NIH Request For Information: Soliciting Input on How Best to Advance ME/CFS research

2) Case definitions of ME/CFS should require the presence of post-exertional malaise
Post-exertional malaise (PEM) or a marked symptom exacerbation after minimal exertion is considered to be the hallmark symptom of ME/CFS and should therefore be a mandatory requirement in diagnostic criteria for this illness.

For several decades, PEM has been described as the characteristic symptom of ME/CFS. In 1985, Behan et al. emphasized that all of the 50 postviral fatigue syndrome patients in their study had “the same primary symptom that of gross fatigue made worse by exercise.” [1] Thirty years later, an influential report by the National Academy of Medicine described ME/CFS as a systemic exertion intolerance disease, noting there to be “sufficient evidence that PEM is a primary feature that helps distinguish ME/CFS from other conditions.” [2] PEM helps to differentiate ME/CFS from related conditions such as depression [3], multiple sclerosis [4] or chronic idiopathic fatigue [5] and is predictive of a poor prognosis [6].

Some of the characteristics of PEM may be unique to the ME/CFS patient population. An in-depth investigation of PEM by researchers at Stanford University concluded:

“There exists no medical condition the authors are familiar with where exertion or emotional distress causes immune/ inflammatory-related symptoms like sore throat, tender lymph nodes, or flu-like feelings, yet 60% and 36% of our subjects, respectively, reported these symptoms with either stimuli and about a quarter experienced all 3 with exertion.” [7]​

We therefore recommend that diagnostic criteria for ME/CFS require the presence of PEM. The most commonly used case definition, the so-called Fukuda-criteria [8], do not meet these standards and should therefore be amended or retired.

References:

[1] Behan PO, Behan WM, Bell EJ. The postviral fatigue syndrome--an analysis of the findings in 50 cases. J Infect. 1985 May;10(3):211-22.

[2] Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, D.C.: The National Academies Press, 2015.

[3] Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int J Behav Med. 2006;13(3):244-51.

[4] Cotler J, Holtzman C, Dudun C, Jason LA. A Brief Questionnaire to Assess Post-Exertional Malaise. Diagnostics (Basel). 2018 Sep 11;8(3). pii: E66.

[5] Maes M, Twisk FN, Johnson C. Myalgic Encephalomyelitis (ME), Chronic Fatigue Syndrome (CFS), and Chronic Fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012 Dec 30;200(2-3):754-60.

[6] Taylor RR, Jason LA, Curie CJ. Prognosis of chronic fatigue in a community-based sample. Psychosom Med. 2002 Mar-Apr;64(2):319-27

[7] Chu L, Valencia IJ, Garvert DW, Montoya JG. Deconstructing post-exertional malaise in myalgic encephalomyelitis/ chronic fatigue syndrome: A patient-centered, cross- sectional survey. PLoS One. 2018 Jun 1;13(6):e0197811.

[8] Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994 Dec 15;121(12):953-9.

 

3) Robust findings: replication, larger samples, and better controls
In 2015, a review report by the National Academy of Medicine identified more than 9000 scientific publications on ME/CFS. [1] Few of these, however, have produced robust findings. With the exception of psychosocial research, sample sizes rarely exceed 100 ME/CFS patients. Additionally, there is a lack of independent replication. Most findings in ME/CFS have not been replicated by other research teams, which makes the status and implication of such results uncertain. Intriguing findings such as an elevation of lactate levels in the brain [2], beneficial effects of carnitine on ME/CFS symptoms [3] or defunct endogenous pain inhibition after exercise [4] have received few attempts of independent replication with larger sample sizes.

Thirdly, ME/CFS research has mostly used healthy controls. This makes it easier to find significant results but cast doubt on the relevance of the findings. Ill persons differ in multiple ways from healthy persons, so that any biological difference might be due to a generic deterioration in health such as deconditioning, rather than ME/CFS. Differentiating ME/CFS from sedentary but healthy controls is usually not an issue in clinical or research settings, as it merely requires to ask the patient a few questions. There is however a pressing need for findings that are unique or characteristic of ME/CFS and help to differentiate it from related conditions such as fibromyalgia, multiple sclerosis or post-treatment Lyme disease syndrome. Such results would help to refine diagnostic criteria of ME/CFS and make patient samples less heterogeneous. Using controls with related conditions to ME/CFS instead of healthy controls might thus be another way to make research findings more robust.

We therefore recommend a strategy to obtain more robust research findings by focusing on replication, larger sample sizes and the use of better controls.

References

[1] Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, D.C.: The National Academies Press, 2015.

[2] Natelson BH, Vu D, Coplan JD, Mao X, Blate M, Kang G, et al. Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia. Fatigue. 2017;5(1):15-20.

[3] Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome. Neuropsychobiology. 1997;35(1):16-23.

[4] Van Oosterwijck J, Nijs J, Meeus M, Lefever I, Huybrechts L, Lambrecht L, et al. Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. J Intern Med. 2010 Sep;268(3):265-78.

 

4) Clinicians with expertise in ME/CFS
The diagnosis of ME/CFS requires specific expertise. Studies have shown that approximately 40% of patients expected to have ME/CFS in primary care have other conditions after examination in a specialist center. [1-4] Because there is no biomarker for ME/CFS, clinicians need to recognize the symptom pattern and exclude other conditions that might cause these symptoms.

For research to obtain reliable results it is vital that participants have ME/CFS and not a related but overlooked condition. A reliable diagnosis of ME/CFS forms the foundation of each study and an expert clinician is at the heart of each ME/CFS research team. The use of questionnaires is rarely a viable alternative as less than 20% [5,6] of patients who meet ME/CFS symptom criteria, turn out to have ME/CFS after clinical examination.

Unfortunately, very few physicians have expertise in ME/CFS. This makes it difficult for research to enlist large and representative samples of ME/CFS patients. Furthermore, many of the expert clinicians who have spurred ME/CFS research, such as Daniel Peterson and Nancy Klimas, are reaching retirement age. This indicates an urgent need for clinicians trained in the diagnosis, management, and care of ME/CFS.

To further research in the field of ME/CFS we would therefore recommend training expert clinicians, specialized in ME/CFS.

References:

[1] Newton JL, Mabillard H, Scott A, Hoad A, Spickett G. The Newcastle NHS Chronic Fatigue Syndrome Service: not all fatigue is the same. J R Coll Physicians Edinb. 2010 Dec;40(4):304-7.

[2] Darbishire L, Ridsdale L, Seed PT. Distinguishing patients with chronic fatigue from those with chronic fatigue syndrome: a diagnostic study in UK primary care. Br J Gen Pract. 2003 Jun; 53(491): 441–445.

[3] Johnston SC, Staines DR, Marshall-Gradisnik SM. Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients. Clin Epidemiol. 2016 May 17;8:97-107.

[4] Mariman A, Delesie L, Tobback E, Hanoulle I, Sermijn E, Vermeir P, Pevernagie D, Vogelaers D. Undiagnosed and comorbid disorders in patients with presumed chronic fatigue syndrome. J Psychosom Res. 2013Nov;75(5):491-6.

[5] Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003 Jul 14;163(13):1530-6.

[6] Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, et al. A communitybased study of chronic fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.

 

I've focused on the above four proposals because I thought these would be generally accepted by most. But that's also a weakness: much of this is probably known at the NIH or will be addressed by other stakeholders as well.

The NIH also asks about ways to identify "potential approaches to enhance ongoing research collaboration" between researchers and "individuals with ME/CFS". So it would be good if we could add some creative proposals on how the researchers could collaborate with and use the online ME/CFS community. I've quickly (don't focus on the exact wording) written down two ideas:

A closer look at how patients report symptoms
Long-term patients know their symptom well and often better than researchers. This means they are a vital tool in developing and refining questionnaires and symptoms assessments. The development of the PEM questionnaire at DePaul University offers an example of how valuable the involvement of the patient community can be.

In-depth investigation of how patients describe post-exertional malaise, have shown it to be a not one but a complex myriad of symptoms. Some of these such as a delayed onset and prolonged recovery time may be characteristic of ME/CFS and help in differentiating it from related conditions.

Other symptoms such as cognitive impairment, orthostatic intolerance and light, and sound sensitivity have not received the same in-depth investigation. These symptoms have mostly been recorded by singular questions or by questionnaires that were developed for other illnesses. A closer examination might reveal symptoms or descriptions that are distinctive for the ME/CFS patient population. A research team could, for example, collect all statements of how ME/CFS describe their neurocognitive problems, as specific and detailed as possible. They could then make an extensive questionnaire out of the responses and test it in related conditions to see if some statements are distinguishing of ME/CFS.

The use of activity trackers:
As ME/CFS patients experience post-exertional relapses, their activity pattern might offer valuable clues into the nature of this disease. Activity trackers such as fitbits or Apple watches have become reasonably affordable, making it possible to do large studies on the activity pattern of ME/CFS patients. Patients in the online community could be asked to use a device for a certain period of time and send the information to research teams to analyze the data.

 

I'm now going to tag some smart people, in the hope that others take it over from here (apologies to all the smart people I forgot, it's a long list).

@wigglethemouse @strategist @Hutan @Trish @Andy @Graham @Robert 1973 @JohnTheJack @Adrian @Woolie @Snow Leopard @Dolphin @Esther12 @Barry @Sasha @Cheshire @Daisybell @Inara

We have until April 15 to submit a response to the NIH.

 

Yes! I'm on the super list! I'm afraid I'm feeling really dim at the moment though @Michiel Tack and I'm struggling just to follow PACE developments. I think that this is something where it would be really valuable for people to be submitting things - we know that people working against us will be, so it's worth trying to at least balance that out.

To me, your final points look worth including. I don't really know that much about good research tbh - it's only the rubbish stuff that interests me. Thanks for all your work on this, and good luck to everyone planning to submit something.

 

I'm recovering from yesterdays latest medical procedure so don't want to get too involved but a thought I have is:
Make use of patient forums (fora?). While it can be understandable that these places are viewed as 'patient zones' which wouldn't be welcoming to 'outsiders', established, specialist forums will tend to have a larger number of longer term patients who have a depth of knowledge about their condition. S4ME was set up with the aim to encourage interaction between patients and researchers, we have researchers who join in our discussions as well as those who just regularly read the forums to keep themselves up to date - often forums such as S4ME will have discussion threads on all the new ME/CFS research papers as soon as they are published, allowing researchers an overview of other work going on and informed patients reactions to it.

If anything else comes to mind then I'll come back to this thread.

 

Just a reminder that the deadline is April 15. It usually takes a week for S4ME to vote on a proposal. So if we want the forum to make a submission, the time to act and write a proposal is pretty much now.

It would be somewhat disappointing if S4ME would not submit advice. We discuss science and ME/CFS papers, comment on their flaws and ways to improve them, all the time. So now that we are giving the opportunity to provide feedback to the most influential research institute in the world, it would be unfortunate not to use the occasion.

 

There is definitely still value in people writing as individuals. Sorry for not putting time into this. IMO these sorts of things are a really sensible priority for people to try to contribute towards.

 

I would alter this to say have been rejected on irrational grounds repeatedly.

Does anyone have a link to the crazy letter that was sent to Ron Davis a couple years back?

 

Yeah, you're right, it's probably too late already. Forgot that the committee had to consider it first. I will try to work on a personal submission, as you suggest.

Perhaps I should have formulated my thoughts more carefully, cause I didn't want to suggest S4ME or forum members should have done more (the forum is actually very vibrant and running smoothly, huge thanks to those making this possible!). I guess I simply wanted to express my disappointment that things didn't pan out to work on this with others, cause it seems like an interesting and valuable project (finally something different than analyzing BPS-nonsense).

Just to be clear: It's not that I wanted my text to be a S4ME submission, I just wanted to get the discussion going. I started by listing some proposals and ideas hoping that others would join in. When that didn't happen and the deadline came closer, I decided to work out some proposals, hoping that would spark the debate. I know little about the NIH and US situation compared to other members on this forum.

Good point. I sort of interpreted their call as: "tell us what's hampering ME/CFS research and we'll see what we can do about it." So training might not be within their remit, but perhaps they can help with this problem in other ways (for example by trying to establish another research centre or databank where the diagnosis of ME/CFS is assured by an expert clinician). I'm also not familiar with what the NIH can and cannot do, to be honest.

 

I'm writing one, but I'll be lucky to finish by the 14th. It takes a lot of energy.

 

It looks like there are various programs for training new researchers, and there's a funding structure (not currently funded) for developing or improving continuing education.

So it's possible.

Most people seem to look to CDC to do that internally, but it seems reasonable to ask NIH to fund it. Especially from the new consortium of experienced doctors. Of course, they'd have to make a grant request, but there would first have to be a T15 grant opportunity.

 

@Michiel Tack - Nice job laying those out. A few thoughts - hopefully not redundant with what you wrote and/or dumb ideas as I am writing when I should be sleeping....

1) absolutely agree with the need for RFAs. Might be useful to call out specific types of RFAs that should be included - IMO, I dont think its too early for an RFA for a diagnostic. And while I dont know if "RFA" is the right type of grant, we also need set-aside funding for the creation of a clinical trials consortium and clinical trials. The clinicians are using a number of drugs off-label and we need further studies of them. We also need work on outcome measures to be able to better assess efficacy

2) Case definition - yes! NIH's CDE effort left this unresolved and its been an issue for years that NIH has ignored. I'd add that its not just requiring PEM but also the method for how it is evaluated/operationalized. The CDE effort defined it but did not agree on how it would be assessed. Jason has done some work here that might be useful. I think there might be at least one or two other criterion that are common across definitions and could stand further definition/operationalization. On the RFA note - If I remember correctly, an RFA for another field was directed at addressing case definition assessment methods so this might be another opportunity for an RFA

3)totally agree

4) Clinician training - huge issue that impacts our ability to ramp up research. For instance - total number of patients we can get into research and also location - Jax Lab in CT works with Bateman in Utah to get patients so if patients in CT want to participate, they have to go to Utah. But while NIH provides training to clinicians on how to be researchers, NIH does not provide medical education to clinicians on how to diagnose and manage the disease. On the other hand, NIH has or must have a position with the major medical societies who I imagine have strong interests in medical research and NIH can/must do much more to actively use its leadership position to promote awareness, correct negative perceptions and stigma

One other I might add is support for a clinical trials consortium and tx trials. The consortium could help the field get ready for big multi-site trials while starting to drive some smaller trials to help develop methods, advance approaches, and use trials to learn more about disease mechanism

 

Yes, I agree with this. I'm thinking more and more that this might be more important than which criteria is used (CCC, ICC or IOM-criteria). If you simply ask patients 'do you have post-exertional malaise?' or 'do you feel worse after exertion?' that might not reveal much.

But if I'm not mistaken, the only method to assess PEM is what the NINDS/CDC Common Data Elements proposed, namely the two-stage process with The DePaul Post-Exertional Malaise Questionnaire followed by clinician assessment. A document by S4ME shows the problems with this approach. I think (or rather hope) that Jason's new questionnaire will lead to a better approach, but currently, there isn't a good method to operationalize PEM as far as I see.

Really? Does that mean there's a ME/CFS research center without anyone in the center who can reliably make the diagnosis of ME/CFS? That would really indicate the need for more expert clinicians.

This is a little bit out of topic, but I suspect we could a lot more ME/CFS research going if we had more expert clinicians willing to collaborate on research. Patients go a long way to see these experts. So they would have a constant flow of potential research subjects. Even if they would simply record what they are seeing, like in the K. Rowe study on the prognosis of adolescents in Australia, we would have more reliable information without much cost.

This is not only true for the US. In Belgium for example, the government has invested in clinicians at Univerity hospitals who can make the (Fukuda)diagnosis of ME/CFS. So they are constantly diagnosing ME/CFS patients at a university setting but very little is reported on this. If they would simply hand out the questionnaires Leonard Jason's team is developing or report on prognosis that would already be valuable.

Apologies, for this digression. I guess what I wanted to say is that isn't all about funding or innovative ideas. I suspect we could more reliable data on ME/CFS fairly easily if we got more expert clinicians and diagnostic centres who are willing to report and publish on the patients they see.

 

An example of this is Derek Enlander, who has said on numerous occasions that they proved that exercise is bad for pwME, having run a trial but did not publish the results. I suspect there are similar other instances where clinicians could publish results of their observations/tests of patients (even better if they could collaborate with others and combine data) but don't.

 

@Michiel Tack, thank you so much for working out a proposal! I always think your documents are well worded. I would be interested to sign this proposal to NIH if you decide to send it as an individual. I could also help where needed - please let me know.
Personally I think it is more important to raise a voice than to make it perfect, so now that time is running I'd just send it. Because I think it is very good already. Also I wouldn't think too much about if sth. falls into their remit or not - let them decide. Either way, they have heard our suggestion, which seems more important to me.

 

@Michiel Tack I agree with @Inara. I certainly think you should send on the work you have done, you make excellent points.

I feel the NIH need to visit their current position in relation to funding of trials for ME/CFS as there is no mechanism in place for us at present. We still haven't one approved treatment after decades, it's outrageous.

I am happy to sign your completed proposal if you think that is appropriate. Again, many thanks. So many like myself have such limited cognitive ability, I am so grateful to those whose brains are intact!!

 

If I understand, the concerns included that the DSQ PEM questions used did not cover the breadth of the experience of PEM and people wanted a questionnaire that came up with a yes/no without a clinician having to make a judgement. The process used a two step process to ensure that situations where a patient was pacing so effectively that they didnt experience PEM or alternatively was working 60 hours a week and clearly did not have PEM. The DSQ questions didnt cover those circumstances.

Jason did an extensive survey following that and has come up with a revised tool for assessing PEM that would be good to look at. Agree that the first version of operationalization wont be perfect. But it should certainly be better than "Do you have post-exertional fatigue?" which is about where we are now - if that.

Exactly. NIH's funded CRCs are collaborative research centers but most (all?) of the clinicians involved are not in the same academic center, although Levine is in the same city as Columbia.
Cornell has a group at the Weill Medical School but I dont know of a clinical ME practice there. Cornell also works with Workwell in California.