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P2P: The Question They Will Not Ask

July 21st, 2014

by Mary Dimmock and Jennie Spotila

cornerstone-contentThe most important question about ME/CFS – the question that is the cornerstone for every aspect of ME/CFS science – is the question that the P2P Workshop will not ask:

How do ME and CFS differ? Do these illnesses lie along the same continuum of severity or are they entirely separate with common symptoms? What makes them different, what makes them the same? What is lacking in each case definition – do the non-overlapping elements of each case definition identify a subset of the illness or do they encompass the entirety of the population?

Boiled down to its essence, this set of questions is asking whether all the “ME/CFS” definitions represent the same disease or set of related diseases. The failure to ask this question puts the entire effort at risk.

This fundamental question was posed in the 2012 application for the Office of Disease Prevention to hold the P2P meeting (which I obtained through FOIA). It was posed in the 2013 contract between AHRQ and the Oregon Health & Science University for the systematic evidence review (which I obtained through FOIA). It was posed to the P2P Working Group at its January 2014 meeting to refine the questions for the evidence review and Workshop (according to Dr. Susan Maier at the January 2014 Institute of Medicine meeting).

And then the question disappeared.

The systematic evidence review protocol does not include it. Dr. Beth Collins-Sharp said at the June 2014 CFSAC meeting that the Evidence Practice Center is not considering the question because there is “not enough evidence” in the literature to answer the question. However, she said that the P2P Workshop could still consider the question.

But the draft agenda for the Workshop does not include it. Furthermore, every aspect of the P2P Workshop treats “ME/CFS” as a single disease:

  • The P2P description of ME/CFS refers to it as a single disorder or illness throughout the meeting webpage.
  • The P2P website characterizes the names myalgic encephalomyelitis and chronic fatigue syndrome as synonymous.
  • Every section of the Workshop agenda lumps all the populations described by the multiple case definitions together, discussing prevalence, tools, subsets, outcomes, presentation, and diagnosis of this single entity.

A 20 minute presentation on “Case Definition Perspective” is the only lip service paid to this critical issue. This is completely inadequate, if for no other reason than because the presentation is isolated from discussions on the Workshop Key Questions and dependent topics like prevalence and natural history. As a result, it is unlikely to be thoroughly discussed unless one of the Panelists has a particular interest in it.

Why is this problematic? Because both the P2P Workshop and the evidence review are based on the assumption that the full set of “ME/CFS” case definitions describe the same disease. This assumption has been made without proof that it is correct and in the face of data that indicate otherwise, and therein lies the danger of failing to ask the question.

What if the case definitions do not actually describe a single disease? If there are disparate conditions like depression, deconditioning, non-specific chronic fatigue and a neuroimmune disease characterized by PEM encompassed by the full set of “ME/CFS” definitions, then lumping those together as one entity would be unscientific.

The most important part of designing scientific studies is to properly define the study subjects. One would not combine liver cancer and breast cancer patients into a single cohort to investigate cancer pathogenesis. The combination of those two groups would confound the results; such a study would be meaningful only if the two groups were separately defined and then compared to one another to identify similarities or differences. The same is true of the P2P evidence review of diagnostics and treatments: assuming that all “ME/CFS” definitions capture the same disease (or even a set of biologically related diseases) and attempting to compare studies on the combined patients will yield meaningless and confounded results if those definitions actually encompass disparate diseases.

There is a growing body of evidence that underscores the need to ask the fundamental question of whether “ME/CFS” definitions represent the same disease:

  • The P2P Workshop is focused on “extreme fatigue” as the defining characteristic of “ME/CFS,” but fatigue is a common but ill-defined symptom across many diseases. Further, not all “ME/CFS” definitions require fatigue or define it in the same way. For instance, Oxford requires subjective fatigue, and specifically excludes patients with a physiological explanation for their fatigue. But the ME-ICC does not require fatigue; instead it requires PENE, which is defined to have a physiological basis.
  • When FDA asked CFS and ME patients to describe their disease, we did not say “fatigue.” Patients told FDA that post-exertional malaise was the most significant symptom: “complete exhaustion, inability to get out of bed to eat, intense physical pain (including muscle soreness), incoherency, blacking out and memory loss, and flu-like symptoms.”
  • Multiple studies by Jason, Brenu, Johnston and others have demonstrated significant differences in disease severity, functional impairment, levels of immunological markers and patient-reported symptoms among the different case definitions.
  • Multiple studies have demonstrated that patients with PEM have impairment in energy metabolism and lowered anaerobic threshold, and have shown that patients with depression, deconditioning and a number of other chronic illnesses do not have this kind of impairment.
  • Multiple studies have demonstrated differences in exercise-induced gene expression between Fukuda/CCC patients and both healthy and disease control groups.
  • The wide variance in prevalence estimates shines a light on the case definition problem. Prevalence estimates for Oxford and Empirical populations are roughly six times higher than the most commonly accepted estimate for Fukuda. Even Fukuda prevalence estimates vary widely, from 0.07% to 2.6%, underscoring the non-specificity of the criteria. Nacul, et al., found that the prevalence using CCC was only 58% of the Fukuda prevalence. Vincent, et al., reported that 36% of Fukuda patients had PEM, representing a smaller population that would be eligible for diagnosis under CCC.
  • The work of Dr. Jason highlights the danger of definitions that include patients with primary psychiatric illnesses, especially because such patients may respond very differently to treatments like CBT and GET.

By contrast, there have not been any published studies that demonstrate that the set of “ME/CFS” definitions being examined in P2P encompass a single entity or biologically related set of entities. From Oxford to Fukuda to ME-ICC, there are significant differences in the inclusion and exclusion criteria, including differences in the exclusion of primary psychiatric illness. The magnitude of these differences makes the lack of such proof problematic.

Given that treating all “ME/CFS” definitions as a single entity is based on an unproven assumption of the clinical equivalence of these definitions, and given that there is ample proof that these definitions do not represent the same disease or patient population, it is essential that the P2P “ME/CFS” study start by asking this question:

Does the set of “ME/CFS” definitions encompass the same disease, a spectrum of diseases, or separate, discrete conditions and diseases?

The failure to tackle this cornerstone question up-front in both the agenda and the evidence review puts the scientific validity of the entire P2P Workshop at risk. If this question is not explicitly posed, then the non-ME/CFS expert P2P Panel will swallow the assumption of a single disorder without question, if for no other reason than that they do not know the literature well enough to recognize that it is an assumption and not established fact.

 

This post was translated into Dutch with my permission.

 

  1. Chris Heppner
    July 21st, 2014 at 12:05 | #1

    Many thanks, Mary and Jennie, for putting a-the-key question forwards so clearly, with sufficient documentation to offer strong support. It may well be–it probably is-the case that there are several subsets within ME/CFS, but those definitions that focus on simply fatigue–and worse still in the case of the Oxford, subjectively defined fatigue–and include those with depression triggered fatigue–really do make impossible the task of arriving at seriously useful definitions and recommendations for treatment.
    But your evidence suggests that “they” are not listening. Maybe Bateman’s optimistic report on the work being done in the IOM should give us a bit of cheer–wouldn’t it be loverly if the IOM report ended up being at loggerheads with the P2P stuff, and the HHS had the problem of trying to reconcile irreconcilable perspectives for both of which it had to accept responsibility?
    Chris

    • Jennie Spotila
      July 21st, 2014 at 13:31 | #2

      What scares me is that P2P will come out first – and that makes no sense. The timing of these initiatives is completely screwy, and that is one of the many arguments we made in our to Dr. Collins. Seems perfectly reasonable to suspend P2P until the IOM report is out so that the Panel can benefit from the report. I do not understand why this simple decisions has not been made.

  2. Ess
    July 21st, 2014 at 12:53 | #3

    Last para sums it all up, Mary and Jennie; that is the crux of this and the name of the game. Thanks for all the articulation of points in this post–of course, they are excellent points.

    Most UNfortunately, these Qs are not asked because it doesn’t matter in their agenda of ‘what is to be done with ME/CFS’–lump all ‘fatigue’ into one clump–muddy the waters even further– and pat themselves on the back for the accomplishment. Fatigue is the ‘interest’–here . . . ME/CFS buried. Mission accomplished.

    Of course–your points make sense and are KEY.

    AND, of course–if the objective were to really get to work for ME/CFS patients–these Qs would be asked–there would be ALL ME/CFS experts on the P2P jury model panel–there would be ALL ME/CFS experts on the IOM.

    Ohhh, wait now–if the objective is to really help ME/CFS patients–there would be NO IOM committee and NO P2P jury model panel to redefine ME/CFS (and bury us).

    Instead–the HHS would have adhered to the recommendations of the International ME/CFS Experts and Researchers to STOP/CANCEL the IOM committee and adopt the CCC. Further, the Experts in their letters to HHS Secretary Sebelius warned of the HARM to patients with a redefinition of ME/CFS by the IOM committee.

    With all of this in mind–the HHS, IOM and P2P–are right on ‘their’ target.

  3. Carrie
    July 21st, 2014 at 18:31 | #4

    THANK YOU for bringing up these important points, Jennie. This has been on my mind, too. The waters are getting muddied again right from the start. This reminds me of something my dad used to say, “Any job worth doing is worth doing right.” Isn’t this job worth doing right?

  4. emma6
    July 21st, 2014 at 18:57 | #5

    I personally summarise it thus:

    CFS is a predominantly depressive disorder that produces physical symptoms of fatigue and discomfort. It can be cured or alleviated with some therapies and treatments.

    ME is a physiological illness exemplified by swelling of the brain stem and spinal cord and lesions on the brain visible on a SPECT scan. It causes malfunctions in every system connected to the brain stem or spinal cord (i.e. all of them: renal, pulmonary, cardiac, musculo-skeletal, digestive, cognitive, lymphatic, and whatever i’ve forgotten). It causes sound sensitivity, sensitivity to light, smells, touch, taste and mood changes. It appears to be connected in some way to mitochondrial malfunction (that may be what causes the PEM). It is degenerative and incurable. It will bring you an early, slow, painful, lonely and miserable death.

    I really couldn’t care less about the terminology any more. What worries me is the UK Government’s persistent refusal to give money to find a cause/treatment/cure. Every penny in the UK goes to psych research only, and if we want biomedical research, we have to find the money ourselves. THAT’s the real issue here. The mere fact that the link at the bottom of this page to the next article is entitled “ME/CFS Mortality”; THAT’s what we need to tell the world. Not that we still haven’t agreed on a pigging name for it.

  5. July 22nd, 2014 at 01:19 | #6

    how do i get your blog by e.mail please

    i have m.e .

    mark

    • Jennie Spotila
      July 22nd, 2014 at 08:51 | #7

      I’m in the process of moving to a new hosting arrangement that will support email subscription. I’ve added you to the list of people who have asked to be notified when the feature is available. Thanks!

  6. July 22nd, 2014 at 04:42 | #8

    In 2010, Peter White and Anthony Komaroff wrote a report for the IOM suggesting that they do research into ME/CFS, and Peter White set out suggestions such as concern for ‘directionality’, clearly meaning that they were meant to find out that people with ME/CFS were psychologically sick first (you know, the ‘directionality’ that people who have had it for a long time mostly believe they are physically ill, and many have joined support groups – so the White/Wessely version of ‘directionality’ is that believing you have a physical illness and belonging to a support group become ‘perpetuating factors’, and the treatment is to change the belief and get them out of support groups. Wonder if this works for cancer, diabetes, MS, etc? The next important document is the one that this site gave us access to a few weeks back – the letter from Strauss to Fukuda, congratulating Fukuda on developing guidelines that focused on fatigue, and expressing his hope that the focus could remain on fatigue as a common and very general issue, therefore that CFS as a separate disease entity could ‘evaporate’, a conclusion that he very much hoped for. The report produced by the IOM on Gulf War already presupposes that ‘CFS’ is a ‘functional’ disorder, belonging in the category of Chronic Multisystem Illnesses, and treatable by CBT and GET. All that this elaborate and expensive charade is intended to do, and will do, no matter what anyone does, as far as I can see, is continue to carry out the wishes of White and Strauss and Wessely – it seems evident that this is its purpose and will be the outcome. The irony in this is that if you look up chronic multisystem illness as a category before these guys co-opted it, it includes MS and lupus – both illnesses that used to be labelled psychiatric.

  7. July 22nd, 2014 at 14:26 | #9

    What they said doesn’t matter, that’s just a distraction.

    It doesn’t matter whether they are talking about ME or CFS or ME/CFS or CFS/ME, whichever they are deciding to call this illness.

    The P2P For ME “Research Protocol” has a MAJOR BIOETHICAL VIOLATION- its in violation of the WMA 1964 Declaration of Helsinki just like the PACE trial was.

    1964 Declaration of Helsinki- “Ethical Principles for Medical Research Involving Human Subjects”

    ARHQ can go on and on and on saying that it is not in violation but it is, Its not our job to search through their website, its THEIR job to have it in the review. “Informed Consent” which is what this is about, takes precedence in a Malpractice case, even if the case is weak.

    There is no way they can do this with their so-called Jury because its in violation of the Declaration of Helsinki- what the heck to non medical lay people or non expertise people know about this illness- Nothing, NADA! VIOLATION! PERIOD!

    Wessely and White forgot about that little technicality because they are “psychiatrists” with little experience with medical patients. If you look at their curriculum vitaes which are online, you will see that. They know nothing!!! That’s why they tell people with unresolved viral infections to exercise because they know nothing!

    Its not a valid study.

    So yes Jennie- it is screwy, the study is no good!

    Informed Consent: very important medical-legal issue and is OUR tool!

    The Informed Consent issue in this P2P study which is published as a “Research Protocol” is our Medical Legal tool for when a group of our people have to go in front of the committee like the Gulf War people did to get their IOM study done over, and we all know there was no definition out of that one. That panel said their illness was “too complex”.

    Gotta stay 10 steps ahead of these people!

  8. Anne Örtegren
    July 23rd, 2014 at 06:21 | #10

    Jennie, thank you for this and all your amazing advocacy work.

    You deserve to be hired as a (part-time, working from home) senior advisor at the DHHS with full influence over all their decisions regarding ME/CFS.

    THEN we’d be getting somewhere…!

    • Jennie Spotila
      July 23rd, 2014 at 09:24 | #11

      LOL, something tells me I would not enjoy working for HHS!

  9. July 23rd, 2014 at 14:03 | #12

    Why ask a question you can’t answer? There are studies contrasting the Fukuda and other definitions but too few of them to definitively separate ME from CFS.

    I do agree though that they should take a stab at separating ME from CFS; it would be short stab, but it set the table for the future.

    Absent the ability to definitively separate the two using research studies I don’t know what P2P can do other than look at ME/CFS and assess the different definitions associated with it – which I believe that they’re doing. They state that they will “the accuracy and concordance of diagnostic methods”. To me that means they are not viewing ME/CFS as one entity but are taking the heterogeneity associated with the different definitions into account.

    Given that I hope the group will recommend research to assess whether the an ME (PEM) or CFS (fatigue plus PEM) definition will prevail.

    I think the P2P committee recognizes that this is likely a very heterogeneous disorder. The recent biomarker paper on ME/CFS referred to the ‘vast heterogeneity’ present in ME/CFS (vast!).

    I disagree that ‘extreme fatigue’ is a common aspect of many illness. Fatigue is but the extreme fatigue present in ME/CFS is relatively rare in the medical worlds.

    For me the change to focus on treatment studies will means they will be reading a lot of CBT and GET studies is the most dangerous part of this study. Hopefully the CDC multisite studies which will assess (I hope!) other treatments will be counterweight to them. I can”t imagine but that those studies won’t be coming soon.

    • Jennie Spotila
      July 24th, 2014 at 08:29 | #13

      In my opinion, science is all about asking the question you can’t answer and then devising the means to answer it.

      Regarding the “accuracy and concordance of the diagnostic methods” being examined in the systematic evidence review, remember that the evidence review will include Oxford studies right along side CCC and ICC. We know for a fact that Oxford CFS patients are different from CCC and ICC patients. Even apart from Jason’s work showing that Oxford includes people with depression/anxiety and not something like Fukuda CFS, the Oxford definition itself excludes any patient with a physiological explanation for their fatigue. Only people with subjective fatigue are included. That means that because I have a two day CPET report showing that I have a metabolic dysfunction that contributes to my fatigue, I am excluded from Oxford by its own criteria. Yet the evidence review will lump Oxford studies and studies that include people like me together. By lumping us together, they may obscure the very real differences between the groups and decide that we are simply too heterogeneous. Finally, the Solve ME/CFS Initiative wrote to NIH and said the evidence review search strategy will bias the results towards CBT/GET studies and miss the very important biomarker studies. How can we have confidence in an evidence review with so many strikes against it?

      You describe research to assess “ME(PEM) or CFS (fatigue plus PEM)”. But Cort, ME (Ramsay definition) is much more than PEM, and Oxford CFS or even Fukuda CFS are not fatigue plus PEM. We (meaning researchers and advocates, including me) use the terms ME and CFS, and we may understand each other, but it is not precise or accurate enough for a Panel with no ME/CFS experience. Oxford CFS has nothing to do with PEM, and Fukuda CFS does not require PEM. So to say that CFS is fatigue plus PEM is your own definition of CFS, not one of the case definition papers.

      Extreme fatigue is absolutely a common aspect of many illnesses. Talk to cancer patients or narcolepsy patients or AIDS patients. FDA has remarked that every single disease that they have examined in the Patient Focused Drug Development meetings has included severe fatigue in what patients report to them. The “extreme fatigue present in ME/CFS” is actually not what is relatively rare. PEM, and the fact that PEM is triggered by low levels of physical or cognitive activities, is what is relatively rare.

  10. Anonymous
    July 24th, 2014 at 11:50 | #14

    @cort
    “The recent biomarker paper on ME/CFS referred to the ‘vast heterogeneity’ present in ME/CFS (vast!).”

    Which paper is this, please? (Anyone know?) Thanks!

  11. Mary Dimmock
    July 24th, 2014 at 19:04 | #15

    @Cort, The problem with asking whether ME and CFS differ is that everyone is using the terms differently and will inevitably come up with different answers to that question. The question can’t be answered because its an ill-defined question.

    But at its heart, this question is asking whether the different “ME/CFS” definitions represent the same disease or instead encompass a set of biologically unrelated conditions. And in my opinion, that question can be answered – there is a significant amount of evidence that shows that these definitions encompass unrelated conditions. If that’s true, then there is no foundation from which to assess the accuracy and concordance of diagnostic methods because the different studies are looking at different conditions. Its like comparing the accuracy of a diagnostic method used for Oxford CFS to a diagnostic method used for MS, which also causes fatigue. It would be a useless comparison.

    I struggle with the use of the term “heterogeneity” in “ME/CFS”. I agree that CCC and ME-ICC undoubtedly describe a heterogeneous disease. But the “heterogeneity” seen across the full set of “ME/CFS” definitions is the result of mixing overly broad definitions/unrelated conditions together that shouldn’t have been lumped together in the first place. Its a man-made and unscientific heterogeneity.

  12. Mary Dimmock
    July 24th, 2014 at 22:10 | #16

    @Anonymous
    The paper is “Chronic fatigue syndrome: the current status and future potentials of emerging biomarkers”. The authors are David B. Fischera, Arsani H. Williama, Adam C. Straussab, Elizabeth
    R. Ungerc, Leonard A. Jasond, Gailen D. Marshall Jre & Jordan D.Dimitrakoff
    http://www.tandfonline.com/doi/abs/10.1080/21641846.2014.906066#preview

  13. floydguy
    July 26th, 2014 at 08:47 | #17

    @Jennie Spotila

    Be careful of oversimplification. Many seem desperate to isolate themselves from the “crazy” CFS people who they label as just tired. I am in the position of having relatively mild PEM – who knows though, like most, it’s never been CONFIRMED by OBJECTIVE testing – and very low VO2 max (aerobic exercise intolerance despite being a former competitive tennis player) despite being relatively “active” (eg walk over 10000 steps a day). I have the same labs as most with ME: very low NK function, high EBV, HHV-6, Cocksackie (and other infections) out of whack cytokines, etc. And I have seen Natelson, Komaroff and Klimas. My challenge is not “fatigue” but severe autonomic dys-regulation. But since I have 50% lower activity then before….

    In my opinion, there is probably a distinct illness called ME or something similar and of the 1MM people in the US with “CFS” only 5-10% have ME. The important question I think is whether there something called “CFS”. I am rather doubtful of that. It’s most likely a grab bag of various and sundry conditions of difficult Lyme cases, biotoxin sensitivity, depression, auto-immune patients, etc.

    • Jennie Spotila
      July 26th, 2014 at 16:36 | #18

      Actually, I agree with you. Oversimplification is so easy, and so tempting. Plus we don’t have data that would give us answers to some of those questions.

      I have wondered for a long time what is left in Fukuda CFS if you take the ME people out. Is it just a grab bag of misdiagnoses? Or is there something else? And is the prevalence, as you suggest, 50-100,000? More? Less?

      What makes me crazy is that we’ll NEVER get the answers if the questions are not asked.

  14. floydguy
    July 27th, 2014 at 09:35 | #19

    @Jennie Spotila

    I think the other thing that needs to be advocated for is a rigid diagnostic workup that is mandatory for people to be given a “ME” label. Even if that requires patients traveling to see a handful of “experts”. The CCC and ICC is an attempt but I have no confidence that the average – and in most cases (at least in my experience) disbelieving – can properly assess this criteria. The status quo of putting people together with nothing in common – except “un-wellness” – has got to end.

    If people don’t fit than they should not receive any diagnosis. Insurance companies and busy MDs like to bucket people but I hope even the balkanized “ME” community can agree that is unscientific and frankly should be regarded as highly unprofessional.

    One of the first things we learn as kids is to identify like objects. We do not fit square pegs in round holes. In medicine and research, this lesson seems to be forgotten or justified with mumbo jumbo.

  15. Billie Moore
    July 27th, 2014 at 10:12 | #20

    I continue to hold to the position that many who have been labeled as having CFS do have ME. For decades the disease has been called CFS; many of the expert doctors still refer to it that way. While it has been shown that some who have been diagnosed with CFS by the Fukuda definition do not have ME, I would posit that the vast majority of those who have had “CFS” for many years actually do have ME, not only by the CCC definition but also the ICC definition, requiring PEM. (We really do have to work on getting another term than “malaise.”)

    Billie

  16. floydguy
    July 28th, 2014 at 09:16 | #21

    @Billie Moore

    It might be an interesting question to the “experts”: What percentage of your patients meet the CCC or ICC definition? In regards to this, every patient should be given an assessment form that is filled out showing how they are meeting the criteria. In my case, Komaroff says I do not fit the strict criteria but Klimas and Natelson believe I do. Moreover, I find it very difficult to believe that 1MM Americans meet a strict interpretation of the CCC.

  17. N.A.Wright
    July 29th, 2014 at 10:32 | #22

    I suggest a thought experiment –

    Two groups of patients A & B, each of 100 individuals

    Groups A and B are defined by diagnosis of two distinct illnesses which have exactly the same symptomatology, where diagnosis for both is by invasive procedure only and where there are no gross signs indicative of aetiology in either disease.

    Both groups are broadly demographically matched

    Both groups show the same distributions of mild, serious and severe impairment in broad ratios of: 20% asymptomatic, 40% mild symptomatology , 20% serious and 20% severe. There are no identifiable patterns of progression in either disease, and both diseases are characterised by moderate rates of partial and total remission of symptoms.

    The medical records of both groups are wholly mixed, and no record of test results survive. What sorting of patients would result in meaningful data ? …………………!

    The intuitive approach would be to sort patients into groups by severity, by symptom and by demography, yet there is no statistical basis by which such a process would achieve proportionality (50:50) of the underlying disease procesess. Now consider instead of just two disease processes there 3, 5, or even 10. Then allow multiple factors producing instead of easily distinguished disease processes, nuanced variations depending on a demonic mix and match in which genetics, infection, autoimmunity and environment combine to produce unique expressions of core diseases. Intuitive sorting is incapable of dealing with such a level of complexity, and that seems to be precisely where we are with ME/CFS.

    The question: are CFS and ME the same thing ? clearly has validity, for both scientific and advocacy reasons, but we shouldn’t be seduced into believing that there is a ready answer.

  18. Ess
    July 29th, 2014 at 18:57 | #23

    @Billie Moore
    I agree with your comment #20 Billie.

  19. floydguy
    July 31st, 2014 at 07:54 | #24

    @N.A.Wright

    Actually the more rational approach would be to sort based on objective testing: ANS dysfunction, swollen lymph nodes, low VO2 max, etc. Sorting on vague symptoms such as “fatigue”, “pain” and “difficulty concentrating” leads…to where we currently are. The idea that there are only “symptoms” is plain wrong – at least for a slice of the “CFS” population.

  20. N.A.Wright
    July 31st, 2014 at 14:01 | #25

    floydguy :@N.A.Wright
    Actually the more rational approach would be to sort based on objective testing: ANS dysfunction, swollen lymph nodes, low VO2 max, etc. Sorting on vague symptoms such as “fatigue”, “pain” and “difficulty concentrating” leads…to where we currently are. The idea that there are only “symptoms” is plain wrong – at least for a slice of the “CFS” population.

    Surely ANS dysfunction, swollen lymph nodes, low VO2 max are all symptoms, certainly to date none have been shown to be unique active processes of disease in ME/CFS. Any symptom or groups of symptoms may turn out to be a basis for classification within the broad ME/CFS patient group – but without identification of unique active disease processes, we are as blind as anyone looking at the mixed group in my proposed thought experiment. Isolating symptoms by group, or by severity or provocation effect and deriving patient groupings based on that and then ascribing different disease names would only be a semantic exercise, and would tell us very little if anything about underlying disease processes within the groupings.

    • Jennie Spotila
      July 31st, 2014 at 15:34 | #26

      Low VO2max is a sign, not a symptom, and research suggests that some patients have results unique to Fukuda or Canadian ME/CFS distinct from those who are simply fatigued or sedentary or depressed (these are also patients who would meet the Oxford CFS definition). We won’t be able to firmly establish unique active disease processes without tightly defining groups based on signs and symptoms as a starting point.

  21. floydguy
    July 31st, 2014 at 19:42 | #27

    @Jennie Spotila
    So isn’t swollen lymph nodes and proven ANS dysfunction which is why I included them. “Fatigue” is a symptom as well as “difficulty concentrating”, “weakness”, “malaise” and I would argue “PEM” but I am sure that won’t be popular. Essentially anything on a questionnaire should be frowned upon and not likely to define much of anything, except some type of “un-wellness”.

    • Jennie Spotila
      August 1st, 2014 at 08:46 | #28

      Yes, I agree that swollen lymph nodes and ANS dysfunction (perhaps established through tilt table or other testing) are both signs. They are not unique to ME/CFS, though. It would be necessary (and I assume this is what you’re thinking too) to establish the constellation of signs that is definitive for this disease. I think that patient-reported PEM would have to be very very carefully measured, perhaps through a validated PRO instrument. It would be preferable to establish PEM through two day CPET, once that has been validated in a larger study.

  22. Ren
    August 1st, 2014 at 03:00 | #29

    Thank you, Mary for sharing the paper info.

    Otherwise, please forgive the long post. The following (extracts) just seemed so fitting. From Balint et al. 2006; Clin Rheumatol; “A brief history of medical taxonomy and diagnosis”:

    “In the seventeenth century Thomas Sydenham (1624-1689)… often referred to as the ‘English Hippocrates’, advocated classification of disease, not according to speculation or theory, but an accurate clinical description. Sydenham urged that the same attention to detail be taken in diagnosis of disease as botanists took in the classification of plants:

    ‘In the first place, it is necessary that all diseases be reduced to definite and certain species, and that with the same care which we see exhibited by botanists in their phytologies; since it happens, at present, that many diseases, although included in the same genus, mentioned with a common nomenclature, and resembling one another in several symptoms, are, notwithstanding, different in their natures, and require a different medical treatment’… [End Sydenham quote]

    [The word] Diagnosis…is derived from Greek meaning to distinguish or discern distinctive characteristics in precise terms…

    Progress in medicine results from increased discrimination…

    In general the more experienced the physician the less the observer error…

    It was Thomas Sydenham who first recommended ‘splitting’ rather than ‘lumping’:

    ‘We all know that the term thistle is applied to a variety of plants, nevertheless, he would be a careless botanist, indeed who contented himself with the general description of a thistle; who only exhibited the marks by which the class was identified; who neglected the proper and peculiar signs of the species, and who overlooked the characters by which they were distinguished from each other.

    On the same principle, it is not enough for a writer to merely note down the common phenomena of some multiform disease; for, although it may be true that all complaints are not liable to the same amount of variety, there are still many which authors treat alike, under the same heads, and without the shadows of a distinction, whilst they are in their nature as dissimilar as possible’.” [End Sydenham quote]

    • Jennie Spotila
      August 1st, 2014 at 08:48 | #30

      Excellent quotes, Ren!

  23. Mary Dimmock
    August 1st, 2014 at 10:20 | #31

    Thank you for this, Ren. Excellent and to the point.

  24. N.A.Wright
    August 1st, 2014 at 10:46 | #32

    Sign is a classification, basically something that is measurable as opposed to a subjective report such as pain, fatigue etc. But many ‘signs’ are also symptoms (useful article here: http://www.medicalnewstoday.com/articles/161858.php ) Low VO2 max isn’t proposed as a disease process in itself, and would therefore be considered a consequence of underlying illness. It could be argued that a symptom must be evident to the patient and that Low VO2 max is just a performance measure, but the reduced performance associated with Low VO2 max must reasonably be considered a symptom, so the issue is really definitional rather than a physiological distinction.

    There is clearly a problem with too wide a selection criteria, but exclusion on the basis of low symptom severity or adherence to a specific measurement of a sign runs the danger of excluding patients from studies who may actually have aetiologies which are common to a large patient group and which are substantially less occulted than those in patients with greater severity of symptoms. It is intuitive that more illness should equal more obvious disease, but that is not necessarily the case where multiple factors are involved and lots of small processes can serve to obscure major processes. It’s not difficult to hypothesise a disease which is largely asymptomatic in its developmental stage and where microscopically active disease processes are readily evident, but which when the disease becomes symptomatic, the disease processes becomes occult. In such a disease, lesser symptomatic patients might offer the best evidence of disease processes. In ME/CFS research Fukada is probably a ‘good enough’ criteria with CCC a useful comparator, beyond that further tightening of patient selection may serve only to exclude valuable subjects.

    • Jennie Spotila
      August 1st, 2014 at 13:39 | #33

      The puzzle we face is how tightly or widely to draw the circle around the patients to examine/analyze for underlying disease processes. If Fukuda cohorts produce mixed results, then shouldn’t we ask if a tighter circle would produce more unified results that could then be applied to a wider circle? I’m thinking of other diseases, such as Alzheimer’s, where diagnosis was originally made on the basis of recognizable dementia. But more recently, the criteria were broadened to include pre-dementia patients. If they hadn’t started with the most severely affected, how would they have discovered the tools that can now be used on earlier stage patients?

      I agree that excluding less severe patients could be risky. I would not, for example, want to focus only on the most severely ill, bedridden patients. And I know many patients who are able to work or exercise, but a dramatically different cost than before their illness. But we’ve had Fukuda for 20 twenty years, and the scientific advances have been limited. Obviously there are multiple reasons for that, but one of them may be Fukuda itself.

      So what is the way out of this mess? Could we start with patients who have the drop in VO2max on the second day of CPET, or patients with the gene expression markers found by the Lights, and study the crap out of those people? What other signs and symptoms do they have? Do they cluster at certain severity points, or other common characteristics? What if that group yielded a new biomarker that could then be used on the broader group of patients, identifying those with less severity but with a shared disease process?

      It just seems to me that Fukuda hasn’t gotten us far enough down the road. So what should we try to change the game?

  25. floydguy
    August 2nd, 2014 at 09:47 | #34

    @N.A.Wright
    So if Fukuda is good enough than why do we have hundreds of studies suggesting that more research is needed due to completely ambiguous results?

    In my personal experience, as I look back I think the way I’ve explained my “symptoms” was not good. If I don’t trust my own assessment I am certainly not going to trust Suzy’s from San Diego. And the way MDs examined me was even worse.

    Once it became clear that a lot of these “symptoms” are the result of ANS dysfunction than a lot of things fell into place. So for example that “anxiety” is not really “anxiety” but Sinus Tachycardia. What would you rather have as a symptom to do research on: people with proven ANS issues or those with “anxiety”?

  26. floydguy
    August 2nd, 2014 at 09:59 | #35

    @Jennie Spotila

    I agree! It seems the best place to focus are on:

    - Brain/ANS issues (POTS, Tachycardia, etc are common “symptoms/signs”)
    - Exercise issues (seems like with some effort an acceptable marker could be found; I’d look out for ANS issues being the reason for some people)
    - Immune Dysfunction
    - Various Infections (EBV, HHV-6, etc.)

    I certainly don’t advocate leaving out those that aren’t bed bound (I am not) but I am advocating that people be left out that don’t have ANY objective sign/symptom or whatever. Being “unwell” + several other random “symptoms” shouldn’t be the criteria, ie Fukuda.

  27. N.A.Wright
    August 5th, 2014 at 11:27 | #36

    @Jennie Spotila
    Alzheimer’s research is an interesting model, but like MS which is also a illness from where we might want to take a research model, there was from the outset of its description a definitive process of organic disease. And of course with Alzheimer’s there is a very clear epidemiological focus – it is age related and it is progressive. ME/CFS (under whatever name) has from Ramsay onwards, been an illness of broad symptoms in search of a collective causation, there’s no clear epidemiology other than that infants seem immune, and there’s no discernable pattern of progression. Nearly 60 years on from the Royal Free event, we have to accept the very strong probability that there is not a single disease, but that ME/CFS represents a range of organic impacts that produce the symptomatolgy which can be classed by Fukada.

    To identify Fukada as a source of a lack of progress, seems to me to miss two very important points: Firstly the whole direction of medical research and disease classification is changing radically, for a now almost out of date paper (2007 !) see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1948102/ Secondly people diagnosed under Fukada are ill, one can not argue for Governmental funding of illness research and at the same time also arbitrarily demand that because of poor diagnostic performance that there must be a section of the diagnosed whose ill health does not warrant investigation. Also the argument that the lack of specificity of Fukada means that all research data is obscured doesn’t seem to have foundation. If we look at all the cytokine studies, the problem has not been identifying abnormalities within study groups, it is that there is little commonality of abnormalities across the study groups. If it really is the case that lack of specificity of diagnosis is causing attenuation of data, then the cytokine results are either non meaningful or are indicative of illness processes which would have to be deemed non ME/CFS relevant. I’ve not heard that argument made, and personally I think it would be perverse reasoning.

    Chasing down specific signs and/or symptoms might well be a way forward, but the most effective way of doing that would most likely be by comparing cohorts rather than excluding those who do not meet a given selection criterion. So using the VO2 max measure, one might take fifty, randomly selected Fukada patients, assessed but not excluded under the CCC, put all through one and two day VO2max testing, from that develop two or more cohorts based on the results and then look for differences in cytokine and other biometrics and epidemiological data between the cohorts. One would then ideally start looking for genomic differences. None of this requires reinventing the wheel of diagnosis – it does require money. Lots of money, involving multiple co-operating institutions focussed on common ends, not piecemeal distribution of grants with researchers riding their own hobbyhorses.

    • Jennie Spotila
      August 5th, 2014 at 15:30 | #37

      I completely agree with your study design in the last paragraph. I would say take 1,000 Fukuda patients, assessed but not excluded with CCC, and then but them through the works. Two day CPET, gene expression, cortisol, cognitive testing, everything. See if patients who have PEM cluster in certain lab results. See if cognitive problems overlap with certain cytokine signatures. And so on. And yes, my dream study would cost millions of dollars – but I bet it would be the straightest line to identifying/confirming clusters or essential features.

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