NIH Responses Put Major ME/CFS Study On Right Track

Cort

Founder of Health Rising and Phoenix Rising
Staff member
This is great news. A powerful study just got more powerful with the lead investigator, Dr. Nath, clarifying the definition criteria and emphasizing his commitment to exhaustively explore the key symptom of ME/CFS - post exertional malaise. It turns out that an incomplete version of the study was accidentally posted. We'll get more complete answers soon and Dr. Nath will be speaking on the study next week.

From Bob and Courtney Miller

Robert and I had a well-timed chance to discuss with NINDS some questions about the protocol that was posted this weekend for the NIH Clinical Center study. There will be additional information posted on a website for patients and the community which may take a week to be live, they said.

[fright]
Nath-Avindra.jpg
[/fright]We asked questions about the criteria for enrollment, reference to Reeves criteria in the protocol, role of ME/CFS experts and the choice of control groups. According to the principal investigator of the study:
  • Enrollees will meet all definitions for ME/CFS, including Canadian Consensus Criteria, IOM, Fukuda and Reeves, in addition to post-infectious onset.
  • Post-exertional malaise (PEM) is a criteria, and will be specifically studied with extensive testing before and after exercise challenge.
  • The SF-36 criteria to measure functional impairment stated in the protocol online is inverted mistakenly. “Greater than” is meant to be “less than” in the SF-36 measures.
  • Dr. Ian Lipkin of Columbia University’s Center for Infection and Immunity has been advising the investigators on the study design and protocol.
  • Expert clinicians will be used in patient selection.
  • Control groups: Asymptomatic Lyme was chosen to contrast post-infectious ME/CFS patients to patients who recovered from an infection. Functional Movement Disorder was chosen to contrast post-infectious ME/CFS patients with a very well-studied group of patients with clear psychological illness with neurological presentation.
  • They seek to have 40 PI-ME/CFS patients, and they will study them longitudinally, hoping to learn how and whether the disease changes over time.
  • Testing will be extensive.
We are very excited to know that the NIH intramural study is moving forward, and that it will deeply study patients with infectious onset against a battery of biological tests. We are reassured by these answers, and eager to have this kind of data to move our disease toward discovery.
 
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Simone

Member
It really is such a shame that the study details were posted in the way that they were. Surely the NIH must be aware of how closely the ME/CFS community would be watching this study, as a measure of how well its actions were going to match their words? Thank goodness Courtney and Robert Miller were able to clarify these details, though it would've been better if NIH had proactively managed this PR oops itself.

This study suggests that there is much to hope for.
 

Catnap

Member
I hope that neurocognitive symptoms/brain damage will be properly studied as well. I believe they must be. PEM is critically important but is by no means everything.

It was reported that, "...Dr. Ian Lipkin... has been advising the [NIH] investigators on the study design and protocol." Let us not forget that we do not know the extent to which NIH is actually implementing Dr. Lipkin's advice. These are very different things.

I agree with Simone that the way in which details of the NIH study became public was handled poorly and accomplished the opposite of building trust. If only the NIH would be more respectful of the ME/CFS community going forward; time will tell and they have a long history to overcome.
 

gowwab

Member
I hope that neurocognitive symptoms/brain damage will be properly studied as well. I believe they must be. PEM is critically important but is by no means everything.
I completely agree that this needs to be emphasized in a big way to counteract all the misunderstanding the name CFS has caused. And more importantly to get it right. It's a challenge because no 2 of us are alike and sometimes we are very different in our symptons
For me it was always the biggest problem even though I said I was tired from the start it was a whole new kind of tired, weird and inexplicable. Only in retrosect after learning about PEM did I look back on the previous 16 years and see that I had PEM but mostly for the brain and nervous system.

It worried me when I saw an interview Collins did with Charlie Rose where he kept speaking about how studying CFS would help the understanding of other fatiguing illnesses. The way he spoke about it it was clear he had a simplistic and maybe wrong understanding of the illness.
 

Courtney Miller

New Member
I hope that neurocognitive symptoms/brain damage will be properly studied as well. I believe they must be. PEM is critically important but is by no means everything.

It was reported that, "...Dr. Ian Lipkin... has been advising the [NIH] investigators on the study design and protocol." Let us not forget that we do not know the extent to which NIH is actually implementing Dr. Lipkin's advice. These are very different things.
Hi, this is Courtney Miller. What we learned from the Principal Investigator for the NIH study is that functional MRI (fMRI) will be used before and after exercise challenge, among other tests to study neurocognitive impairment. Additionally, 1,000 proteins and 1,000 cytokines, as well as phenotypes. We don't know everything, but there will be more testing in this study than ever done before in post-infectious ME/CFS. As to your other question, the Principal Investigator (who is an infectious neurologist) and Dr. Ian Lipkin have worked together on many studies across different diseases and infections, so from that fact and my own knowledge of Dr. Lipkin, I sincerely believe there is real advising going on. This is a serious study.
 

IrisRV

Well-Known Member
I agree with Simone that the way in which details of the NIH study became public was handled poorly and accomplished the opposite of building trust. If only the NIH would be more respectful of the ME/CFS community going forward; time will tell and they have a long history to overcome.
I also agree with this. At the same time, I want to encourage new movement in the right direction and constantly bringing up bad things that happened in the past to tar anything new is probably not in our best interest. The individuals involved now need to feel encouraged and positive, not like they're forever being punished for somebody else's past misdeeds.

We need to get straight with all these organizations about their pasts. I'm sure they'd prefer to sweep it all under the rug if they can. I don't think we should allow that to happen. However, I think we need to separate their past from the present in our dealings with them. Collins is not responsible for what Reeves did twenty or thirty years ago. There are two different advocacy strands here.

We also need to give them some time to adjust and grow. A lot of change needs to happen and it's not going to happen overnight. They are children with regards to understanding both the science and the current political/social situation of ME. We need to let them make some small mistakes they can learn from and not slam them every time they haven't got everything exactly right.

They will sometimes trip themselves with their own shoelaces. When that happens, we should pick them up, dust them off and send them on their way rather than spank them for not tying their shoes. At the same time, we cannot let them run into traffic. Give them room to learn from their mistakes, but don't let them kill themselves (or us).

They are trying. That is a big step in the right direction. They have a lot to learn, so we should keep a very close eye on them and point out problems as they occur without screaming at them and slapping them down.

As for this study, we had every reason to say, "Um, what the heck is going on here?" and expect a good answer and self-correction. We got that. We don't need to keep haranging them about it. (Not that I'm saying anyone here is doing that, but I've seen some serious haranging from other patients). Trust them by the littles and keep a very careful eye on them. Correct gently at first and only bring out the bigger responses when the gentle correction is not working.

Wessely, White, Chalder, and the whole PACE gang, on the other hand, are in no way trying to improve. If anything, they are putting their best efforts into shoving us even further under the bus. For their own profit, no less. They have shown they have no intention of learning and growing. They are doing nothing that deserves encouragement. They just need to be stopped. Gentle correction has fallen on deaf ears, been scorned even. It's time to get serious about saying loudly and firmly, "No, this is completely unacceptable. No video games for you for the rest of week. And clean your room!" :D
 
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IrisRV

Well-Known Member
It worried me when I saw an interview Collins did with Charlie Rose where he kept speaking about how studying CFS would help the understanding of other fatiguing illnesses. The way he spoke about it it was clear he had a simplistic and maybe wrong understanding of the illness.
I saw it differently. I saw a very politically savvy researcher pointing out that any research funded for CFS wouldn't just apply to that limited group of "those people." It will help people with a whole bunch of other illnesses. Isn't that useful and economical? Efficient use of limited research funds and all that. Even if you aren't on board with helping people with CFS, surely you can support research that will help MS patients, and post-treatment cancer patients, and lots and lots of other people you do care about. Isn't that worth spending a little piece of the MS/cancer/whatever budget on? It will be a big help to those patients, after all.

Pretty slick, I thought.

But we're both guessing. Either one of us could be right. Time will tell.
 

gowwab

Member
I agree with you IrisRV that it is savvy to point out how studying our disease will further our understanding of other diseases, I think this is so true of our disease precisely because it affects just about every bodily system there is. That's why his emphasis on profound fatigue left me a little worried that that is what they will emphasize to the public and researchers.

I'd rather see a message that yes, profound fatigue can be an issue but there is so much more going on in this disease that the name has done a disservice to the patients and doctors trying to help them.

He said we can't get out of bed , but many can and do seem normal going to work or school and silently struggling. So while I agree with you that he seems to care and wants to help, getting an accurate picture out to the public and doctors is really important.

I do think and hope he is genuine, but needs our help as a community to point out when he gets it wrong, it's confusing to even our experts. I think as a scientist he would want the information.

You're right though, we are both just guessing and you are a glass half full person and after 30 years of this I might have turned into a curmudgeon on this subject:)
 

weyland

Well-Known Member
This is a serious study.
I look forward to the NIH publicly posting the actual protocol. Unfortunately, they still have not addressed the other major concerns with the study. British and American research has shown that large percentages of ME patients have active, persistent enterovirus infections. This study design purposefully excludes patients with active infection. This means that a large percentage of very prototypical ME patients will be excluded from the study.

They have not provided justification for using a functional (psychogenic) neurological disorder as a control arm. If they fail to find statistically significant biological abnormalities, they risk improperly conflating this organic disease with a psychogenic disorder. This comparison arm is reckless and unnecessary in an exploratory study.

They have also not provided justification for using a post-lyme (not PTLDS) group as a control arm. There is no evidence in the medical literature that Borrelia spp. is associated with onset of ME or CFS. If they want to compare the difference between someone who recovers from infection and someone who develops ME or CFS from infection, it would make more sense to use the actual pathogens that have been associated with onset of the disease, such as enteroviruses or Epstein Barr virus. Diagnosis of these infections is far less controversial and error prone and incidence of these infections is more widespread which will make control recruitment easier and less error prone.
 

serotone9

Member
That's a great update, and very gratifying to see how responsive the NIH and researchers are to inquiries. This looks to be one of the best studies ever done on ME/CFS. Eagerly anticipating the results.
 

ScottTriGuy

Active Member
That's a great update, and very gratifying to see how responsive the NIH and researchers are to inquiries. This looks to be one of the best studies ever done on ME/CFS. Eagerly anticipating the results.
It is unfortunate that the NIH has repeatedly failed to consult or communicate with the ME patient population.

It was only by chance that the authors had the meeting and could raise concerns. It does not mean the NIH will listen.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
It is unfortunate that the NIH has repeatedly failed to consult or communicate with the ME patient population.

It was only by chance that the authors had the meeting and could raise concerns. It does not mean the NIH will listen.
Scott I agree with you that the NIH is doing this on their own (so far). That's unfortunate - but doesn't it seem that the NIH did listen - or at least is communicating?

I think this study willl be a good one..
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I look forward to the NIH publicly posting the actual protocol. Unfortunately, they still have not addressed the other major concerns with the study. British and American research has shown that large percentages of ME patients have active, persistent enterovirus infections. This study design purposefully excludes patients with active infection. This means that a large percentage of very prototypical ME patients will be excluded from the study.

They have not provided justification for using a functional (psychogenic) neurological disorder as a control arm. If they fail to find statistically significant biological abnormalities, they risk improperly conflating this organic disease with a psychogenic disorder. This comparison arm is reckless and unnecessary in an exploratory study.

They have also not provided justification for using a post-lyme (not PTLDS) group as a control arm. There is no evidence in the medical literature that Borrelia spp. is associated with onset of ME or CFS. If they want to compare the difference between someone who recovers from infection and someone who develops ME or CFS from infection, it would make more sense to use the actual pathogens that have been associated with onset of the disease, such as enteroviruses or Epstein Barr virus. Diagnosis of these infections is far less controversial and error prone and incidence of these infections is more widespread which will make control recruitment easier and less error prone.
Actually I don't think studies, except for Chia's stomach biopsies, have really indicated active enterovirus infections are present. Lipkin's study didn't find any active infections. I think active infections may be there - but it's hard to find them in the blood - so to the NIH they will look like infections are not present.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
I completely agree that this needs to be emphasized in a big way to counteract all the misunderstanding the name CFS has caused. And more importantly to get it right. It's a challenge because no 2 of us are alike and sometimes we are very different in our symptons
For me it was always the biggest problem even though I said I was tired from the start it was a whole new kind of tired, weird and inexplicable. Only in retrosect after learning about PEM did I look back on the previous 16 years and see that I had PEM but mostly for the brain and nervous system.

It worried me when I saw an interview Collins did with Charlie Rose where he kept speaking about how studying CFS would help the understanding of other fatiguing illnesses. The way he spoke about it it was clear he had a simplistic and maybe wrong understanding of the illness.
Actually he got that from Ron Davis who is using that idea to prompt the NIH to devote more research into ME/CFS; i.e. it could help understand other fatiguing illnesses. Who knows? Maybe it could, maybe it couldn't but it's a way to get more funding.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
It really is such a shame that the study details were posted in the way that they were. Surely the NIH must be aware of how closely the ME/CFS community would be watching this study, as a measure of how well its actions were going to match their words? Thank goodness Courtney and Robert Miller were able to clarify these details, though it would've been better if NIH had proactively managed this PR oops itself.

This study suggests that there is much to hope for.
Guess what. The NIH has NEVER encountered a disease community like ME/CFS before. Apparently they often post incomplete drafts of study protocols on their site. They've never had a disease community discover them before! :woot:

They were astounded that we did.

They learned something about us. For one this community is engaged like no other communities. That's really something.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
As I noted in an above comment the NIH had never had a disease community pick up on a draft of a study that was listed on their site before. They didn't realize anyone was looking. Usually no one is. ;)
I hope that neurocognitive symptoms/brain damage will be properly studied as well. I believe they must be. PEM is critically important but is by no means everything.

It was reported that, "...Dr. Ian Lipkin... has been advising the [NIH] investigators on the study design and protocol." Let us not forget that we do not know the extent to which NIH is actually implementing Dr. Lipkin's advice. These are very different things.

I agree with Simone that the way in which details of the NIH study became public was handled poorly and accomplished the opposite of building trust. If only the NIH would be more respectful of the ME/CFS community going forward; time will tell and they have a long history to overcome.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
SO
I also agree with this. At the same time, I want to encourage new movement in the right direction and constantly bringing up bad things that happened in the past to tar anything new is probably not in our best interest. The individuals involved now need to feel encouraged and positive, not like they're forever being punished for somebody else's past misdeeds.

We need to get straight with all these organizations about their pasts. I'm sure they'd prefer to sweep it all under the rug if they can. I don't think we should allow that to happen. However, I think we need to separate their past from the present in our dealings with them. Collins is not responsible for what Reeves did twenty or thirty years ago. There are two different advocacy strands here.

We also need to give them some time to adjust and grow. A lot of change needs to happen and it's not going to happen overnight. They are children with regards to understanding both the science and the current political/social situation of ME. We need to let them make some small mistakes they can learn from and not slam them every time they haven't got everything exactly right.

They will sometimes trip themselves with their own shoelaces. When that happens, we should pick them up, dust them off and send them on their way rather than spank them for not tying their shoes. At the same time, we cannot let them run into traffic. Give them room to learn from their mistakes, but don't let them kill themselves (or us).

They are trying. That is a big step in the right direction. They have a lot to learn, so we should keep a very close eye on them and point out problems as they occur without screaming at them and slapping them down.

As for this study, we had every reason to say, "Um, what the heck is going on here?" and expect a good answer and self-correction. We got that. We don't need to keep haranging them about it. (Not that I'm saying anyone here is doing that, but I've seen some serious haranging from other patients). Trust them by the littles and keep a very careful eye on them. Correct gently at first and only bring out the bigger responses when the gentle correction is not working.

Wessely, White, Chalder, and the whole PACE gang, on the other hand, are in no way trying to improve. If anything, they are putting their best efforts into shoving us even further under the bus. For their own profit, no less. They have shown they have no intention of learning and growing. They are doing nothing that deserves encouragement. They just need to be stopped. Gentle correction has fallen on deaf ears, been scorned even. It's time to get serious about saying loudly and firmly, "No, this is completely unacceptable. No video games for you for the rest of week. And clean your room!" :D
So well said IrisRV - I agree! :)
 

weyland

Well-Known Member
Actually I don't think studies, except for Chia's stomach biopsies, have really indicated active enterovirus infections are present.
Then you are not familiar with the literature.

Galbraith DN, Nairn C, Clements GB. Evidence for enteroviral persistence in humans.
Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence.
Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach.
Chia JK, Chia AY. Ribavirin and Interferon-a for the Treatment of Patients with Chronic Fatigue Syndrome Associated with Persistent Coxsackievirus B Infection: A Preliminary Observation.
Douche-Aourik F, Berlier W, Féasson L, Bourlet T, Harrath R, Omar S, Grattard F, Denis C, Pozzetto B. Detection of enterovirus in human skeletal muscle from patients with chronic inflammatory muscle disease or fibromyalgia and healthy subjects.
Galbraith DN, Nairn C, Clements GB. Phylogenetic analysis of short enteroviral sequences from patients with chronic fatigue syndrome.
Cunningham L, Bowles NE, Lane RJ, Dubowitz V, Archard LC. Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA.
Gow JW, Behan WM, Clements GB, Woodall C, Riding M, Behan PO. Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome.
Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase.
E. G. Dowsett, A. M. Ramsay, R. A. McCartney, E. J. Bell Myalgic encephalomyelitis--a persistent enteroviral infection?
McGarry F, Gow J, Behan PO. Enterovirus in the chronic fatigue syndrome.
J. Richardson Viral Isolation from Brain in Myalgic Encephalomyelitis
Fegan KG, Behan PO, Bell EJ. Myalgic encephalomyelitis--report of an epidemic.

Lipkin's study didn't find any active infections.
Please link me to the published, peer reviewed study where Ian Lipkin demonstrates his methods and results on virological testing on whole blood, PBMCs, and/or tissue samples from ME patients.

You can't. Because it doesn't exist. As far as I understand, Ian Lipkin tested some leftover plasma from some cohort and found nothing. This is not comprehensive. It's not peer reviewed. It's meaningless.
 

serotone9

Member
It is unfortunate that the NIH has repeatedly failed to consult or communicate with the ME patient population.

It was only by chance that the authors had the meeting and could raise concerns. It does not mean the NIH will listen.
You're undoubtedly right that they could do a lot better, and perhaps they have not listened well up to now. I was just glad to see that in this case, regarding this study, they seemed to respond to some of the major concerns I've seen by clarifying the points above about diagnostic criteria, PEM, etc. Hopefully the outcome of this study can really shine a spotlight both on the reality and the severity of ME/CFS, and help to bring our voices forward in all arenas.
 

Catnap

Member
This is a serious study.
Thank you for the additional information, Courtney, much appreciated. "Serious" is a nice but vague attribute and is nowhere near the core issue (in my judgement). What matters is that NIH doesn't just "try", as another participant wrote. Lives are at stake and while "trying" is important, it isn't anywhere near enough. NIH has grave responsibilities to millions of M.E. patients, their caregivers, friends, families, and employers/former employers. NIH must deliver the best work possible, not just try to do it; this means communicating with and leveraging the knowledge, experience, expertise, and insights of M.E. physicians, experienced M.E. researchers and M.E. patients.

I have not yet seen evidence of an earnest, comprehensive and inclusive effort of this kind (for example, have they sought guidance from Ron Davis? Have they sought input from more than a patient or two and not just after the fact?). Given the history between government and patients, and given what we have read of NIH's proposed study thus far (excluding your description - I'm talking about direct communication from NIH), I, for one, am expecting and, frankly, demanding, a higher quality process in which NIH designs, delivers, and analyzes the study and resulting data with input from the best-informed and most expert/experienced medical and scientific minds available, includes input from all types stakeholders (including more than a couple of patients!), and so on. I am doing my best to explain but am exhausted. Struggling with "M.E. brain" is brutal.

Moving on... Do you happen to know more about any of the following?

Does NIH intend to consult with Dr. Ron Davis in any serious way and if not, why not? I am deeply troubled by the fact that he has not been invited to participate. His genius, depth of knowledge and commitment are incalculably valuable resources that should absolutely not be sidelined or wasted. In my opinion, not involving him is an affront to M.E. patients and everyone who has a stake in the outcome of NIH's study. Wasting the breadth and depth of his knowledge would be unforgivable because we truly need the very best and very brightest to work on this problem.

Will Staci Stevens, Dr. Christopher Snell, and/or any of the other experts at The Workwell Foundation be consulted for their expertise in conducting the CPET?

Will the ME/CFS neuropsychologist expert Sheila Bastien, Ph.D. of Berkeley, California be invited to consult on efforts to conduct neuropsychological/neurocognitive testing?

For how long after the CPET will patients be monitored?

Exclusion criteria for all participants includes, "Current immunologic disorder (e.g. Type 1 diabetes, rheumatoid arthritis)", yet the IOM ME/CFS Clinicians Guide lists “Immune impairment” as an "additional symptom" on page 9 of the guide/page 13 of the PDF : https://iom.nationalacademies.org/~/media/Files/Report Files/2015/MECFS/MECFScliniciansguide.pdf. This seems inconsistent and a significant contradiction. Don't many/most/all M.E. patients have some form of an immunologic disorder - at the very least, autoimmune thyroid disease? What is the scientific justification and/or reasoning to exclude M.E. patients who have a “current immunologic disorder”?

Additional exclusion criteria for participants with CFS: "Underlying illness that may cause fatigue such as thyroid dysfunction..." - see observations and questions listed just above.

Why would NIH publicly mention Reeves - to what benefit? Did they not know how Reeves is thought of by expert physicians, M.E. researchers and M.E. patients - and if not, why did NIH not know this?

"Enrollees will meet all definitions for ME/CFS, including Canadian Consensus Criteria, IOM, Fukuda and Reeves, in addition to post-infectious onset." In all honesty, their list reads like the contents of the kitchen sink. Wouldn’t the study benefit from selecting more focused criteria, say the CCC and/or ICCC? What is being said by listing all of these different criteria? (struggling to make sense of this)

I was shocked by the omissions in the so-called “Diagnostic Algorithm” on page 14 of the IOM’s “Beyond ME/CFS, Redefining an Illness: Report Guide for Clinicians”. I and countless others can say with absolute certainty that neither insurance companies (that sell long term disability policies) nor Social Security would ever approve a disability claim based on the diagnostic algorithm published in the IOM report. How on earth could something so vague be published and be expected to help patients? Unfortunately not even one diagnostic blood test was recommended - such as those administered at Stanford’s CFS Clinic or the Open Medicine Clinic in Mountain View. How does NIH expect M.E. patients and their caregivers to respect use of the IOM report when it lacked any real specificity on critical topics such as this?

Has the NIH offered a meaningful explanation as to why their initial study does not focus on – or even include (!) – severely ill M.E. patients – instead of being limited to no more than moderately ill M.E. patients?

How many of each type of participant (PI-ME patient; healthy volunteer; Documented Lyme Infection Asymptomatic; functional movement disorders) will be included in the study?

Why does the study exclude PI-M.E. patients for whom fatigue onset occurred more than 5 years prior to study enrollment??
 
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