RFI responses from patient advocacy organizations

296 Pages·2016·2.49 MB·English

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[…]
Subject: RFI ME/CFS

Research
- HHV-6 associated mononucleosis preceding onset of ME/CFS
- Pathogen-induced VDR dysfunction
- Gut Enterovirus infection
- Prevalence of SIBO in ME/CFS patients; Does treatment of SIBO improve symptoms of CFS in a subset
of patients?
- Define Subsets of patients
- Sore throat causes in ME/CFS patients; Is it found only in a certain subset?
- Nutraceuticals trial
Education
- Include ME/CFS in Medical School Curriculum

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Subject: CFS

I have had CFS for over 49 years and have consistently searched for a cause and a cure. Last year I was
diagnosed with intestinal colonization of staph aureus and epidermis. I had no idea that it was possible
to have an internal staph infection such as this. I am convinced that this is the initial cause of CFS. The
colonization of staph produces biofilms and toxins which the immune system attempts to clear and
cannot. Since 85 % of the immune system is in the intestines the immune system spirals down and the
many viruses and bacteria , such as HHV 6, CMV , and EBV then can become active causing more severe
health issues. Once health deteriorates to a certain level , whatever illnesses you may disposed to
could take over. Internal staph infections are contagious and easily passed from person to person and
can also be sexually transmitted.

I am suggesting to look at this first and determine if this could be correct. Dr. Davis is looking at the end
result of CFS and the mitochondrial issues that are created. I think this happens later in the cycle. When
I first became ill I knew almost immediately that something was wrong with my immune system. Any
cut or scratch took much longer to heal but never healed completely. If I was around any person that
had a cold or flu I would get it immediately.

I could write a book or two about my experiences, discoveries, what has helped, what I think will
provide a cure going forward. However I wanted to keep this short. I hope there is interest in moving
this forward to determine if I am correct. I think it is a good place to start.

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[…]
Subject: ME/CFS

I am a patient that has had CFS for twenty years. I was unable to adequately care for my children who
are now 21 for the majority of their childhood.(triplets) I was not as sick as my daughter. My daughter
developed CFS with my identical symptoms two and half years ago. She was bedridden for most of this
time. She lost twenty pounds, could not stand, could not eat, was short of breathe, slept 20 out of 24
hours , had horrific migraines, wore an eye mask due to light sensitivity, lost most of her hair, and after
9 months we thought she would die. No one would help us, no one understood what was happening to
our goal oriented, highly productive child. We have been helped my Dr. Jose Montoya at Stanford
University. The therapies that proved to have the most promise and improvement for me and my
daughter have been antivirals, specifically, VALCYTE. My daughter improved on COLCHICINE due to its
anti inflammatory properties as well as VALCYTE. My daughter had to leave her university and stay
home where we can care for her. She was president of her high school student body and graduated with
a 4.2 GPA. She was premed in college and wanted to travel to underdeveloped countries to aid in global
healthcare. She will not realize her dream of becoming a physician. She hopes to someday in the future
to finish college. She was strong, determined and had a plan for her future. All that has changed with
her diagnosis of CFS. My husband is a very well trained physician having attended Dartmouth Medical
School but do to his lack of training and education in this devastating disease he is completely helpless
and ill equipped to treat out daughter. We went to no less that 25 physicians to receive a diagnosis,that
stress alone greatly exacerbated our condition. Although I improved greatly from the Valcyte my
daughter has had many relapses and her quality of life is poor. My daughter makes bracelets and
donates the money to CFS research through Dr Montoya because she knows our government has not
provided the research funds needed to help her fight her illness. There are no approved treatments and
no bio markers to diagnosis our disease. I know so many children and adults wasting away in
wheelchairs and in bed with no hope. We need to educate doctors to be able detect this illness and we
need research funds to help find diagnostic markers and eventually treatments that will help. The fear
and hopelessness I, a registered nurse and my husband, a physician feel as we care for our daughter at
home without any guidance or or help from the healthcare community is paralyzing. We beg and
implore the CDC and the NIH to make sure physicians are educated, research funds are equitably
allocated, and to pursue a cause and a cure for this illness that effects more than 2.5 million Americans
and people globally. We should not be alone in this battle to regain our health.

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Subject: ME/CFS research

Anonymous submission
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Emerging needs and opportunities:
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Need to explore potential of immunomodulatory pharmacological treatments extensively.
Opportunity to consider both pharmacological and non-pharmacological treatments that reboot
immune system e.g. bone marrow transplant.
Opportunities to collaborate with those researching both pathophysiology and treatments in other
fatiguing illnesses e.g. MS, primary biliary cirrhosis, RA etc.
Opportunity to add an ME/CFS group to studies investigating treatments in other fatiguing diseases –
this could be a cost-effective way of finding out which treatments might be worth pursuing in larger-
scale studies in ME/CFS. As a patient it is frustrating to know that drugs and treatments known to
reduce fatigue in other diseases have simply not been trialled in ME/CFS, e.g. Plaquenil in Sjogren’s,
various immunomodulators.
Again, opportunity to investigate possible common pathophysiology between cognitive fatigue/sensory
overload across conditions e.g. ME/CFS, stroke, traumatic brain injury – very striking similarities based
on my clinical and personal experience.
Challenges or barriers to progress:
Gross underestimation of the profoundly disabling nature of ME/CFS throughout medical field –
resulting in reluctance to fund/do studies on “strong” drugs or non-pharmacological approaches that
could actually help.
Lack of objective outcome measures has led to ineffective therapies being recommended. Very easy in
modern world to quantify people's activity levels pre- and post-treatment.
Potential harm to patients involved in research given negative consequences of cognitive and physical
exertion. I think doctors often assume post-exertional malaise is temporary and reversible, and that
patients do not deteriorate over time, but these are not safe assumptions. Extremely careful monitoring
and reporting of harms should be part of all research. People with ME/CFS care about
relapses/exacerbations/deteriorating over time, not just hospitalisations and death – researchers should
too.
Some in medical field have strong beliefs in deconditioning and/or somatisation as cause of ME/CFS.
This has stifled research, led to at best ineffective and at worst harmful therapies being widely
recommended for people with ME/CFS, and shattered patients’ trust in doctors. Patients’ trust will be
rebuilt only by a consistent commitment to research that is based in careful science, not beliefs.
Gaps and opportunities across the research continuum from basic through clinical studies
Long-term and retrospective studies detailing natural progression of disease to inform
o accurate prognosis
o pathophysiology
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o accurate advice to prevent relapse and maximise chances of improvement/recovery.
As a patient interacting with other patients I see a number of potential patterns that are not mentioned
anywhere in the literature – e.g. initial improvement followed by relapse(s) and subsequent ongoing
deterioration, significant drop in functioning at approx. 3 years post-onset.
Opportunity for researchers to tap into resource of millions of patients worldwide with access to
internet. Potential for extremely useful data to be collected.
I trust that ME/CFS researchers with a lot more energy than me will share valuable insights.
Looking forward to seeing the fruits of NIH-back research into ME/CFS.

[...]
Subject: ME/CFS: response to request for information. Notice Number: NOT-NS-16-024

Challenges or barriers to progress in research on ME/CFS.
The central blockage to ME/CFS research is the combined problem of a dearth of researchers in the field
and the (widely reported) difficulty that existing ME/CFS researchers experience with respect to
obtaining funding. The two issues together create a viscous cycle whereby new researchers refuse to
enter the field because of a lack of funding, and the lack of new researchers means fewer researchers
are applying for funds and researching ME/CFS. It is frequently reported that young researchers view a
career in ME/CFS as career suicide because of the lack of career and funding opportunities, which in turn
leads to a long-term shortage of new researchers in the field.
Many existing CFS researchers report that they experience disproportional difficulty in obtaining funding
compared to other diseases. High profile scientists such as Prof Ian Lipkin and Prof Ron Davis, but also
many others, have to resort to crowd funding in order to scrape together resources to enable then to
carry out any research. Some of the more successful ME/CFS researchers manage to carry out research
only by adding ME/CFS cohorts onto funded studies that primarily investigate other illnesses, such as
gulf war illness, because the other illnesses are so much easier to attract funding.
Existing ME/CFS researchers have said that the reasons given by reviewers for the refusal of grant
applications (for ME/CFS research) can be spurious. For example, a reviewer may make unfounded
assumptions about the nature of ME/CFS, and declare that the research would be a waste of time based
on ignorant and outdated prejudiced presumptions. Other reviewers may give other prejudiced and
uninformed reasons (e.g. that ME/CFS isn't a serious illness so it doesn't warrant investigation of drugs
with potentially serious side effects).
The NIH claims that a fair and rigorous funding mechanism is always adhered to, and that all researchers
have a level playing field when applying for funding, however, ME/CFS researchers have repeatedly and
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historically repeated the same claims about the disproportionate difficulties of attracting funding for
biomedical investigations into ME/CFS. Perhaps this raises the question of whether there is an
unidentified and unintentional institutional bias at the NIH, and other funding bodies, that may arise
from factors such as: individual reviewer bias and ignorance about the illness; a lack of procedural
oversight to ensure a fair playing field in funding opportunities for little-understood and low-profile or
controversial illnesses; budget constraints that may result in an informal targeting of misunderstood,
unrecognised or non-prioritised diseases.
The NIH must take responsibility for this historic problem and reverse the institutional issues that have
historically caused funding problems. If it is widely known that research funds are available then the
researchers will flock to the field. The Solve ME/CFS Initiative has has great success over the past few
years in attracting new researchers to the field, who are currently experts in other firms, by making seed
funding available and by providing access to a patient registry and biobank. However, the Solve ME/CFS
Initiative is only able to provide small amounts of seed funding.
The funding issue is the most pressing issue within the field and must be transformed so that
researchers can be confident that long-term investment in the field is guaranteed and that a move into
ME/CFS research is a huge and exciting career opportunity and accelerators rather than a career end.
Gaps and opportunities across the research continuum from basic through clinical studies.
Recommendations for action:
1. Massively increased biomedical research funding, proportionate to funding for other diseases, such as
cancer, MS, and Parkinson's.
2. Immediately fund (i.e. fast-track) research grant applications from existing experts who have had
research applications declined, such as Prof Ron Davis, Prof Ian Lipkin, Dr Nancy Klimas, etc.
3. Promote, enable and instigate a massive and comprehensive hunt for biomarkers and pharmaceutical
treatments.
4. Promote, enable and instigate a massive and comprehensive biomedical research program including
(but not restricted to) research in the following areas:
i. The immune system and immune cell abnormalities/dysfunction;
ii. Cellular abnormalities/dysfunction (e.g. via metabolomics & proteomics etc);
iii. Cellular function e.g. genomics and epigenetics and miRNA;
iv. Endogenous retroviruses;
v. The potential role of common pathogens;
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vi. The vagus nerve infection hypothesis.
vii. Clinical trials of rituximab and other promising pharmaceuticals, and interventions with potential to
treat the illness, such as immune modulators and cytokine inhibitors. A very large repurposing study of
immune related drugs would have enormous potential and could be run in coordination with
pharmaceutical industry.
viii. A thorough investigation of a possible autoimmune connection. i.e. a comprehensive search for
autoantibodies and auto-immune-type disease processes. Carry out a thorough full scale investigation of
autoimmune possibilities or autoimmune-like activity (that isn’t necessarily caused by autoantibodies,
but could be caused by e.g. cell receptors that are abnormal by frequency, function, type or structure).
5. Determine subgroups for whom experimental treatments (e.g. Rituximab, Ampligen and anti-virals
are effective).
6. Investigate and quantify the biological post-exertional effects in ME/CFS. The specific post-exertional
effects seen in ME/CFS are a unique biological feature of the illness, and may be a prime place to start to
observe the biomedical mechanisms of the illness. For example, the following studies (please see below)
carried out certain biomedical tests before and after exercise, and demonstrated clear and intriguing
cytokine and epigenetic abnormalities after exertion compared to controls. This research objectively
demonstrates post-exertional abnormalities (the central feature of ME/CFS) and needs to be replicated
on a large scale in order to better understand the disease mechanism. This type of research
demonstrates the disease process in action and it is vital to gaining insights into the biomedical
mechanisms of the illness.
Studies:
White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, Light KC. (2010) Severity of symptom
flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome.
Psychophysiology. 47:615-24. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-
8986.2010.00978.x/abstract
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC. (2012) Gene expression
alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and
Fibromyalgia Syndrome. J Intern Med. 271:64-81. http://www.ncbi.nlm.nih.gov/pubmed/21615807
Other unmet needs.
Set up a network of in-patient clinical centres to care for severely ill patients at their time of greatest
need, to be run by clinical experts who understand that ME has a biomedical basis. Currently, the needs
of all patients are utterly neglected, but especially severely affected patients, who have access to
practically no medical care our medical input. Typically, unsupported families are left to learn about the
illness and to support their lived ones living at home in darkened rooms, or severely affected patients
are driven to suicide because they cannot meet their basic care needs or their symptoms are
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unmanageable or too severe to cope with. This group of patients can be considered an enormous
research asset, who can help to inform researchers and clinicians about the illness in its most severe and
most unrecognised form. The data collection potential from these patients is enormous, and the insights
gained from these patients would help to alleviate the widespread stigma associated with the illness and
to reverse the universal neglect experienced by most, if not all ME/CFS patients. A series of in-patient
centres of excellence would be an enormous and very welcome asset to the patient community, and
would definitely save lives. I know of numerous lives that would undoubtedly have been saved if
adequate and trustworthy in-patient care (i.e. on a biomedical basis) had been available to patients at
their time of greatest need.
A network of clinical centres of excellence to provide services to all patients would also provide
essential, currently unmet, needs of the patient population. Centres of excellence would be an
enormous clinical and research asset.

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[…]
Subject: Response to Notice NOT-NS-16-024; Request for Information: Soliciting Input for New Research
Strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

To: The Trans-National Institutes of Health (NIH) ME/CFS Working Group
Re: Response to Notice NOT-NS-16-024; Request for Information: Soliciting Input for New Research
Strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Dear Working Group:
The following is my response to NOT-NS-16-024; Request for Information: Soliciting Input for New
Research Strategies for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Emerging needs and opportunities that should be considered as new ME/CFS research strategies are
developed:
Analyze samples of blood and spinal fluid taken during post-exertional malaise.
Analyze samples from the severely ill and from children for possible biomarkers.
Challenges or barriers to progress in research on ME/CFS:
The lack of a consensus case definition for ME/CFS poses a major stumbling block to progress in
research.
Substantially greater funding is needed to address the complex problem of ME/CFS.
Gaps and opportunities across the research continuum from basic through clinical studies:
A carefully conceived, long-term research plan is needed.
Thank you for your consideration and your service.
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[…]
Subject: Potential Research Pathways for Research Into ME/CFS

1) Muscle Failure, not Fatigue.
ME is a long illness, with a long acute phase and apparently whatever the pathogen is, is stimulated by
exertion of any type, but especially muscular exertion.
The IOM states that this is a disease in which exertion of any type may adversely affect many organ
systems, and the deleterious effects of exertion have been reported in the large survey of patients done
by the UK ME Association, and in the Invest in Me book 'Lost Voices From A Hidden Illness', an account
of patients who have severe ME, many of whom were very athletically active before the illness, and who
became severely ill only after following a program of exercise.
http://www.ncbi.nlm.nih.gov/books/NBK284910/. Chapter 7, Page 14
http://www.meassociation.org.uk/2010/05/managing-my-me-me-association-publish-results-of-huge-
survey-report/
'Lost Voices from a Hidden Illness, by Natalie Boulton, published by Invest in ME
The reason for this seems to lie in the fact that the body's aerobic muscle metabolism does not function
properly. Even minimal exertion becomes anaerobic, with the consequences one would expect for a
person engaging in ongoing anaerobic exertion - a build-up of metabolites, pain, eventual muscle failure,
and damage. Severe ME is characterised by ongoing severe and intractable pain, non-epileptic
involuntary contractions and spasms, and intermittent paralyses.
Myalgic Encephalomyelitis and Postviral Fatigue States, A Melvin Ramsay, MA, MD, published by the ME
Association

Researchers during the polio era noted that during the period after the initial viral attack, when the virus
was in the process of attacking the central nervous system, physical exertion was dangerous, as
exercised muscles tended to be the ones which ultimately became permanently paralysed. They
regarded complete rest as an essential protective measure during this stage of the disease.
http://www.positivehealth.com/article/cfs-me/lost-in-translation-the-me-polio-connection-and-the-
dangers-of-exercise
Dr. Melvin Ramsay, (see above) the infectious disease consultant who dealt with the 1955 Royal Free
Hospital outbreak noted that complete rest from the inception gave the best prognosis, and the
impression gained from his writings was that a proportion of patients went on to become chronically ill,
but not all. This implies that many made a complete recovery, which would be considered very rare
these days, when the importance of rest is overlooked.

If, as seems likely, the pathogen(s) involved in ME remain in the system and are stimulated by exertion,
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this would serve to reinforce the importance of rest as an immediate and urgent treatment
recommendation (ME diagnosed by interview, exclusion, and recognition of the complex but easily
identifiable constellation of symptoms of muscle metabolism failure, cognitive difficulties, failure in
endocrine regulation, and signs of an activated immune system. A differential diagnosis from
depression is relatively simple: a depressed person suffers from sadness and apathy...not fatigue...and
will find their mood improved by exercise. The ME sufferer is highly motivated, willing to attempt
anything, encounters almost immediate muscle failure (not fatigue), and is likely then to become
frustrated and upset. The differences in motivational state and the sequence of change of emotional
state are very distinct. The misuse of the term 'fatigue', which is incorrect in both conditions, is the only
thing that confabulates them. Several questionnaires used to diagnose depression do conflate
depression with ME in this way.

The IOM (see above). sets a 6 month duration of symptoms as a diagnostic necessity, but also affirms
that ME can be diagnosed by careful interview and routine tests, and that symptoms should be treated
without waiting for the 6 months to pass. Clearly, if a treatment, such as complete rest, is urgent at the
start, as Ramsay insisted, then waiting for six months may lose any opportunity the patient may have to
make a complete recovery, so investigation into the potential of offering an extended period of
complete rest from the inception should clearly be one line of research.
ME is expensive to health services, government disability services and medical insurers. Up to now,
agencies concerned have used the labelling of ME/CFS as a psychiatric condition, and insistence on
cooperation with 'the best treatments' e.g. CBT and GET as a way of attempting to deal with this. The
result is that patients either do not fully engage with GET, or they engage with it in good faith and
become too ill even to get to the places where the treatment is offered. In either case, financial help
can then be denied on grounds of failure to cooperate. And no one gets better. If, instead, genuine
improvement or even recovery can be brought about by offering nothing more complicated or
expensive than several weeks of rest from the inception, this would benefit patients, make return to
work a possibility, and be both much less expensive and much more effective than the present system of
services which is in place.
http://www.nhsmanagers.net/guest-editorials/a-radical-care-pathway-for-mecfs/

It should be recognised that with an illness which at best has a very protracted acute stage, and at
worst, becomes a permanent feature in the system (like the latent herpes viruses), then rehabilitative
treatments, as differentiated from treatments aimed at attacking the cause of the disease, or enabling
the immune system to launch an effective attack, are inappropriate. There is so much evidence that
programmes based on increasing physical activity actually prolong and intensify the disease that it is
surprising that this approach is still regarded as acceptable. If the evidence available in relation to
exercise and ME/CFS were in relation to a drug treatment, that drug would have been withdrawn years
ago. The PACE Trial, which is the source of support for CBT and GET, and has been internationally
influential, has been widely discredited. During the trial, the original criterion for recovery (85 on the
Chalder Fatigue Scale) was lowered to 60 on that scale. The criterion for being sick enough to enter the
trial was a score of 65, so that a patient could become slightly worse during treatment and still be
recorded as 'recovered'. It is not ethical to change an important criterion during a research study. It is
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not easy to understand how, in view of these facts, this study have been given so much credence and
had so much influence on policy.
http://www.stats.org/pace-research-sparked-patient-rebellion-challenged-medicine/

Leslie O Simpson, Ph.D., a researcher in hemorheology with a particular interest in chronic diseases,
sheds light on a potential mechanisms for this. In many chronic illnesses, immediately-fixed sample of
blood show distinct shape changes in the erythrocyte population, with a variety of non-discocyte forms
which are unable to traverse the microcirculation. As the function of the red blood cells is to deliver
oxygen and remove metabolites. This appears to provide a relatively simple explanation for the failure
of the aerobic muscle metabolism, cognitive difficulties, and endocrine problems---all of these areas are
particularly vulnerable to lack of oxygen and the build up of metabolites.
Ramsay's Disease - Myalgic Encephalomyelitis (ME) and The Unfortunate Creation of Chronic Fatigue
Syndrome (CFS), by Leslie O Simpson, Ph.D. and Nancy Blake BA, CQSW.

The research implications of the above are that

1) A trial of complete rest upon diagnosis (made immediately, not after six months) should be done. A
diagnostic protocol on the lines suggested above could be developed, patients interviewed, and those
which met the criteria should be dividing into one group put on a regime of virtually complete rest for
several weeks, and one given 'usual medical care', and the long-term outcomes studied.

2) A retrospective study of the effects of exercise programmes needs to be conduThere is much
evidence of harm, but this needs to be formalised and the results made operational in future political
and management policies.

3) Les Simpson's research needs to be revisited, carefully reproducing his protocols. The implications
for treatment should be included in future recommendations and guidelines. Hemorrheology is not
included in medical education and the medical canon, which means that treatments to improve blood
flow, which would be beneficial in many chronic illnesses, particularly diabetes as well as ME/CFS, are
not offered by doctors.

4) The narrative of many ME people includes a serious commitment to exercise. The role of exercise
as both a precipitating and a perpetuating factor needs to be studied. The evident lack of a narrative
that could explain a psychiatric condition has lead to the assertion, by psychiatrists, that a somatoform
or functional disorder (psychiatric problem) can occur without a relevant narrative. The impllications of
the much more common narrative involving commitment to exercise has not been explored because it is
a cultural imperative to think of exercise as universally beneficial. The IOM, along with the early doctors
(Ramsay, Acheson) are unequivocal in stating that exertion in this disease, can have systemic adverse
effects, and the research into exercise and polio suggests one possible explanation.

5) Not related to anything above, Dr. Gary Kaplan has explored the role of sequential challenges to the
microglia in producing permanent upregulation, inflammation and chronic pain, and this seems an
avenue to explore in relation to the pain of severe ME, as well as the apparent range of events which
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