things will be done. I think it’s probably just a matter of time before you see all these things happen. But there is no lack of interest in achieving those goals.

Q: I'm Steve Monroe, Associate Director for Lab Science and Safety. I have a question for Dr. Nath. Given the consensus of the role of immune dysregulation and the symptoms of the disease, can you elaborate a little bit on the kind of functional immune assays that you are projecting to do with the upcoming study.

Nath: I’ve put together a panel of really outstanding immunologists to guide me. Although I do consider myself to be a neuroimmunologist, every immunologist is not the same. There are people who specialize in B-cells, and T-cells, and NK cells, and so on and so forth. So what I did was I called on Dr. Neal Young, who is an expert immunologist at NIH and Ronald Germain, who is a National Academy of Science member, and so we sat and discussed various kinds of things. I think what we’re going to do is we’re going to collect a lot of lymphocytes both from blood and from CSF [cerebrospinal fluid]. Initially, we’ll be storing them and what we’ll be doing is looking at cell-free fluid in the CSF and the serum for not just a small number of cytokines, actually 1,500 lysates, analytes. But we want to be very comprehensive and I have developed a proteomics assay in my own lab which will look at about at least 2,500 proteins. So when we look at the composite, I think that it will be very clear to us what cell types may be dysfunctional in these patients and how we can subgroup those individuals, and that will then allow us to go back and say, well, this looks like an NK cell function, let’s look at it, or this looks like a B-cell, because there are innumerable amounts of very time-consuming tedious assays for each cell type that you could potentially do on interactions between cell types. Instead of doing that at the get-go and everything you could possibly think , I think that’s a good screening tool, and then we can focus on the real aspects that we think are really dysfunctional.

Q: Do you think primary care providers can offer appropriate services to chronic fatigue patients or would it better for them to refer to specialists?

Komaroff: Yes, I think primary care providers can provide adequate services, particularly if they have people in ID, neurology backups when something doesn’t add up. But primary care providers need to be better educated than most are currently.

Lapp: I would agree with that and as a primary provider myself, and former family physician and internist and pediatrician, we’re at the forefront. The family physicians, the family doctors, are the ones who really see the majority of these cases first, not the specialists. So, as Tony [Dr. Komaroff] has pointed out it’s very important for these providers to be educated and know how to recognize the patients when they walk in the door. I should point out from previous studies done by the CDC that not only the primary providers but also the mid-level providers are doing a lot of the diagnosing and initial treatment of patients too.  I think it is very important to address that group of individuals.

I would like to say that since the IOM report came out and the P2P, that we’ve seen a great deal of movement from the government. The patients always want to hear that, that there is something being done. From my perspective, working with this wonderful group, I’ve seen a lot of movement on behalf of the CDC and the National Institute [sic] of Health and even some positive statements from Dr. Francis Collins, who seems to be supporting a movement for more research into chronic fatigue syndrome.

Q: I’m Brenda Robertson, and I’m a nurse at Emory and Grady. My background is community health and divinity. And I want to know if there is anyone at the CDC or NIH or beyond looking at research into environmental triggers, such as the chemical loads that have been added to the food industry since the ‘70s and ‘80s, like phosphates, fructose, citric acid, and I wonder if anyone’s looking at that as serious triggers because this is a widespread illness.

Unger: We don’t have a specific focus on that. We are aware that there are environmental triggers in some patients, but it is something that we have in mind, but we don’ t have an active program in that right now.

Nath: At the intramural program we don’t have that kind of expertise. Our focus will really be on immune dysfunction. But the sample will certainly be stored. Once the extramural community gets involved, that have expertise in those areas, we would be delighted to work with them and provide them whatever resources we have in patient samples.

END PART II




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