October 29, 2021

expert reaction to updated NICE guideline on diagnosis and management of ME/CFS

The National Institute for Health and Care Excellence (NICE) has published its updated guideline on the diagnosis and management of myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS).

Mrs Caroline Kingdon, Research Fellow, Research Nurse and UK ME/CFS Biobank Lead, London School of Hygiene & Tropical Medicine, and member of the NICE committee for this guideline, said:

“The new NICE guideline will positively influence the future diagnosis and treatment of people with ME/CFS in the UK and beyond.  It aims to improve the understanding and awareness of the disease and when to suspect it, so that people are diagnosed earlier and receive better care and symptom management.  Importantly, the guideline recognises that ME/CFS can cause profound, long-term illness and disability, and that people with ME/CFS may have experienced prejudice, disbelief and stigma.  While treatments that could cause further harm to people with ME/CFS have been removed, CBT continues to be recommended as an adjunct therapy – as in any chronic illness.  Those profoundly affected by ME/CFS and their carers will welcome the emphasis on the provision of individualised care by a multidisciplinary team.  The guideline promises to treat people with ME/CFS with compassion, ensuring that the care they receive is safe and of the highest standard, and is delivered appropriately according to the needs of the individual.”

Prof Trudie Chalder, Professor of Cognitive Behavioural Psychotherapy, Institute of Psychiatry Psychology & Neuroscience (IoPPN), King’s College London, said:

“The NICE guidelines for CFS/ME are at odds with the research evidence.  Researchers from different Institutions in different countries have found graded exercise therapy and cognitive behaviour therapy to be effective for some patients with CFS.  Evidence has shown they reduce fatigue and improve functioning without harm, if delivered by trained therapists in specialist clinics.  Being a clinician and researcher in this field I can’t help but think clinicians will be confused by this message from a respected organisation.”

Prof Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“Given the considerable numbers of people who suffer from ME/CFS themselves, who in many cases are very seriously affected for very long periods of time, and also their families, friends and colleagues who are indirectly affected, it’s very good to see that this NICE guideline has eventually appeared.  It’s concerning that there has been so much unclarity for so long about the condition and how it should be managed, and I just hope that the new guideline will lead to more consensus and more progress.

“Although there was a previous NICE guideline on this, dating back to 2007, this new one has had to change quite a lot.  One change is in the name of the condition – the previous guideline called it CFS/ME, and the name has changed in this one to ME/CFS – I know that names do matter.  I’ll comment on just a few aspects, mostly to do with the process of producing the guideline.  NICE have a very detailed set of procedures for producing guidelines like this.  Although any such process must, to some extent, involve human judgement, the NICE procedure requires a lot of documentation on the evaluation of the evidence behind the guideline to be published.  In this case there are 10 separate documents of evidence reviews, amounting to over 2,600 pages in all.  (Needless to say, given the timescales, I have not had time to read every word.)  But the openness on their evidence evaluations is important.

“One area that the NICE guideline committee reviewed was, essentially, the identification and diagnosis of ME/CFS.  They looked at previous published criteria for diagnosing the condition, nine of them, and decided that seven had what they called “Very serious limitations” and the other two, including the criteria defined in the 2007 NICE guideline, had “Serious limitations”.  So the new guideline contains new diagnostic criteria.  Importantly, though, they do refer to these new criteria in the section of the guideline on recommendations for more research; they say, “In people with suspected ME/CFS, how effective is the NICE 2021 consensus-based diagnostic criteria in identifying people with ME/CFS?”  I think it’s right that they want more research into whether their new criteria are working, given what they say about the limitations of previous criteria.

“What are now perceived to have been problems with previous criteria have had a clear impact on their analysis of evidence for and against various interventions intended to help people deal with the symptoms of ME/CFS.  One of the problems with those criteria (though certainly not the only one) was that some of them did not require a person to have post-exertional malaise (PEM) in order to be diagnosed with ME/CFS.  The guideline defines PEM as: “The worsening of symptoms that can follow minimal cognitive, physical, emotional or social activity, or activity that could previously be tolerated. Symptoms can typically worsen 12 to 48 hours after activity and last for days or even weeks, sometimes leading to a relapse.”  It’s important in clinical research investigating interventions or treatments that there’s a clear definition of who can be included in a trial or other study as a person with the disease or condition of interest.  Many previous trials used a definition of ME/CFS that did not require the trial participants to have PEM, so that on the new NICE diagnostic criteria (and on some other sets of criteria), these studies could have included people who did not have ME/CFS because they did not report post-exertional malaise.  This means that some awkward decisions had to be made on the value of evidence from those studies.  As in almost every trial of a new intervention or treatment, there will be some people who benefit, and others who do not benefit.  If a trial included people who didn’t actually have ME/CFS, maybe those who benefitted mostly did not have the condition after all, so that the results can’t tell us enough about what actually works in patients that do have ME/CFS.

“The NICE committee used what’s now a standard method, also used in many other contexts than their own work, for putting together and evaluating evidence from several studies, the so-called GRADE approach.  This requires a systematic evaluation of the evidence, using standard criteria, though inevitably it can’t take out all the subjectivity.  It does end up rating the evidence on specific aspects on a scale that has only four points, labelled Good, Moderate, Low and Very low.  That doesn’t mean that the people evaluating the evidence take account only of this scale, but it is generally an important part of the consideration.

“For most of the process of reviewing the evidence for the guideline, if a study or trial used diagnostic criteria that didn’t insist on PEM, the NICE committee downgraded the quality of its evidence by one point, on the grounds on ‘indirectness’.  This means that the study doesn’t provide direct evidence on how effective its intervention is, because the results relate to people who might not in fact have had ME/CFS on the new criteria.  Most of the relevant evidence is assessed in the evidence reviews on non-pharmaceutical management of ME/CFS, which are in Evidence Reviews G and H (all 1,230 pages of them).  This includes 95 pages of tables of evidence summaries, including GRADE assessments (several on each page).  None of them is “Good”; almost all are “Low” or “Very low”, which isn’t only because of the issue of PEM not being in the diagnostic criteria used, but that does play a very important role in these assessments.  (There are two rated as “Moderate”, based on a single study evaluating a programme of  self-management, but in fact that study found no evidence that the programme was different in effectiveness from the usual care that people would have got anyway.)

“Actually the fact that there are 95 pages of tables is itself pointing to a different issue with previous research on ME/CFS.  Each of the GRADE evaluations refers to a particular comparison, usually between people receiving different interventions or treatments or involving different measures of the health outcomes involved.  Generally in reviews of this sort you’d expect to see that a number of different studies had contributed to a particular comparison – but in these pages of tables, the vast majority of the comparisons are based on just a single study.  In other words, there’s been no shortage of research, but different studies have looked at different management approaches and measured their outcomes in different ways, which makes it hard to see the overall picture.  That has led to another important recommendation, in the new guideline, for further research, on a core set of measures of health outcomes than can be used for trials of treatments for ME/CFS or of managing the symptoms of ME/CFS.  If a core set is produced and agreed, that should make it very much clearer to assess what works and what doesn’t.

“There was concern that the downgrading of so many studies, because they used diagnostic rules that didn’t insist on PEM and so might have included people who did not actually have ME/CFS on the new consensus criteria, may have meant that some relevant evidence was being ignored in producing the new guideline.  After all, if, in a study that had been downgraded for using the wrong criteria, actually most of the participants did in fact have PEM, the study could still be providing relevant information that should be taken more seriously.  This concern led the NICE committee to carry out a late re-analysis of the evidence.  (This is in Appendix G of Evidence Review H, if you really want to look.)  The committee agreed that a study should not be downgraded “if a high proportion of study participants had PEM and this was adequately described.”  They decided on specific rules to determine which studies should not, after all, be downgraded.  In fact they decided that this re-evaluation did not make any different to their assessments of most of the interventions that they considered.  It did make some differences of detail to their assessment of Graded Exercise Therapy (GET), which has always been controversial for a range of reasons.  However, all the studies that had previously been downgraded because of the diagnostic criteria were still downgraded, and the NICE committee did not change its overall view about GET.  One could argue about the detailed criteria that were used to reconsider the downgrading, but I’m not sure how much difference that would in the end have made.

“The new guideline, therefore, recommends that Graded Exercise Therapy (GET) should not be offered to people with ME/CFS.  However, there are again important issues of the meaning of words here, which seem to have led to confusion in the past.  The guideline points out that “Graded exercise therapy is a term used in varying ways by different services supporting people with ME/CFS.”  It then defines what it means by GET, as involving fixed increases in the time spent being physically active.  That isn’t the same as an individualised approach to a physical exercise or exercise programme, overseen by therapists experienced in ME/CFS, and which makes flexible adjustments in the amount of exercise rather than fixed increases.  Perhaps that approach would have also been called GET by some services in the past.  But the new guideline makes it clear that such a programme might be appropriate and isn’t included in the recommendation against GET, as long as it’s done properly and flexibly, and with a clear understanding between therapist and patient of what it might achieve and what it can’t achieve.  In particular, physical activity or exercise programmes must not be offered as something that can cure ME/CFS.  Maybe a key point is that an exercise programme that isn’t GET, according to the definition in the new guideline, must definitely not be called GET.  As I said before, names do matter.

“Of course, it would be really good news if there were a cure, of whatever sort, but the new guideline makes it very clear indeed that “ME/CFS symptoms can be managed but there is currently no cure (non-pharmacological or pharmacological) for ME/CFS”.”

Dr Karl Morten, Principle Investigator at the Nuffield Department of Women’s & Reproductive Health (NDWRH), University of Oxford, said:

“This is a transformative step for treatments offered to ME/CFS patients in the UK.  I am hopeful that the move away from graded exercise to supporting patients in  how they manage their daily activities will lead to more patients entering a recovery phase.  It is important that the appropriate support from clinicians and healthcare professionals be put in place and this a key component of  the new guidelines.”

Prof Peter White, Emeritus Professor of Psychological Medicine, Queen Mary University of London (QMUL), said:

“Having looked after many patients with this illness, I worry that this guideline seems to suggest that patients need to learn to live with CFS/ME, rather than be helped to recover from it.  NICE have banned graded exercise therapy, in spite of it being found to be helpful in a major Cochrane systematic review, while recommending an energy management programme, which involves “staying within your energy limits”, for which there is little evidence for it helping, and some evidence that it doesn’t.”

Dr David Strain, Senior Clinical Lecturer, University of Exeter, said:

“The publication of these guidelines will be welcomed by health care providers and people with lived experience of ME and/or CFS alike.

“For people with lived experience, it highlights the importance of post exertional malaise in the diagnostic criteria.  This differentiates chronic fatigue due to other causes from those with the specific myalgic encephalomyelitis (ME) syndrome.  It also absolutely clarifies that Graded Exercise Therapy, with fixed incremental escalation of activity is not an appropriate treatment for people with ME, indeed for many people does harm.  This is in keeping with last year’s report by Baroness Cumberledge, emphasising the need to listen to people with lived experience when producing guidelines and treatment pathways.

“For many health care providers, the clarity that their patient-centred approach to activity management was indeed the appropriate strategy, indeed is now recommended by NICE.  It has moved the role of Cognitive behavioural therapy (CBT) from a potential treatment to an essential component for helping people live with their condition, and helping them to cope with, effectively, a bereavement response to the components of their life that is missed due to this disease.  This may be time that they never have with their children, partners or parents, or indeed to cope with the family that this disease prevents them from having.

“Most importantly, the documents highlights the significant deficits in an evidence base in ME diagnosis, treatments and support for patients.  We hope that this acknowledgment heralds the advent of a research program, aligned with the excellent research program that the NIHR have put into the related condition, long Covid, with the intention of finding appropriate treatments for the ¼ million people living with this disease in the UK.”

Prof Chris Ponting, Principal Investigator at the MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, said:

“The new NICE guidelines will improve the lives of people with ME worldwide, well beyond England and Wales.  They will improve awareness that graded exercise often makes ME symptoms worse.  NICE took due care and attention developing these guidelines, applying their rigorous methods and listening to highly regarded professionals and lay people.  Low and very low quality scientific evidence was rightly discarded.  Graded exercise therapy and cognitive behavioural therapy cannot now be offered as cures.  The new guidelines vindicate the longstanding views of many people with ME, their carers and families.”

Dr Alastair Miller, Consultant Physician in Infectious Disease and Internal Medicine, said:

“It is unfortunate that NICE continue to misrepresent GET as “fixed incremental increases in physical activity or exercise” whereas in practice, the approach in most CFSME clinics has always been to tailor increasing activity to individual’s needs and requirements in line with their current recommendations in section 1.11.  It is also unfortunate that they say that exercise/activity cannot be regarded as a “cure” for CFSME and yet they accept that it may relieve symptoms.  There is no such thing as asymptomatic CFSME therefore if you have no symptoms you have no disease.  It is unfortunate that so much emphasis is given to working “within current energy limits” rather than a gentle and controlled pushing of those limits.  However, it is to be welcomed that clinics will still be able to provide appropriate personalised activity and exercise programmes for those patients in whom it is felt to be appropriate.”

NICE Guideline: ‘Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management’ by was published at 00:01 UK time on Friday 29 October 2021.

Declared interests

Mrs Caroline Kingdon: “Member of this NICE committee.”

Prof Trudie Chalder: “Prof Chalder is a principal investigator on the PACE trial.  Prof Chalder is an author of self-help books on CFS.  Prof Chalder has conducted workshops on CBT for CFS for which she has received payment.

“I am the director of the persistent physical symptom service at South London and Maudsley NHS trust.  I recently published papers on patient reported outcomes related to CBT and GET.”

Prof Kevin McConway: “I am a Trustee of the SMC and a member of its Advisory Committee.  My quote above is in my capacity as an independent professional statistician.”

Dr Karl Morten: “No conflicts of interest.”

Prof Peter White: “Professor White undertook three trials of graded exercise therapy and other therapies, is a member of the Independent Medical Experts Group, which advises the MoD about its Armed Forces Compensation Scheme, and is a paid consultant for a re-insurance company.”

Dr David Strain: “I am medical advisor to Action for ME. Clinical Lead for COVID services RD&E. Academic and Co-clinical lead for Department of Healthcare for Older People. Chair of BMA Medical Academics Staff Committee. BMA UK Council and Board of Science. University of Exeter Medical School.”

Prof Chris Ponting: “Prof Chris Ponting is an Investigator on the DecodeME genetics study and supervises a PhD student funded by the Chief Scientist Office (Scotland) and Action for ME.”

Dr Alastair Miller: “Alastair Miller is an Infectious Disease Consultant Physician who was Clinical Lead at the Royal Liverpool University Hospital CFS service from 2006-2014.  He was Principal Medical Adviser for Action for ME from 2010 till 2016 and chaired the British Association for CFS and ME (BACME) 2013 till 2016 (having previously been deputy chair from 2010).  He acted as a reviewer of serious adverse events on the PACE trial and was a member of the trial steering committee for the GETSET trial.”