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 here: CDC Grand Rounds: Chronic Fatigue Syndrome: Advancing Research and Clinical Education, Part I
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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.
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.
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