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Encouraging new ideas for CFS/ME research

Three images from the conference: Stephen Holgate speaking (top); feedback post it notes (middle) and panel discussion (bottom)

(Image copyright: Clare Ogden and Sonya Chowdhury)

At the inaugural conference of the UK CFS/ME Research Collaborative in September researchers in the field of chronic fatigue syndrome and myalgic encephalomyelitis got together with scientists from a range of other fields in an effort to spur on research into new areas. Here Professor Stephen Holgate, MRC Clinical Professor of Immunopharmacology at the Faculty of Medicine in Southampton, and Chair of the collaborative, explains why the conference was so significant, and what came out of it.

CFS/ME is a complex disease. In fact, it may not be just one disease at all. I say ‘may’ because there’s a lot we don’t know about CFS/ME ― and we desperately need research to get some answers.

It is a chronic condition characterised by severe fatigue, weak and painful muscles and/or joints, poor memory and concentration, and poor sleep. Not everyone will have the same symptoms, or the same severity of symptoms. We’re not certain what causes it, and although it often occurs after an infection or accident, it can also come on gradually.

So, we have a condition with no known cause, that manifests itself in different people in different ways and severities, and at different times. It’s obviously a field that is ripe for discovery. But so far, for a variety of reasons, we haven’t been able to get these answers.

Part of the reason for the lack of answers in CFS/ME is that researchers haven’t been able to deliver enough high-quality proposals to funding bodies. By bringing a diverse group of researchers together at the conference, we hoped to generate new ideas and collaborations that could result in these high-quality applications.

New ideas often come from new people. Moreover, to progress and deliver excellent research we need to make sure we continuously build capacity ― support established researchers already working in the field and attract new ones to work on CFS/ME. In the end 70 researchers and clinicians with an interest in CFS/ME attended the September conference. They came from all over the world, and while some have worked in this area for years, others are entirely new to the field.

It was great that so many PhD and medical students attended the event, because capacity building is what growing a scientific discipline is all about. We want early-career researchers to see the field as an attractive one in which they can do interesting and important work.

We talked about a range of research at the conference. Topics under discussion included pain, the immune basis of fatigue and the association of CFS/ME with sleep. I really want us to capitalise on this coming together of interdisciplinary researchers so that we can develop standard protocols for things such as banking biological samples, describing symptoms, and applying ‘omics’ technologies to large numbers of patients.

Though the conference was for researchers, we included a session in which around 60 patients and carers got together with researchers too. This is because we want to make research accessible to the patients, and also to take advice from them on the level of involvement in research that patients are likely to accept. For example, what kinds of biomedical tests would they be willing to undergo? How many questionnaires would they fill in?

Emerging themes included: the likelihood that CFS/ME probably has many causes; the need to ‘stratify’ or group patients with similar symptoms together to see whether they share common causes or markers of biological processes; the need to recognise that what causes CFS/ME might be different to what maintains it; and the need to understand that diseases may not necessarily be either biological or psychological but may, in fact, be both.

That last point is an important one: we need to shout about the fact that CFS/ME has a biological basis. Regardless of any psychological involvement ― you can’t have psychology without biology.

The sooner we find this biological basis, or indeed bases, the better.

The CFS/ME field has been marred by a breakdown in trust between patients, clinicians, researchers and funders; disagreement about research results; and a lack of investment by industry. But as I said at the conference, this isn’t about finishing something, it’s about starting something. The conference gave me the energy and enthusiasm to think that we can move this field forward.

Stephen Holgate

Read the full conference report.

Stephen Holgate is Chair of the MRC Translational Research Group. The MRC contributed to the costs of holding the conference and is an observer of the collaborative.

11 Comments Post a comment
  1. phil #

    i think the basis for the disease is this:-

    due to auto-immune activity or infection, a part of the brain that produces a placatory messenger molecule to the immune system becomes compromised.
    this leads to further interleukin release within the immune system that leads
    to further antagonism to this brain area.

    a vicious cycle of illness is hence set up.

    the nice thing about this model is that it can encompass and explains the minor improvements seen via some psychological therapies such as CBT, GET, and hypnotherapy. these therapies are probably capable of stimulating the brain into releasing more of the so said depleted immuno-inhibitory molecules.

    Are there neuro-peptide receptors on certain interleukin producing white blood cells ? if yes, can we measure these levels in patients and controls ?

    we know that suppressing the B cells can ‘cure’ ME, but its risky. if the above is correct, it would be better to have neuro-peptide based therapy.

    November 13, 2014
  2. Dan Clarke #

    “The CFS/ME field has been marred by a breakdown in trust between patients, clinicians, researchers and funders;”

    While I agree with much of this blog, I disagree with this and think that, given the poor quality of much of the research in the area and the way in which results have often been misrepresented, it is vital that patients do not just trust clinicians, researchers or funders: many of them have shown that they are untrustworthy, so the breakdown in trust should be recognised as a good thing. Any attempt to increase patients’ trust in those who have authority over them without first taking steps such as requiring the release of the PACE trial’s results in the manner laid out within it’s protocol, will do more harm than good.

    It is important that we do not allow irrelevant truisms about about the inevitable role of ‘psychological factors’ in all human experience or the biological underpinnings of the human mind to distract from the legitimate concerns of patients about those who have exaggerated the benefits of their biopsychoosocial interventions for CFS or promoted the routine medicalisation of the psychosocial aspects of CFS patient’s lives without informed consent from the patient.

    For those not aware of the any of the specifics of problems in this area, I’ll use the PACE trials use of the SF36-PF scale as an example of one of the many concerns patients and patient organisations have with the way CFS research is too often conducted.

    The £5 million+ PACE trial is the most expensive piece of CFS research funded by the MRC[1] and was a non-blinded trial using subjective self-report measures as it’s primary outcomes[2]. It’s published protocol defined ‘recovery’ as requiring an SF-36 Physical Functioning (SF36-PF) questionnaire score of at least 85 out of 100, while the trial’s entry criteria required a score of 65 or under, which was taken to indicate that patients’ fatigue was disabling[2]. The post-hoc criteria for recovery allowed patients with an SF36-PF score of 60 to be classed as recovered. This change was justified by the claim that a threshold of 85 would mean “approximately half the general working age population would fall outside the normal range.”[3] In fact, the data cited showed that the median score for the working age population was 100, less than 18% of the general working age population had a score under 85 when 15% had declared a long-term health problem[4,5].

    An SF36-PF score of 60 was claimed in the Lancet PACE paper to be the mean -1sd of the working age population, and thus a suitable threshold for ‘normal’ disability[6]. They had in fact used data which included all those aged over 65, reducing the mean physical function score and increasing the SD[4]. For the working age population the mean -1sd was over 70, requiring patients to score at least 75 to fall within this ‘normal range’[5]. Also, the trial’s protocol makes it clear that the thresholds for recovery (including ≥85 for SF-36 PF) were intended to be more demanding than those for the mean -1sd, reporting that: “A score of 70 is about one standard deviation below the mean… for the UK adult population”[2].

    The post-hoc criteria for recovery so clearly overlapped with the trial’s own criteria for severe and disabling fatigue that a specific requirement mandating that ‘recovered’ patients not also fulfil every aspect of the trial’s criteria for CFS[3] needed to be used. Even so, patients could still have been classed as recovered when reporting no change, or even a decline, in either one of the trial’s primary outcomes.

    Even using the loose post-hoc criteria for recovery, only 22% of patients were classed as recovered following treatment with specialist medical care and additional CBT or GET[3]. Regardless, the BMJ had reported that PACE showed CBT and GET “cured” 30% and 28% of patients respectively[7], a Lancet commentary claimed that about 30% recovered using a “strict criterion” for recovery[8], and a paper aimed at NHS commissioners stated PACE indicated a recovery rate of 30-40% for CBT and GET[9,10]. It is wrong for such misstatements of fact to be allowed to go on affecting how doctors treat their patients, how funding decisions are made, and the information that patients are provided with before deciding whether to consent to particular interventions.

    The changes to the outcome measures used in the PACE trial may not be deliberately deceptive, but they were misguided, justified by inaccurate claims, and have been misleading to others. The refusal to allow patients access to data on the outcome measures laid out in the trial’s protocol, and seemingly contradictory nature of the responses to Freedom of Information requests for this data reflects a sad dismissal of their right to be informed about the medical treatments they are being encouraged to pursue[11,12,13].

    There was a time when it was claimed by some that even homeopathy was a promising medical treatment, based upon minor improvements in subjective self-report measures following non-blinded trials. It is now more widely and that it is not ethical to promote homeopathy as a legitimate form of medicine.

    In the case of cognitive and behavioural interventions for CFS/ME, we have evidence from the PACE trial that they are able to lead to modest improvements in patient questionnaire scores in a non-blinded trial, without leading to improvements in real world outcomes such as employment rates, or claims for disability benefits[14]. A meta-analysis of actometer data from CBT trials for CFS also found that CBT was able to lead to improvements in questionnaire scores in non-blinded trials, but not to improvements in the amount of activity that patients were actually able to perform[15]. Sadly, the PACE trial dropped actometers as an outcome measure, although they were purchased and used at baseline[16].

    Recent evidence from a large study of NHS CFS/ME specialist services indicated that reported results for CBT and GET are poorer than those reported in PACE, and that centres offering CBT and GET achieved marginally worse results than centres offering ‘activity management’[17]. We do not currently have compelling evidence that CBT or GET are more effective medical interventions for ME/CFS than homeopathy, despite some of the claims made by proponents.

    It should be seen as no more acceptable for those with financial, professional or ideological interests in promoting CBT or GET as treatments for ME/CFS to exaggerate the value of these interventions than it is for others to exaggerate the value of homeopathy. Anyone with a real interest in helping patients with ME/CFS, and in allowing them to make informed decisions about their own health care, should now call for the release of results for all of the outcomes laid out in the PACE trial’s published protocol[2].

    [1] http://gtr.rcuk.ac.uk/project/7EC0DBA0-0FC2-44F1-8708-8676EBEDA4C9

    [2] White PD, Sharpe MC, Chalder T, DeCesare JC, Walyin R: Protocol for the PACE trial: a randomised controlled trial of adaptative pacing, cognitive behaviour therapy and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol 2007, 7:6

    [3] White PD, Johnson AL, Goldsmith K, Chalder T, Sharpe MC. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med 2013;1-9, published online 31 Jan. doi:10.1017/S0033291713000020.

    [4] Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, The Health Survey for England and the Oxford Healthy Life Survey. J Publ Health Med 1999, 21: 255–70.

    [5] Office of Population Censuses and Surveys. Social Survey Division, OPCS Omnibus Survey, November 1992. Colchester, Essex: UK Data Archive, September 1997. SN: 3660, http://dx.doi.org/10.5255/UKDA-SN-3660-1

    [6] White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O’Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011;377:823-36.

    [7] BMJ Short Cuts: ‘All you need to read in the other general journals’ BMJ 2011;342:d1168

    [8] Knoop H, Bleijenberg G. Chronic fatigue syndrome: where to PACE from here?. Lancet 2011; 377: 786-788.

    [9] Collin SM, Crawley E, May MT, Sterne JAC, Hollingworth W: The impact of CFS/ME on employment and productivity in the UK: a cross-sectional study based on the CFS/ME national outcomes database. BMC Health Serv Res 2011, 11:217.

    [10] Interview with Amy Chesterton and Esther Crawley. Available at http://www.thenakedscientists.com/HTML/content/news-archive/news/2384/

    [11] Freedom of Information request http://www.meassociation.org.uk/?p=6171

    [12] Freedom of Information response http://www.meassociation.org.uk/wp-content/uploads/2011/06/FOI from Queen Mary.pdf [3]

    [13] Follow up Freedom of Information request: https://www.whatdotheyknow.com/request/pace_trial_recovery_rates_and_po

    [14] McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. (2012) Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis. PLoS ONE 7: e40808.

    [15] Bleijenberg G, Prins JB, Wiborg JF, Knoop H, Stulemeijer M,. ‘How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity.’ Psychol Med. 2010 Aug;40(8):1281-7.

    [16] PD White, MC Sharpe, T Chalder, JC DeCesare, R Walwyn, for the PACE trial management group: Response to comments on “Protocol for the PACE trial” http://www.biomedcentral.com/1471-2377/7/6/comments#306608

    [17] Crawley E, Collin SM, White PD, Rimes K, Sterne JA, May MT; CFS/ME National Outcomes Database. (2013) Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. QJM. 106:555-65.

    November 13, 2014
  3. kath #

    I had my annual flue jab in 2010 I did not know what hit me….I was so ill and my GP’s made me worse as they would not believe how ill I was and gave me tranquilisers !!!
    I crawled around my home for 2 years,A locum GP came to see me one day when I felt I couldn’t go on any more,he wrote to my GP saying he thought I had M,E ….I was told ” yes it is M.E and you will just have to pull yourself out of it”
    On looking back I realised I had had M.E for 20 yrs and that it had come on very gradually.

    November 14, 2014
  4. Andrew Kewley #

    The problem with CFS/ME research is that there is more talking than doing.

    It is extremely hard to get funding to do high quality research in this field, so it is hard to attract researchers into the field. This necessarily results a deficit of research capacity.

    When we ask medical research bodies such as the NIH (US), MRC (UK) or NHMRC (Au), they claim that the reason why the research funding is so low (a magnitude of order lower than expected from the societal disease burden), is because of lack of high quality applications.

    Yet when high quality applications are made (eg Ian Lipkin’s recent proposed study), they are rejected anyway.

    This is clearly a catch-22 situation.

    Nothing will change until those who are funding research do so in a way that encourages building research capacity for CFS/ME. (For both small scale pilot studies and large scale replications)

    Talking about how the research must improve won’t solve the problem. Building research centres and dedicated channels of funding will.

    I’ll say that again: we need to focus on why high quality research proposals are repeatedly turned down by funding agencies, when similar proposals are being accepted in different fields.

    November 14, 2014
  5. UK CFS/M.E. Research Collaborative is another political move by the promoters of the psychosocial view of ME/CFS to monopolise research funding. It appears to be a response to the success of Invest in ME efforts to establish a biomedical research base in Norwich, which is now up and running. Looking at the careful wording of Holgate’s comments, look at who the sponsors are, look at who was there, but keeping a low profile (PD White), look at the location (Esther Crawley’s home territory). All they are doing is appearing to move on to medical research territory as a way of keeping the power and influence they have while attempting to persuade advocates of the biomedical view that they are coming on board with it. The effect will be to divert MRC funding away from the real medical researchers. Invest in ME held its tenth conference in London in May this year, attracting, as usual, researchers into the medical aspects of ME/CFS from all over the world. Did you hear about it? No? Every year the organisers invite science reporters from the mainstream media to attend, and every year the invitations are ignored. Jeremy Laurence, of The Independent, Ben Goldacre, of The Guardian, both of whom should know better, seem to be in thrall to the Wessely perspective, as, apparently, are other reporters who should be interested in the science of this illness. But the UK CFS/M.E. Research Collaborative is unlikely to be ignored, given its connections.

    November 14, 2014
  6. Jim #

    You’re looking for new ideas? Here’s one:

    QUIT FUNDING PSYCHOBABBLE. START FUNDING BIOLOGICAL RESEARCH. NOW.

    Got it?

    November 15, 2014
  7. T Campbell #

    I have had ME for 30 years after the Epstein Barr Virus gave me Glandular Fever. I diagnosed myself after 8 years of suffering and I told my GP that I thought I might have ME. She referred me to a neurologist who confirmed it.

    This year after more research, on my part, I believed that I may well have Ehlers-Danlos Syndrome (EDS) which is a connective tissue disorder, as I was looking into spinal, joint problems and IBS which I have always had and also Postural Orthostatic Tachycardia Syndrome (PoTS), which has given me BP and HR problems for many years. I sent information to my GP who referred me to a cardiologist and rheumatologist who diagnosed me with both after testing. I scored 7/9 on the Beighton Score for EDS and the tilt table test revealed Neurocardiogenic Syncope and PoTS.

    All of my ME symptoms I can now attribute to EDS and POTS. Both are common conditions but rarely diagnosed and I think many people diagnosed with ME may well have EDS/PoTS.

    November 16, 2014
    • phil #

      but did you have the very severe ME brain fog – bad enough so that you cant read and remember anymore or know what day of the week it is without thinking hard ?

      ME should not be diagnosed without these crippling cognitive symptoms

      there are plenty of illnesses that cause severe fatigue, and plenty that cause
      severe muscular pain, but its having the triplet inc the cognitive symptoms
      ( so bad that you think you have dementia ) that is essential for ME diagnosis
      in my opinion.

      November 17, 2014
  8. Maralyn Hepworth #

    Professor Holgate is re-iterating what those of us who have been involved, even if only as a patient, have known for 20 years. Over that time, there have been many small-scale research projects both in the UK and around the world, that have showed changes in the body. These have been ignored as too small, or not conclusive enough etc. Whilst the PACE trials, which were so badly run, were accepted and acted upon.
    Why not a project to look at all the small- scale research, finding common denominators, and acting on them? Or, shock, horror, doing a large scale, well run research programme on some of the main issues regarding bio-medical malfunctions?

    November 17, 2014
  9. “… CFS/ME field has been marred by a breakdown in trust between patients, clinicians, researchers and funders …” And left a wide breach for quacks to flourish in. Indeed Constant Fatigue Syndrome is probably not “one” disease or rather, there are people who are just constantly “burnt out” due to e.g. marital or working conditions, a bad childhood, an allergy like repetitive hay fever etc. And then there MAY be a “classical” CFS – who knows. And then the average physician has too little time or gets too little funds allotted by health plans to chase a “mirage”. Like with e.g. rheumatic diseases, there should probably be specialized “points of call” where such patients can be referred to instead of leading to a “constant treatment syndrome”.

    November 21, 2014

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