Elizabeth Haney, MD; M.E. Beth Smith, DO; Marian McDonagh, PharmD; Miranda Pappas, MA; Monica Daeges, BA; Ngoc Wasson, MPH; Heidi D. Nelson, MD, MPH
Disclaimer: The findings and conclusions in this document are those of the authors, who are responsible for its content, and do not necessarily represent the views of the Agency for Healthcare Research and Quality (AHRQ). No statement in this report should be construed as an official position of AHRQ or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank the following individuals for their contributions to this project: Richard Bryant, MD, for providing expert consultation throughout the report; Andrew Hamilton, MLS, MS, for conducting literature searches; and Spencer Dandy, BS, for assistance with preparing this report (all are located at the Oregon Health & Science University). They also thank Suchitra Iyer, PhD, Task Order Officer at the Agency for Healthcare Research and Quality; Carmen Green, MD, National Institutes of Health (NIH) Working Group Chair; the NIH; the Technical Expert Panel; and reviewers of the draft report.
Financial Support: By the Agency for Healthcare Research and Quality (contract 290-2012-00014-i, task order 4), Rockville, Maryland.
Disclosures: Dr. Haney reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Ms. Daeges reports grants from the Agency for Healthcare Research and Quality during the conduct of this study. Authors not named here have disclosed no conflicts of interest. Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0443.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Elizabeth Haney, MD, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Haney, Smith, McDonagh, and Nelson; Ms. Pappas; Ms. Daeges; and Ms. Wasson: 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239.
Author Contributions: Conception and design: E. Haney, M.E.B. Smith, M. McDonagh, H.D. Nelson.
Analysis and interpretation of the data: E. Haney, M.E.B. Smith, M. McDonagh, M. Pappas, N. Wasson, H.D. Nelson.
Drafting of the article: E. Haney, M.E.B. Smith, M. McDonagh, M. Pappas, H.D. Nelson.
Critical revision of the article for important intellectual content: E. Haney, M.E.B. Smith, M. McDonagh, H.D. Nelson.
Final approval of the article: E. Haney, M.E.B. Smith, M. McDonagh, M. Pappas, N. Wasson, H.D. Nelson.
Obtaining of funding: M.E.B. Smith, M. McDonagh, H.D. Nelson.
Administrative, technical, or logistic support: M. Pappas, N. Wasson.
Collection and assembly of data: E. Haney, M.E.B. Smith, M. Pappas, N. Wasson, H.D. Nelson.
The diagnosis of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is based on clinical criteria, yet there has been no consensus regarding which set of criteria best identifies patients with the condition. The Institute of Medicine has recently proposed a new case definition and diagnostic algorithm.
To review methods to diagnose ME/CFS in adults and identify research gaps and needs for future research.
MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; and reference lists.
English-language studies describing methods of diagnosis of ME/CFS and their accuracy.
Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria, and discrepancies were resolved through consensus.
Forty-four studies met inclusion criteria. Eight case definitions have been used to define ME/CFS; a ninth, recently proposed by the Institute of Medicine, includes principal elements of previous definitions. Patients meeting criteria for ME represent a more symptomatic subset of the broader ME/CFS population. Scales rating self-reported symptoms differentiate patients with ME/CFS from healthy controls under study conditions but have not been evaluated in clinically undiagnosed patients to determine validity and generalizability.
Studies were heterogeneous and were limited by size, number, applicability, and methodological quality. Most methods were tested in highly selected patient populations.
Nine sets of clinical criteria are available to define ME/CFS, yet none of the current diagnostic methods have been adequately tested to identify patients with ME/CFS when diagnostic uncertainty exists. More definitive studies in broader populations are needed to address these research gaps.
Agency for Healthcare Research and Quality. (PROSPERO: CRD42014009779)
Summary of evidence search and selection.
* Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and Cochrane Database of Systematic Reviews.
† Identified from such sources as reference lists, hand searches, and suggestions by experts.
‡ Studies that provided data and contributed to the body of evidence were considered "included."
§ Studies included for the treatment key questions are reported elsewhere (13).
|| The Institute of Medicine case definition (9) is an additional case definition, which was released subsequent to the search.
Table. Comparisons of Symptoms Using Different Case Definitions
Appendix Table 1. Included Studies of Methods Used to Diagnose Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Appendix Table 2. Included Studies Evaluating the Concordance of Different Diagnostic Criteria and Comparisons Between Populations
Appendix Table 3. Included Studies of Harms of Diagnosis
Appendix Table 4. Measures Used as Diagnostic Tests for ME/CFS
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Ellen M Goudsmit, PhD
June 21, 2015
Information on ME and Post Viral Fatigue Syndrome might mislead
As someone who has studied myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) since the 1980s, I appreciate the work completed by The National Institutes of Health Pathways to Prevention Workshops on what is now known as ME/CFS. Unfortunately, some of the information in the two reviews is inaccurate, incomplete and misleading (1,2). For example, in the report on diagnostic methods, the reviewers included the London criteria for ME but gave details in the table based on a version written by a layperson, rather than the four individuals cited in their reference (3). Moreover, they did not consider the updated criteria for ME (4), although one of the authors had emailed the panel on two separate occasions during the consultation phase to alert them to their existence.
The second review (2) encourages further research on subgroups and outcomes other than fatigue and function but did not identify one of the few controlled studies which had employed such a design (5). For instance, in the Appendix, Table 1 lists the programme evaluated by Goudsmit and colleagues under ‘counseling and behavioural therapies’, and describes the treatment as ‘counseling’. It also states that patients were selected using the Oxford criteria, that the duration of follow-up was six months and that the outcomes were function and fatigue.
In fact, the trial evaluated a physician-led multi-component programme comprising medical care, information on the illness, diet and relaxation, as well as advice on activity management and some counselling (5). It was conducted in the naturalistic setting of an NHS hospital clinic, patients were diagnosed using criteria for post-viral fatigue syndrome as well as the Oxford criteria, and data were available for a number of symptoms including cognitive impairment, as well as other variables. Fatigue improved as noted in the review but the latter did not convey that 82% of the patients rated themselves as ‘better’, that 23% were well enough to be discharged at six months and that the improvements were maintained at 1 year. Given the missing details, the study’s rating as ‘poor’ is understandable.
The reviewers concluded that “more definitive studies comparing participants meeting different case definitions, including ME... are needed to fill research gaps”. It was therefore disappointing that they did not recognise the positive aspects of a study that used a different case definition and assessed a range of symptoms, not just fatigue.
1. Haney E, Smith MEB, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Diagnostic methods for myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162: 834-40. [PMID: 26075754] doi:10.7326/M15-0443
2. Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162:841-
50. [PMID: 26075755] doi:10.7326/M15-0114
3. Dowsett E, Goudsmit E, Macintyre A, Shepherd C. London Criteria for myalgic encephalomyelitis. In: Report from The National Task Force on Chronic Fatigue Syndrome (CFS), Post Viral Fatigue Syndrome (PVFS), Myalgic Encephalomyelitis (ME). Westcare. 1994. 96-98. Available from: http://www.actionforme.org.uk/Resources/Action%20for%20ME/Documents/get-informed/national%20task%20force.pdf
4. Goudsmit E, Shepherd C, Dancy CP, Howes S. ME: Chronic fatigue syndrome or a distinct clinical entity? Health Psychol Update. 2009;18(1):26-33. Available from:
5. Goudsmit EM, Ho-Yen DO, Dancey CP. Learning to cope with chronic illness. Efficacy of a multi-component treatment for people with chronic fatigue syndrome. Patient Educ Couns. 2009;77:231–6. [PMID: 19576714 ] doi:10.1016/j.pec.2009.05.015
Ellen M Goudsmit PhD FBPsS
James Webster, MD, MS, MACP
Feinberg School of Medicine of Northwestern University
July 6, 2015
As recommended by Haney et. al. (1) the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is best made using nine sets of "inadequately tested" clinical criteria. These are quite non-specific symptoms and there are no associated positive laboratory findings. Thus it is not surprising that most physicians have problems with the diagnosis much less with the difficult diffuse treatment approaches (2) for this entity. In a large, but admittedly convenience, sample of patients with the symptoms outlined (1) for ME/CFS the experience was that the overlap with the diagnosis of major depression and persistent (formerly dysphoric) depressive disorder (DSM V, 300.4) was huge. For these illnesses there are diagnostic criteria and proven effective therapies which were used to benefit a number of these latter patients. The differential diagnosis of ME/CFS and depressive disorders is difficult, but not impossible (3). The patients with the symptoms of depression and ME/CFS do indeed have real illnesses (4), but to ignore clear psychiatric possibilities and aspects, including the potential for a therapeutic trial, does them a great disservice.1. Haney E, Smith MEB, McDonagh M, et al. Diagnostic methods for myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review for a national institutes of health pathways to prevention workshop. Ann Intern Med. 2015:162:834-840.2. Smith MEB, Haney E, McDonagh M, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome. A systematic review for a national institutes of health pathways to prevention workshop. Ann Intern Med. 2015;162:841-850.3. Hawk C, Jason LA, Torres-Harding S. Int J Behav Med. 2006;13:244-514. Komaroff AL. Myalgic encephalomyelitis/chronic fatigue syndrome: A real illness. Ann Intern Med. 2015;162:871-872.
M.E. Beth Smith, DO, MCR, Marian McDonagh, PharmD
Oregon Health & Science University
February 23, 2016
In Response: We thank Dr. Goudsmit for her comments. She indicated that we had not identified her study but in fact it was identified and reviewed. Eligible outcomes were reported. We considered studies that recruited participants who fulfilled one of the case definitions for CFS, ME, or ME/CFS. Although her study may have considered additional criteria, it met our inclusion based on use of the Oxford criteria. Our review considered interventions in the categories of medications, complementary and alternative treatments, counseling and behavioral therapies, and exercise. Her study was considered in the category of counseling and behavioral therapies. The types of interventions in this category were broad and varied. We elected to categorize these as cognitive behavioral therapy (CBT), counseling including learning coping and self-sufficiency strategies, pragmatic rehabilitation, and supportive listening. The intervention in her study was multifactorial and included elements of CBT, education, and medical care. The lack of formalized CBT did not allow us to compare it to other interventions in that category, and the psycho-educative approach seemed more aligned with other studies in the counseling category.When calling for additional outcomes in future research, we are referring to outcomes universal to the patient population such as post-exertional malaise and harms of interventions rather than individual symptoms such as pain, anxiety, depression. Standardized criteria are used to evaluate each study’s risk of bias or quality as outlined in the appendix. The design of Dr. Goudsmit’s study (pre-post) placed it at high risk of bias, which was reflected in its quality rating.
EM Goudsmit PHD FBPsS
Formerly Visiting Research fellow UEL, UK.
February 25, 2016
A matter of confusion and disappointment
I wish to thank Dr Smith and her colleagues for responding to my letter written in June 2015. Unfortunately, the delay seems to have confused the writers and consequently, they did not deal with the issues I raised. My old eyes may be deceiving me but my copy of the response seems to suggest that I had complained that my study had not been included. From my original comment: " ... in the Appendix, Table 1 lists the programme evaluated by Goudsmit and colleagues under ‘counseling and behavioural therapies’, and describes the treatment as ‘counseling’. It also states that patients were selected using the Oxford criteria, that the duration of follow-up was six months and that the outcomes were function and fatigue." What I focused on were the factual errors relating to the ME research criteria (London criteria of 1993 and 2009). The team reviewed the criteria published in the Westcare report, which, despite the references, were not authored by me or any other scientist she cited. NB If you click on the pdf for those criteria, you will not find any authors listed and it's a mystery why I was linked to what I and others consider was nonsense. The latest ME criteria (2009) which the team overlooked, are not. Re quality. Pre-2000, many studies used alternative criteria for post-viral fatigue syndrome, and the trial I described was one of these. I would have given the study a brownie point for using sound criteria to select a more homogenous sample. And I would also have acknowledged the external validity because it was conducted in a hospital setting, as opposed to a well resourced research clinic. As for the 'pre-post' comment, I'd note that all evaluations of interventions I'm aware of are 'pre-post', so I am mystified at the comment that "The design of Dr. Goudsmit’s study (pre-post) placed it at high risk of bias, which was reflected in its quality rating." The point missed is that a significant number in the Goudsmit et al trial were well enough to be discharged at six months (i.e. after one and a half hours clinic attendance). Isn't that what physicians want to know? Good outcomes in the real world?I see many refer to ME/CFS but they do not know that the ME stands for. And how it differs from CFS. 'Malaise' is a vague lay term for something subjective and difficult to measure. It's why it has been criticised and is being dropped by specialists (in favour of PENE etc, as described in the article). The 2009 ME criteria provides an objective measure to assess criterion 1, which takes some of the guesswork out of diagnosis. I find it strange that none of the authors were interested. Finally, to focus on fatigue and post-exertional malaise is a little like a cancer study which assesses the primary tumour and tiredness and ignores the secondaries and nausea. There's more to ME/CFS than fatigue and malaise. I am so disappointed, both with the original paper and the response. Good science depends on precision to detail. It's the least that we, and patients, deserve.
Haney E, Smith MB, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Diagnostic Methods for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015;162:834–840. doi: 10.7326/M15-0443
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Published: Ann Intern Med. 2015;162(12):834-840.
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