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Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention WorkshopTreatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome FREE

M.E. Beth Smith, DO; Elizabeth Haney, MD; Marian McDonagh, PharmD; Miranda Pappas, MA; Monica Daeges, BA; Ngoc Wasson, MPH; Rongwei Fu, PhD; and Heidi D. Nelson, MD, MPH
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From Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, and Providence Cancer Center, Providence Health and Services Oregon, Portland, Oregon.

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 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 Working Group; 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. Fu reports funds under contract for the Evidence-based Practice Centers IV Program from Oregon Health & Science University during the conduct of this study. Ms. Daeges reports grants from Agency for Healthcare Research and Quality during the conduct of this study. Dr. Nelson reports grants from Agency for Healthcare Research and Quality during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0114.

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: M.E. Beth Smith, DO, 3181 SW Sam Jackson Park Road, Mail Code BICC, Portland, OR 97239; e-mail, smithbet@ohsu.edu.

Current Author Addresses: Drs. Smith, Haney, McDonagh, Fu, 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: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, H.D. Nelson.

Analysis and interpretation of the data: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, N. Wasson, R. Fu, H.D. Nelson.

Drafting of the article: M.E.B. Smith, M. McDonagh, M. Pappas, N. Wasson, H.D. Nelson.

Critical revision of the article for important intellectual content: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, N. Wasson, R. Fu, H.D. Nelson.

Final approval of the article: M.E.B. Smith, E. Haney, M. McDonagh, M. Pappas, R. Fu, H.D. Nelson.

Provision of study materials or patients: M. Daeges.

Statistical expertise: R. Fu.

Obtaining of funding: M.E.B. Smith, M. McDonagh, H.D. Nelson.

Administrative, technical, or logistic support: M. Pappas, M. Daeges, N. Wasson, H.D. Nelson.

Collection and assembly of data: M.E.B. Smith, E. Haney, M. Pappas, N. Wasson, H.D. Nelson.


Ann Intern Med. 2015;162(12):841-850. doi:10.7326/M15-0114
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Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition affecting more than 1 million adults in the United States.

Purpose: To determine benefits and harms of treatments for adults with ME/CFS and identify future research needs.

Data Sources: MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; reference lists; and manufacturer information.

Study Selection: English-language randomized trials of the effectiveness and adverse effects of ME/CFS treatments.

Data Extraction: Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria; discrepancies were resolved through consensus.

Data Synthesis: Among 35 treatment trials enrolling participants primarily meeting the 1994 Centers for Disease Control and Prevention and Oxford case definitions of CFS, the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence). Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence). Counseling therapies and graded exercise therapy compared with no treatment, relaxation, or support improved fatigue, function, global improvement, and work impairment in some trials; counseling therapies also improved quality of life (low to moderate strength of evidence). Harms were rarely reported across studies (insufficient evidence).

Limitation: Trials were heterogeneous and were limited by size, number, duration, applicability, and methodological quality.

Conclusion: Trials of rintatolimod, counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for other treatments and harms is insufficient. More definitive studies comparing participants meeting different case definitions, including ME, and providing subgroup analysis are needed to fill research gaps.

Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014009779)


Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition characterized by chronic and disabling fatigue and several other symptoms, including pain, sleep disturbance, neurologic and cognitive changes, motor impairment, and altered immune and autonomic responses (13). Experts consider postexertional malaise and memory or concentration problems to be critical components (46), and several diagnostic criteria, including those released by the Institute of Medicine in 2015, require the presence of postexertional malaise (12, 79).

There is uncertainty regarding the cause of ME/CFS, whether it is a pathologically discrete syndrome (2, 4), whether ME should be considered a subset of CFS or its own distinct disease (6), and whether symptoms are nonspecific and shared by other disease entities. Some propose that an inciting event initiates an immune response that leads to immune and neuroendocrine dysregulation (1011). Viral causes have been studied on the basis of the observation that most patients report a sudden onset of symptoms that were preceded by a febrile illness with enlarged lymph nodes. However, no specific virus or other infectious agent has been identified, and not all patients experience a preceding febrile illness (10).

The Centers for Disease Control and Prevention (CDC) reported a 0.3% prevalence of ME/CFS in the United States in 1997, corresponding to more than 1 million adults (12). Through use of different case definitions or different diagnostic methods, the rate may be as high as 3.3% (1314).

Given the multitude of symptoms that patients with ME/CFS experience, treatment approaches have been broad, including immunologic, pharmacologic, and behavioral treatments and complementary and alternative medicine. No medications for the treatment of ME/CFS have been approved by the U.S Food and Drug Administration (FDA); however, many have been used without review and approval (off-label), and some are not approved for any indication in the United States (for example, isoprinosine and rintatolimod). In an FDA survey, patients with ME/CFS identified treatments that fell into 2 broad categories: those intended to treat the cause of the disease and those targeting specific symptoms or perpetuating factors (15). Medications to treat causes include immune modulators, antivirals, and antibiotics. Interventions targeting symptoms include medications to treat specific symptoms, such as pain, fatigue, autonomic dysfunction, and sleep dysfunction, and nondrug therapies, such as yoga, exercise techniques, counseling, pacing strategies, and mental exercises (15). In practice, the clinical management of patients varies widely, and many patients receive a multifaceted approach to treatment.

This systematic review is part of a larger report to inform a research agenda for the National Institutes of Health (NIH) 2014 Pathways to Prevention Workshop, an evidence-based methodology workshop (16). This review evaluates and summarizes research on the benefits and harms of medical and nonmedical treatments for ME/CFS based on trials enrolling patients meeting criteria for ME, CFS, or both and identifies limitations of current studies and needs for future research in this area.

Key questions guiding this review were developed in collaboration with the NIH ME/CFS Working Group following a standard protocol, including input from key informants and a technical expert panel, registration in the PROSPERO database for systematic reviews (17), and posting on an Agency for Healthcare Research and Quality (AHRQ) public Web site. Key questions concern the benefits and harms of therapeutic interventions for adults with ME/CFS, how interventions vary by patient subgroups, and characteristics of patients who respond and do not respond to interventions. A technical report details the methods and includes the analytic framework, search strategies, and additional evidence tables (16).

Data Sources and Searches

A research librarian searched the following electronic databases to identify relevant articles published between January 1988 (year of first case definition) and September 2014: MEDLINE (Ovid), PsycINFO, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and National Health Sciences Economic Evaluation Database. Searches were supplemented by references identified from additional sources, including trial registries, scientific information packets from manufacturers, reference lists, and experts.

Study Selection

We included English-language trials that enrolled patients aged 18 years or older who met the criteria for ME, CFS, or both according to at least 1 established case definition. Included were randomized, controlled trials of at least 12 weeks' duration that compared medications, complementary and alternative medicine approaches, counseling and behavior therapies, and exercise therapies with no treatment or other types of treatment. For completeness, we separately summarized additional trials of medications that were designed for shorter durations of treatment. Treatment outcomes were patient centered and included function, fatigue, quality of life, involvement in daily activities, and harms. We did not include studies of the results of laboratory tests or studies focusing on individual symptoms, such as pain.

Two investigators independently evaluated each study to determine inclusion eligibility. Disagreement was resolved by consensus, with a third investigator making the final decision as needed.

Data Extraction and Quality Assessment

From the included studies, one investigator extracted study details and a second investigator reviewed them for accuracy and completeness. Investigators rated the quality (risk of bias) of the individual studies and strength of the body of evidence on the basis of established criteria (18). The strength of evidence consisted of 4 major categories—high, moderate, low, or insufficient—according to the design, quantity, size, and quality of studies; consistency across studies; precision of estimates; and directness of effect. A second investigator reviewed ratings, and disagreements were resolved by consensus, with a third investigator making the final decision as needed.

Data Synthesis

For most treatments, only single trials were available; data were synthesized qualitatively with attention to such factors as patient characteristics and risk of bias. For treatments with more than 2 trials, the appropriateness of statistical meta-analysis was determined by considering internal validity of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. The combined effects were estimated by using a random-effects model based on the profile likelihood method (19). Combined relative risks were calculated for binary outcomes. For continuous outcomes, the combined weighted mean differences were calculated by using the means and SDs at follow-up from each intervention group. The chi-square test based on the Q statistic and the I2 statistic (the proportion of variation in study estimates due to heterogeneity) were used to assess heterogeneity in effects between studies, and sensitivity analyses explored statistical heterogeneity when present. All quantitative analyses were performed by using Stata/IC software, version 13.0 (Stata Corp.).

Role of the Funding Source

The AHRQ funded the review, and a working group convened by the NIH helped develop the review's scope and key questions. Neither had a role in study selection, quality assessment, or synthesis. The investigators are solely responsible for the content.

Among the 6175 abstracts identified by searches, 35 treatment trials in 45 publications met inclusion criteria (Appendix Figure). These included 9 trials of medications (2028), 7 of complementary and alternative medicine (2935), 14 of counseling or behavioral therapies (8, 3648), 7 of exercise (23, 4854), and 4 comparing or combining different therapies (23, 40, 48, 53) (Appendix Table 1). Most trials met criteria for fair quality (24 trials) or poor quality (5 trials). Trials enrolled predominantly middle-aged women from ME/CFS specialty clinics; used CFS case definitions, primarily the 1994 CDC (3) or Oxford criteria (56), to determine participant eligibility; had small sample sizes (27 trials had <100 participants); and were conducted in the United States and Western Europe (16). Outcomes varied across trials and included 20 unique measures as well as various Likert scales developed for individual studies. Even when trials used the same outcome, measures and thresholds were often defined differently, thereby limiting comparisons and statistical meta-analysis. In general, harms were rarely reported.

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Appendix Figure.

Summary of evidence search and selection.

CAM = complementary and alternative medicine; CBT = cognitive behavioral therapy.

* Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and the 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 may be included in more than 1 published article, and this number indicates the number of unique studies included, representing a total of 45 publications. Studies may have provided data for more than 1 type of treatment.

|| Studies included for the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome are reported in the companion article in this issue (71).

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Table Jump PlaceholderAppendix Table 1. Summary of Trials of Therapies 

Major limitations of trials included enrollment of fewer than 20 participants in a study group (8, 20, 25, 2830), dissimilar groups at baseline (31, 43, 50, 52), high loss to follow-up (23, 26, 29, 37, 54), unclear or lack of intention-to-treat analysis (8, 24, 27, 29, 3435, 3940, 42, 54), no reporting of between-group comparisons for key outcomes (27, 30, 32, 35), unclear randomization process (8, 25, 30, 3536, 3940, 42, 45), and inadequate blinding (8, 23, 25, 29, 32, 3537, 39, 41, 4446, 48, 5052).

Medications

Nine placebo-controlled trials of medications evaluated the effectiveness of rintatolimod (21, 27), valganciclovir (28), galantamine (26), hydrocortisone (22), hydrocortisone plus fludrocortisone (24), IgG (20), isoprinosine (25), and fluoxetine (23). None of these medications are FDA approved for CSF. Eight trials met criteria for fair quality (2024, 2628) and 1 for poor quality (25).

Benefits

Rintatolimod, an investigational intravenous immune modulator and antiviral drug, improved measures of exercise performance compared with placebo in 2 fair-quality trials (n = 324) enrolling severely disabled adults (improved cardiopulmonary exercise test tolerance, 36.5% versus 15.2%, P = 0.047; improved exercise duration, 10.3% versus 2.1%, P = 0.007; improved exercise work, 11.8% versus 5.8%, P = 0.01) (low strength of evidence) (21, 27). The clinical implications of these changes are unclear. One of these 2 trials also reported improvement in measures of function (activities of daily living and Karnofsky Performance Scale score) (21), and the other indicated a reduction in use of other medications to relieve CFS symptoms (27). Attrition ranged from 9% to 19% and adherence, from 83% to 91%. In a small, underpowered trial of valganciclovir that enrolled 30 participants with elevated antibody titers who were suspected of having viral-onset ME/CFS, fatigue was improved in the treatment group compared with the placebo group on the basis of 1 scale, but no statistically significant differences were seen for other measures (28). These trials did not report data for patient subgroups.

Trials of galantamine, hydrocortisone, IgG, isoprinosine, and fluoxetine indicated no beneficial effects but were limited by small numbers of participants. Additional trials enrolling fewer than 30 participants and with durations less than 12 weeks indicated no statistically significant differences compared with placebo for acyclovir (57) and showed improved 36-item Short-Form Survey (SF-36) scores for physical health and function with rituximab (58).

Harms

Differences in total withdrawals, withdrawals due to adverse events, and harms of medications were not reported or did not statistically significantly differ between groups for most medications. Participants taking rintatolimod reported flu-like symptoms, chills, vasodilatation, and dyspnea (27). Galantamine was associated with higher rates of withdrawal and attrition than was placebo, demonstrating a dose-dependent relationship; the highest rates were seen at doses of 15 mg or more per day (26). Overall, 90% of participants in the galantamine trial reported harms, with depression, nausea, and headache most common in both the treatment and placebo groups; 2% experienced serious events, although none was attributed to the study drug (26).

In the 2 corticosteroid trials, attrition rates were 10% (22) and 20% (24). Harms that significantly differed between treatment and placebo groups included suppression of adrenal glucocorticoid responsiveness (34% versus 0%; P < 0.001), increased appetite (48% versus 23%; P = 0.02), weight gain (54% versus 23%; P = 0.006), and difficulty sleeping (48% versus 23%; P = 0.02) (22). Participants taking intravenous IgG (1 g/kg) reported significantly more headaches (93%) than did placebo recipients (60%) (20). Participants taking fluoxetine had more withdrawals from medication-associated adverse events compared with the placebo group (13% versus 3%), although total withdrawals did not differ.

Complementary and Alternative Medicines

Seven trials compared complementary and alternative medicine approaches with usual care, placebo, or another intervention (2935). Five small trials evaluated dietary approaches or supplements, including a low-sugar/low-yeast diet compared with a healthy diet (29), antioxidant extract of pollen versus placebo (30), acclydine (a supplement proposed to increase biologically active insulin-like growth factor) versus placebo (31), formulations of l-carnitine compared with each other (32), and melatonin versus phototherapy or placebo (35). Additional trials evaluated distant healing (33) and homeopathy (34). One trial met criteria for good quality (31, 33), 5 for fair quality (29, 32, 3435), and 1 for poor quality (30).

Benefits

Trials of diets, supplements, or phototherapy indicated no statistically significant differences between treatment and comparison groups. A trial of distant healing that used various techniques of prayer or imagining the transmission of healing energy, light, or power compared with usual care also found no statistically significant differences between groups (33). A trial of homeopathy that used various individualized prescriptions for remedies provided by practitioners versus placebo indicated improved general fatigue for the homeopathy group (Multidimensional Fatigue Inventory, 20-item score, 2.70 versus 1.35; P = 0.04) (34). However, the clinical significance of this small change is not clear, and there were no between-group differences for several other outcomes.

Harms

Patients taking formulations of l-carnitine reported sleeplessness and feeling overstimulated (32). No serious harms were reported in the trial of pollen extract (30).

Counseling and Behavioral Therapies

Fourteen trials in 23 publications evaluated the effectiveness of a counseling or behavioral therapy. Therapies included cognitive behavioral therapy (CBT) intended to change behavioral and belief factors that may trigger and maintain symptoms (3638, 40, 4344, 48, 5961); group or individual counseling wherein participants learned coping and self-sufficiency strategies (8, 45); self-instruction through use of informative booklets with assignments (41, 46, 62); pragmatic rehabilitation that provided strategies to promote a gradual progression of activity (40); and supportive listening providing empathic and nondirective support (47, 6364). These therapies were compared with usual care, wait-list control, no treatment, relaxation techniques, adaptive pacing (avoiding activities demanding >70% of a participant's perceived energy), anaerobic therapy that promoted gradual return of pleasurable activities (40, 47, 6364), graded exercise therapy (GET) (48), or an alternate form of counseling or behavioral therapy. Five trials met criteria for good quality (4448), 6 for fair quality (3638, 4041, 43), and 3 for poor quality (8, 39, 42).

Benefits

The effectiveness of counseling and behavior therapies was inconsistent across trials and outcome measures. In some trials, counseling and behavior therapies improved fatigue (8, 3839, 41, 43, 46, 48, 62), physical function (Figure 1) (38, 4041, 4344, 48), quality of life (42, 45), work impairment (38, 48), and the clinical global impression of change scale (38, 48, 59) (low to moderate strength of evidence). No statistically significant differences between counseling and comparison groups were reported for other outcomes. The trials were too heterogeneous to allow us to determine whether one type of counseling intervention was more effective than another, and a small trial comparing face-to-face versus telephone CBT indicated no differences between these therapeutic approaches (37).

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Figure 1.

Effects of various types of counseling therapies on the SF-36 physical function subscale.

CBT = cognitive behavioral therapy; SF-36 = Short Form-36.

* Therapy intended to change behavioral and belief factors that may trigger and maintain symptoms.

† Compared with all participants in control groups in the trial.

‡ Teaches coping and self-sufficiency strategies.

§ Strategies to promote a gradual progression of activity.

|| Use of informative booklets with assignments.

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A meta-analysis of 4 trials of CBT reporting changes in SF-36 physical function scores indicated no statistically significant difference between intervention and control groups (weighted mean difference, 10.42 [95% CI, −3.86 to 24.69]; I2 = 79.6%, 4 trials) (Figure 2) (39, 42, 47, 56). However, physical function scores were higher for the intervention group when an outlier study (59) was removed in a sensitivity analysis (weighted mean difference, 6.02 [CI, 1.05 to 10.88]; I2 = 0.0%; 3 trials) (47, 5657).

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Figure 2.

Meta-analysis of trials of the effects of CBT on the SF-36 physical function subscale.

CBT = cognitive behavioral therapy; SF-36 = Short Form-36.

* Compared with all participants in control groups in the trial.

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Harms

Three trials reported harms with counseling or behavioral therapies. In the largest trial comparing CBT with adaptive pacing or usual care (PACE [Pacing, graded Activity and Cognitive behaviour therapy: a randomized Evaluation] trial), the therapy group reported significantly fewer serious and nonserious adverse events than the other groups (6% serious events versus 11%; P = 0.03) (48). A trial comparing counseling with a wait-list control group reported no withdrawals due to harms (45), and a trial comparing pragmatic rehabilitation with supportive listening or usual care reported no differences between groups for reported harms or withdrawals due to harms (47).

Exercise Therapies

Seven trials evaluated the effectiveness of exercise therapies. These included GET involving an exercise plan with structured incremental increases in exercise over time (23, 48, 50, 5253), qigong exercise (49, 51), and home orthostatic training (54). Trials compared one form of exercise with another, standard medical care, adaptive pacing, CBT, or placebo. One trial met criteria for good quality (48) and 6 for fair quality (23, 4954).

Benefits

GET improved measures of function (SF-36 physical function weighted mean difference, 10.68 [CI, 6.32 to 16.88]; I2 = 0%; 3 trials) (Figure 3) (48, 50, 52), fatigue (4 trials, n = 619), global improvement as measured by the clinical global impression of change score (relative risk, 1.58 [CI, 1.24 to 2.47]; I2 = 0%; 3 trials) (Figure 4) (48, 50, 52); and work impairment (1 trial, n = 475; low to moderate strength of evidence). The largest trial of GET (PACE trial) showed less deterioration of physical function with GET than with control (25% for adaptive pacing versus 18% for usual care versus 11% for GET; P < 0.001), but there were no statistically significant differences in serious deterioration measured by a composite score (48, 65). No differences between comparison groups were reported in a trial of 314 participants that compared GET with CBT or in a trial of 115 participants that compared CBT plus GET versus usual care (53).

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Figure 3.

Meta-analysis of trials of the effects of graded exercise therapy on the SF-36 physical function subscale.

Graded exercise therapy involved an exercise plan with structured incremental increases in exercise over time, qigong exercise, and home orthostatic training. SF-36 = Short Form-36.

* Compared with all participants in control groups in the trial.

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Figure 4.

Meta-analysis of trials of the effects of graded exercise therapy on the clinical global impression of change scale.

Graded exercise therapy involved an exercise plan with structured incremental increases in exercise over time, qigong exercise, and home orthostatic training.

* Compared with all participants in control groups in the trial.

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A trial enrolling 144 participants in China compared qigong exercise with sham qigong (49, 51). Although some measures of fatigue on the Chalder Fatigue Scale were statistically significantly better with the exercise group, others were not. A trial of 38 patients found no statistically significant differences in measures of fatigue between home orthostatic training compared with usual care or sham orthostatic training (54).

Harms

Harms were poorly reported in exercise trials, and no subgroup analyses were performed. One trial reported small but significantly more serious adverse events (17 exercise versus 7 usual care; P = 0.04) and more nonserious adverse events (992 GET versus 977 usual care versus 949 adaptive pacing versus 848 CBT) in the GET versus comparison groups, although adverse reactions attributed to the intervention were similar between groups (48). In a smaller trial of GET compared with placebo or fluoxetine, total withdrawals were greatest with GET (37% versus 22%) (23). In addition, in a trial of GET, 20% of patients declined to repeat exercise testing because of perceived harm of testing (52). There were no differences in total withdrawals in the other 2 trials of GET (50, 52), and no harms were reported in other exercise trials (51, 54).

Characteristics of Responders and Nonresponders

Four trials suggested that younger patients with less impairment, who are less focused on symptoms, adherent to cognitive therapy programs, and avoid over- and underexertion (that is, they stay within their energy envelope) are more likely to improve in some measures of fatigue and function (36, 40, 52, 60, 63).

Thirty-five trials evaluated the benefits and harms of treatments for adults meeting case definitions primarily for CFS; however, evidence is inconclusive (Appendix Table 2). Limited evidence indicated that rintatolimod improved measures of exercise performance compared with placebo in severely debilitated participants (low strength of evidence). Counseling, behavior therapies, and GET improved measures of fatigue, function, global improvement, and work impairment; counseling and behavior therapies also improved quality of life (low to moderate strength of evidence). Results of all other interventions and outcomes were from small single trials that provided insufficient strength of evidence. Although adverse effects were rarely reported in most trials, counseling and behavior therapies were associated with fewer harms (low strength of evidence) than medications and GET (insufficient evidence).

Table Jump PlaceholderAppendix Table 2. Summary of Evidence by Outcomes for Trials With Statistically Significant Between-Group Differences 

These results are consistent with those of previous systematic reviews (6670). A recent systematic review of trials of exercise for patients with CFS found no evidence suggesting that exercise worsens symptoms (70). However, no trials reported harms for participants meeting case definitions for ME or ME/CSF (48), and it remains unclear how more severely disabled patients respond to exercise therapy. One trial considered participants meeting the London criteria for ME (n = 357 of 640 total) and found similar results for outcomes of fatigue and physical function but did not evaluate harms in this subgroup (48). It is possible that adverse effects of exercise therapy could be avoided by careful selection of patients, and additional research is needed to determine which patients would achieve maximal benefits without incurring harm. Although trials of counseling and behavioral therapies reported mixed results, improvements in multiple outcomes are consistent with outcomes seen with similar therapies for other chronic illnesses (6872).

This systematic review was limited by deficiencies of the trials. Most trials enrolled participants on the basis of case definitions for CFS only. The Oxford CFS case definition is the least restrictive, and its use as entry criteria could have resulted in selection of participants with other fatiguing illnesses or illnesses that resolve spontaneously with time (16, 71). The Institute of Medicine recently released new diagnostic criteria for CFS that require the presence of postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance (7, 72). Participants in previous trials did not meet these requirements. In addition, most treatments were evaluated in single trials designed as pilot studies that enrolled small numbers of participants from specialized clinical centers, and outcomes were assessed by using different methods and outcome measures. Some trials were primarily intended to measure intermediate outcomes, such as natural killer cell–mediated cytotoxicity (25), and most were underpowered for the health outcomes relevant to this systematic review. Although several fatigue and function outcomes were based on validated scales and measures, others were not, and the clinical significance of changes in scores over time is not clear for most of them.

This systematic review included only English-language trials. No trials analyzed results by relevant subgroups or compared treatment responders with nonresponders. We could not assess publication bias because of the limited number of trials for each intervention. Whereas this review focused on outcomes that are universal to all case definitions of patients, such as fatigue and function, a review of other types of outcomes, such as postexertional malaise, would also be useful.

Future research would benefit from using consistent clinical criteria and comparing outcomes according to clinical presentation, such as postexertional malaise, neurocognitive status, and autonomic dysfunction. This approach would identify patient subgroups that may respond differently to specific treatments and could provide greater insight into the underlying causes of ME/CFS. Studies should report adverse effects more consistently and completely to improve identification of patients who may be negatively affected. Similarly, stratification of results by patient characteristics, such as age, sex, race, baseline functional status, and intermediate outcomes, would help determine the applicability of different treatments for specific patients and situations.

Definitive treatment trials require larger numbers of participants based on appropriate power calculations for clinically relevant outcomes to determine efficacy, along with more rigorous adherence to methodologic standards, such as blinding of outcome assessors, intention-to-treat analysis, and strategies to minimize patient loss to follow-up. Future trials should enroll more men and racial and ethnic minorities; broader age ranges; and participants with greater disability, such as homebound patients. Given the fluctuating nature of ME/CFS, follow-up periods longer than 1 year would help determine effectiveness and harms over time. The development of a set of core outcome measures, including patient-centered outcomes (such as quality of life, employment, and time spent in activity), would help guide research and facilitate future analyses. Trial registries and collaborations would help consolidate and standardize data. Reporting more information about concomitant treatments and adherence to treatment would improve the applicability of study findings. Given the devastating effect of this condition on patients and families, researchers should consider involving the patient and advocate voice in trial planning and development so that future research is relevant and meaningful to those affected by ME/CFS.

In conclusion, trials of rintatolimod, counseling therapies, and GET suggested benefits for patients with CFS, providing low to moderate strength of evidence. However, these treatments have not been adequately tested in broader patient populations, particularly those meeting more specific case definitions. Other treatments and harms have been inadequately studied. More definitive studies are needed to fill these research gaps.

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Davenport TE, Stevens SR, VanNess MJ, Snell CR, Little T. Conceptual model for physical therapist management of chronic fatigue syndrome/myalgic encephalomyelitis. Phys Ther. 2010; 90:602-14.
PubMed
CrossRef
 
Jason LA, Brown A, Evans M, Sunnquist M, Newton JL. Contrasting chronic fatigue syndrome versus myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue. 2013; 1:168-183.
PubMed
 
Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Pr; 2015.
 
Jason LA, Roesner N, Porter N, Parenti B, Mortensen J, Till L. Provision of social support to individuals with chronic fatigue syndrome. J Clin Psychol. 2010; 66:249-58.
PubMed
 
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. Accessed at www.actionforme.org.uk/Resources/Action%20for%20ME/Documents/get-informed/national%20task%20force.pdf on 26 March 2015.
 
Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011; 31:325-37.
PubMed
CrossRef
 
Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. 2013; 28:523-40.
PubMed
CrossRef
 
Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003; 163:1530-6.
PubMed
CrossRef
 
Jason LA, Brown A, Clyne E, Bartgis L, Evans M, Brown M. Contrasting case definitions for chronic fatigue syndrome, Myalgic Encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis. Eval Health Prof. 2012; 35:280-304.
PubMed
CrossRef
 
Reeves WC, Jones JF, Maloney E, Heim C, Hoaglin DC, Boneva RS, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007; 5:5.
PubMed
CrossRef
 
Center for Drug Evaluation and Research.  The voice of the patient: a series of reports from the U.S. Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative. Accessed at www.fda.gov/downloads/ForIndustry/UserFees/PrescriptionDrugUserFee/UCM368806.pdf on 11 Februrary 2015.
 
Smith M, Nelson H, Haney E, Pappas M, Daeges M, Wasson N, et al.  Diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome. Evidence Report/Technology Assessment No. 219. (Prepared by the Pacific Northwest Evidence-based Practice Center under contract 290-2012-00014-I.) AHRQ Publication No. 15-E001-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2014. Accessed at http://effectivehealthcare.ahrq.gov/ehc/products/586/2004/chronic-fatigue-report-141209.pdf on 26 March 2015.
 
Smith ME, Nelson N, Haney E, McDonagh M, Pappas M, Daeges M, et al.  Diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Accessed at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42014009779 on 11 February 2015.
 
Owens D, Lohr KN, Atkins D, Treadwell J, Reston J, Bass E, et al. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville, MD: Agency for Healthcare Research and Quality; 2011.
 
Hardy RJ, Thompson SG. A likelihood approach to meta-analysis with random effects. Stat Med. 1996; 15:619-29.
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CrossRef
 
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CrossRef
 
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PubMed
CrossRef
 
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CrossRef
 
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Figures

Grahic Jump Location
Appendix Figure.

Summary of evidence search and selection.

CAM = complementary and alternative medicine; CBT = cognitive behavioral therapy.

* Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment, National Health Sciences Economic Evaluation Database, and the 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 may be included in more than 1 published article, and this number indicates the number of unique studies included, representing a total of 45 publications. Studies may have provided data for more than 1 type of treatment.

|| Studies included for the diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome are reported in the companion article in this issue (71).

Grahic Jump Location
Grahic Jump Location
Figure 1.

Effects of various types of counseling therapies on the SF-36 physical function subscale.

CBT = cognitive behavioral therapy; SF-36 = Short Form-36.

* Therapy intended to change behavioral and belief factors that may trigger and maintain symptoms.

† Compared with all participants in control groups in the trial.

‡ Teaches coping and self-sufficiency strategies.

§ Strategies to promote a gradual progression of activity.

|| Use of informative booklets with assignments.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Meta-analysis of trials of the effects of CBT on the SF-36 physical function subscale.

CBT = cognitive behavioral therapy; SF-36 = Short Form-36.

* Compared with all participants in control groups in the trial.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Meta-analysis of trials of the effects of graded exercise therapy on the SF-36 physical function subscale.

Graded exercise therapy involved an exercise plan with structured incremental increases in exercise over time, qigong exercise, and home orthostatic training. SF-36 = Short Form-36.

* Compared with all participants in control groups in the trial.

Grahic Jump Location
Grahic Jump Location
Figure 4.

Meta-analysis of trials of the effects of graded exercise therapy on the clinical global impression of change scale.

Graded exercise therapy involved an exercise plan with structured incremental increases in exercise over time, qigong exercise, and home orthostatic training.

* Compared with all participants in control groups in the trial.

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table 1. Summary of Trials of Therapies 
Table Jump PlaceholderAppendix Table 2. Summary of Evidence by Outcomes for Trials With Statistically Significant Between-Group Differences 

References

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PubMed
CrossRef
 
Jason LA, Brown A, Evans M, Sunnquist M, Newton JL. Contrasting chronic fatigue syndrome versus myalgic encephalomyelitis/chronic fatigue syndrome. Fatigue. 2013; 1:168-183.
PubMed
 
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Jason LA, Roesner N, Porter N, Parenti B, Mortensen J, Till L. Provision of social support to individuals with chronic fatigue syndrome. J Clin Psychol. 2010; 66:249-58.
PubMed
 
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CrossRef
 
Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. 2013; 28:523-40.
PubMed
CrossRef
 
Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003; 163:1530-6.
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PubMed
CrossRef
 
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Hardy RJ, Thompson SG. A likelihood approach to meta-analysis with random effects. Stat Med. 1996; 15:619-29.
PubMed
CrossRef
 
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PubMed
CrossRef
 
Strayer DR, Carter WA, Brodsky I, Cheney P, Peterson D, Salvato P, et al. A controlled clinical trial with a specifically configured RNA drug, poly(I).poly(C12U), in chronic fatigue syndrome. Clin Infect Dis. 1994; 18 Suppl 1:S88-95.
PubMed
CrossRef
 
McKenzie R, O'Fallon A, Dale J, Demitrack M, Sharma G, Deloria M, et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA. 1998; 280:1061-6.
PubMed
CrossRef
 
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Letters

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Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Posted on June 30, 2015
PD White, MD,1 DJ Clauw, MD,2 JWM van der Meer, MD,3 R Moss-Morris, PhD,4 RR Taylor, PhD,5
1. Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University, London, UK 2. Department of Anesthesiology, Medicine and Psychiatry, University of Michigan
Conflict of Interest: PDW, JWMvdM and RMM were principal investigators or co-investigators in some of the trials reviewed. PDW does consultancy work for the UK government and a re-insurance company.
In their systematic review, Smith and colleagues concluded that “trials of … counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for …. harms is insufficient.”(1)

While we support the general conclusion of benefit with these treatments, we suggest that some aspects of this review may be misinterpreted. Firstly, the most frequently tested behavioural intervention has been cognitive behaviour therapy (CBT), which aims to reduce symptoms and improve functioning, and it would be unusual to consider this as “counseling”, which has different objectives and content. One would not combine different types of medicines in a review; why do this with therapies? A review that combines counselling and CBT simply dilutes the efficacy of CBT, which has been amply demonstrated in several previous meta-analyses (2).

Secondly, there is little evidence of harm caused by graded exercise therapy (GET); a Cochrane systematic review of eight trials of exercise therapy for chronic fatigue syndrome (CFS), published this year, concluded that “..no evidence suggests that exercise therapy may worsen outcomes.” (3) Suggesting evidence of harm by stating that “one trial reported significantly more serious adverse events ….and more nonserious adverse events … in the GET versus comparison groups,…” without mentioning that serious adverse events were independently judged to be unrelated to the intervention, and that the differences between non-serious adverse events was not statistically significant, is a potentially misleading representation of the evidence. Adding that “..in a trial of GET, 20% of patients declined to repeat exercise testing because of perceived harm of testing” encourages further misunderstanding by failing to mention that the exercise testing was not part of the therapy and that the proportion of patients in the control intervention who also declined exercise testing was 50% (4). (Incidentally the proportion declining testing in the GET arm was 44%, not 20%.4) There is a world of difference between the effects of maximum exercise testing and graded exercise therapy. It is important not to overemphasise the harms associated with an effective treatment when there are so few others available.

Finally, the authors concluded that we need trials with analyses of patients meeting different case definitions; we agree and this has already happened. White and colleagues found no statistically significant differences in the efficacy of CBT and GET in sub-groups of those patients meeting Oxford criteria for CFS who also met either CDC defined CFS or myalgic encephalomyelitis (ME)(5).

Note: Seven other CFS clinical scientists supported and approved this letter.

References
1. 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.
2. Castell BD, Kazantzis N, Moss-Morris RE. Cognitive behavioral therapy and graded exercise for chronic fatigue syndrome: A meta-analysis Clin Psychol Sci Prac 2011; 18: 311–24.
3. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD003200.
4. Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol 2005; 10: 245–59.
5. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 2011;377:823-36.

Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Posted on July 9, 2015
Tom Kindlon1, Charles Shepherd2
1. Irish ME/CFS Association, Ireland. 2. ME Association, United Kingdom
Conflict of Interest: TK is Information Officer and a committee member of the Irish ME/CFS Association. All his work for the Association is unpaid. CS is medical adviser to a charity (the ME Association) that collects and publishes patient evidence relating to safety and efficacy of graded exercise therapy and pacing.
We concur with Smith and colleagues that evidence regarding harms for therapies such as graded exercise therapy (GET) for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is insufficient.(1,2) The focus in GET trials for ME/CFS has been on efficacy measures which do not provide good information on whether adverse events occurred.(2) A recently published systematic review included an assessment of the reporting of "treatment side effects" in 16 randomized controlled trials (RCTs).(3) Eleven were allocated the lowest mark with only one, the PACE Trial, awarded the top mark.(3,4) One RCT is generally seen as insufficient to make firm recommendations. Moreover, questions remain about the level of compliance with GET in the PACE Trial: the only reported measure of treatment adequacy was the number of appointments attended, not the type, intensity, or duration of activity/exercise performed each week. If participants dutifully complied with the exercise program one would not expect no improvement in fitness in the GET cohort as has recently been reported.(4) If participants do not take their medication in a trial, reliable information on safety will not be provided; similarly if participants do not adhere to an exercise regime, good information will not be obtained about the safety or otherwise of complying with the intervention. An earlier review of three trials of graded activity-oriented interventions for CFS found that following treatment participants had not actually increased their activity levels (objectively measured using actometers) compared to the controls.(5)

Data from outside of RCTs can be useful to assess the safety or otherwise of interventions.(2) A clinical trial can represent a somewhat artificial environment and so outcomes may not correspond directly to those in routine practice.(2) One of us (TK) previously reviewed the data from eight ME/CFS patient surveys from four countries.(2) Fifty-one percent of survey respondents (range 28-82%, n=4338) reported that GET worsened their health. Such findings, along with the aforementioned poor reporting of harms in trials of GET for ME/CFS and the lack of evidence regarding adherence to the intervention in the trial with better harms reporting, mean we should not rush to accept any claims that GET has been found to be safe for ME/CFS.

References

1. 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.

2. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bull IACFS ME.
2011;19:59-111.

3. Marques MM, De Gucht V, Gouveia MJ, Leal I, Maes S. Differential effects of behavioral interventions with a graded physical activity component in patients suffering from Chronic Fatigue (Syndrome): An updated systematic review and meta-analysis. Clin Psychol Rev.
2015;40:123-137.

4. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry.
2015;2:141–152.

5. Kindlon T. Harms of cognitive behaviour therapy designed to increase activity levels in chronic fatigue syndrome: questions remain. Psychother Psychosom. 2011;80:110-1.
First, do no harm: graded exercise therapy and myalgic encephalomyelitis/ chronic fatigue syndrome
Posted on July 11, 2015
Lily Chu, MD, MSHS (1), Lucinda Bateman, MD (2), Todd Davenport, PT, DPT, OCS (3), Eleanor Stein, MD, FRCP(C) (4), Staci Stevens, MA (5)
(1) Independent Consultant, Burlingame, CA, USA; (2) Bateman Horne Center, Salt Lake City, UT, USA; (3) Department of Physical Therapy, Thomas J. Long School of Pharmacy and Health Sciences,
Conflict of Interest: All authors are involved in ME/CFS research. LB, ES, TD, and SS are involved in the clinical care of ME/CFS patients. LB, SS, and TD were members of the International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis Primer Writing Committee. No funding was received in support of this work.
We concur with Smith et al. (1) that graded exercise therapy (GET) can cause harm in some patients with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). However, we believe the benefits from GET would have been reduced and the harms assessed as even greater if the following points had been considered.

(1) The authors recognized that the non-specific nature of the Oxford criteria might recruit subjects “with other fatiguing illnesses or illnesses that resolve spontaneously” (1) yet they analyzed studies using Oxford criteria with those using Fukuda criteria together. This is similar to lumping people who have congestive heart failure, chronic obstructive pulmonary disease, and pneumonia together because all three diagnoses share shortness of breath as a symptom. It would have been more informative had they assessed trials using Fukuda and Oxford separately and then compared those results to the combined results. Darbishire et al. found that the factor most predictive of a poor outcome when a GET or cognitive behavioral therapy (CBT) regimen was applied to a group of subjects suffering chronic fatigue was fitting Fukuda criteria (2).

(2) Nunez et. al. is classified in Appendix Table 1 as not reporting any harms (1). However, this study found not just that the combined GET/ CBT intervention had no benefit but that these treatments caused a significant decline in physical function and increase in bodily pain scores as measured by the SF-36 at 12 months.

(3) Smith et al. appropriately suggest that future research should strive to include the input of patients and advocates. Because their review was based on clinical trials, however, it did not include clinician and patient experiences outside of trials. On average, 50% of thousands of patients internationally have reported worsened health due to treatments involving exercise (3). Clinicians specializing in ME/CFS do not recommend GET and instead advise patients to balance their active periods with rest breaks (4). This cautious attitude is supported by studies (5) showing that patients with ME/CFS do not respond to or recover from physical activity in the same way as healthy people or people with other medical conditions.

As with any medical condition, clinicians need to tailor treatments to the individual patient. If patients describe exacerbation of symptoms and no improvement with exercise-related therapies, rather than attributing those reports to low motivation, distorted thinking, or exaggeration, clinicians should consider that there is a problem and stop the treatment.

(1) Smith MB, 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;162:841-850. doi:10.7326/M15-0114

(2) Darbishire L, Seed P, Risdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005; 186 (4) 350-351.


(3) Kindlon T. Reporting of harms associated with graded exercise therapy and cognitive behavioral therapy in myalgic encephalomyelitis/ chronic fatigue syndrome [Internet]. Chicago, Illinois: International Association for Chronic Fatigue Syndrome/ Myalgic Encepahlomyelitis; 2011 October [cited 2015 July 8]. Available from: http://iacfsme.org/PDFS/Reporting-of-Harms-Associated-with-GET-and-CBT-in.aspx

(4) International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis Primer Writing Committee. ME/CFS: a primer for clinical practitioners [Internet]. Chicago, IL: International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis; 2014 July [cited 2015 July 8]. Available from: http://iacfsme.org/portals/0/pdf/Primer_Post_2014_conference.pdf

(5) Institute of Medicine: Committee on the Diagnostic Criteria for myalgic encephalomyelitis/ chronic fatigue syndrome. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness [Internet]. Washington, DC: National Academies Press; 2015 Feb [cited 2015 July 8]. Available from: http://iom.nationalacademies.org/Reports/2015/ME-CFS.aspx
Diagnostic sub-group analyses in the PACE trial may be unreliable
Posted on July 13, 2015
Alem Matthees
N/A
Conflict of Interest: None Declared
In their comment on this article [1], White et al. state that "White and colleagues found no statistically significant differences in the efficacy of CBT and GET in sub-groups of those patients meeting Oxford criteria for CFS who also met either CDC defined CFS or myalgic encephalomyelitis (ME)".

However, the ad-hoc application of these case definitions in the PACE trial (pacetrial.org) may undermine the reliability of those sub-group analyses. All trial participants were first screened using the Oxford CFS criteria and then further stratified into sub-groups meeting modified versions of CDC CFS criteria and London ME criteria:

a) The Oxford criteria is not entirely compatible with other case definitions, as it uniquely requires that fatigue is the dominant symptom [2][3], and the medical assessments in the trial may have excluded clinical characteristics of ME which are allowed in other case definitions.

b) The trial only counted additional CFS symptoms (including postexertional malaise) over the previous week instead of six months as required by the CDC criteria. [3] Evans & Jason studied different recall time frames for each of the eight additional CDC symptoms and reported that the optimal time frame for reliable reporting was six months for postexertional malaise, unrefreshing sleep, memory/concentration difficulties, muscle pain, headaches, lymph node pain, and sore throat, with one month for joint pain. [4] The authors concluded that researchers interested in the assessment of CFS symptoms should take recall time frame into account.

c) While the modified version of the rarely used London ME criteria requires postexertional fatigue or fatiguability, it does not require postexertional malaise or the fluctuation of other significant symptoms usually worsened or precipitated by either physical or mental exercise, which the original version stipulated was "absolutely characteristic" (see meassociation.org.uk). Goudsmit, one of the authors of the original London ME criteria, has publicly rejected the version used in the trial as flawed, incomplete, and non-representative. [5]

In conclusion, none of the diagnostic criteria as applied in that trial adequately measured or required post-exertional symptomatology. The Institute of Medicine recently released new diagnostic criteria for CFS that require postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance; the IOM noted that participants in therapy trials have not meet these requirements, and called for the retirement of the obsolete Oxford criteria as it can result in the "selection of participants with other fatiguing illnesses or illnesses that resolve spontaneously". [1]

References

1. Smith ME, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, Fu R, Nelson HD. Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015 Jun 16;162(12):841-50. PMID: 26075755. http://annals.org/article.aspx?articleid=2322801

2. Sharpe MC, Archard LC, Banatvala JE, Borysiewicz LK, Clare AW, David A, Edwards RH, Hawton KE, Lambert HP, Lane RJ, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med. 1991 Feb;84(2):118-21. PMID: 1999813. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107

3. White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. 2013 Oct;43(10):2227-35. PMID 23363640. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285

4. Evans M, Jason LA. Effects of Time Frame on the Recall Reliability of CFS Symptoms. Eval Health Prof. 2013 Sep 23. [Epub ahead of print] PMID: 24064428. http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24064428

5. Ellen Goudsmit on PubMed Commons: http://www.ncbi.nlm.nih.gov/myncbi/ellen m.goudsmit.1/comments
Response to White et al.
Posted on July 13, 2015
SBM Kirby
None.
Conflict of Interest: None Declared
I would like to make two points in response to White et al.[1]

Firstly, counselling, with its more modest non-curative goal of helping patients adapt to limitations imposed by chronic disease and disability, does not posit a primary etiological role for cognitive behavioural factors. Whereas the cognitive behavioural model for chronic fatigue syndrome (CFS) does posit such a role, and hence claims curative potential by modifying those factors via cognitive behavioural therapy (CBT).[2]

There are no clinical trials directly comparing counselling and CBT for CFS, but there are two for chronic fatigue, a defining symptom of CFS. Ridsdale et al (2001) reported “equivalent” therapeutic outcomes for counselling and CBT, with the authors suggesting that the choice between the two approaches depends on non-therapeutic factors like cost and accessibility. [3] Ridsdale et al (2012) found no difference between counselling, graded exercise therapy (GET), and usual care plus a CBT booklet.[4] Smith et al were also unable to distinguish between counselling and CBT for efficacy.[5]

These results, plus the low-moderate effect sizes of CBT and GET for CFS, the predominantly subjective self-report basis of those effects and their general discordance with the more objective outcome measures (particularly for CBT), and the principle of parsimony, all question the value of assuming a primary etiological role for cognitive behavioural factors in CFS.[2,5]

Secondly, if CFS patients are already operating at or near maximum physical capacity, then they may not find a “world of difference between the effects of maximum exercise testing and graded exercise therapy.“[1] In clinical trials patients may be, of necessity, substituting formal exercise therapy for other activities without increasing their overall fitness or physical activity. Alternatively, patients may not be adhering to the therapy protocol, and not accurately reporting that fact. Both possibilities could also affect harms reporting.


References
1. White et al response to Smith et al (Reference 5).
2. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, et al.
Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.
The Lancet 2011;377:823-36.
3. Leone Ridsdale, Emma Godfrey, Trudie Chalder, Paul Seed, Michael King, Paul Wallace, Simon Wessely and the Fatigue Trialists’ Group
Chronic fatigue in general practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial
British Journal of General Practice, 2001, 51, 19-24.
4. L. Ridsdale, M. Hurley, M. King, P. McCrone1 and N. Donaldson
The effect of counselling, graded exercise and usual care for people with chronic fatigue in primary care: a randomized trial
Psychological Medicine (2012), 42, 2217–2224.
5. 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.
Graded Exercise Therapy for ME/CFS: ineffective at best, harmful in reality
Posted on July 21, 2015
Miak Speedy, MD
Family Physician
Conflict of Interest: None Declared
Smith et al. concluded that “trials of ... counseling therapies, and graded exercise therapy suggest benefit for some ... whereas evidence for …. harms is insufficient.”(1)

As a doctor, bedridden with ME for over a decade and totally dependent on others, all thanks to a major relapse caused by Graded Exercise Therapy (GET), I'm in a unique position to answer how harmful GET and CBT really are. The basis of GET and CBT is false illness beliefs, meaning it is all in the mind, ignoring all the evidence, for example intracellular immune dysfunctions, which not only restrict exercise capacity, but are also made worse by exercise [2], that this is a physical disease.

ME's main characteristic is an abnormally delayed muscle recovery after doing trivial things, not chronic fatigue, and GET and CBT force you to ignore your symptoms to exercise your way back to full fitness. If you do that, you go over your limit, causing a relapse, and the more you go over your limit, the bigger the relapse and the less likely you are to recover from it.
Many ME patients have been made homebound/bedridden, the result of a major relapse caused by GET and we will only get our health/independence back if we get proper medication.

The Norwegian Rituximab studies suggest that ME is an autoimmune disease and 2/3 of responders are still in remission at the 36-month follow-up. [3] The ME Association recently published a big study, concluding there's no role for CBT, which increases the risk of making things worse, and GET is harmful and should be withdrawn immediately. [4]

Falk Hvidberg et al. recently found that ME/CFS patients have the lowest health-related quality of life of 21 conditions looked at, which included chronic renal failure, strokes, lung cancer etc. [5]

In reality, only two sorts of ME patients can do graded exercise therapy. A small minority where the disease is in remission, and "ME" patients were the diagnosis is wrong.
In all other ME patients, GET causes severe relapses and BREACHES the do no harm principle of medicine.

The alarming findings by Falk Hvidberg et al. [5] show that CBT and GET, tried by most ME patients, are not effective, and that there is an urgent need for effective medication for this debilitating disease, so that we get our health and independence back, can come off benefits and go back to work.

References:
1. 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.

2. Nijs J, Nees A, Paul L, DeKooning M, Ickmans K, Meeus M, et al.
Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. 2014;20:94-116.

3. Fluge Ø, Risa K, Lunde S, Alme K, Rekeland IG, Sapkota D, et al. (2015) B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment. PLoS ONE 10(7): e0129898. doi:10.1371/journal.pone.0129898

4. ME Association, Our CBT, GET and Pacing Report calls for major changes to therapies offered for ME/CFS, 29 May 2015, http://www.meassociation.org.uk/2015/05/23959/
(accessed 18 July 2015)

5. Falk Hvidberg M, Brinth LS, Olesen AV, Petersen KD, Ehlers L (2015) The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS ONE 10(7): e0132421. doi:10.1371/journal.pone.0132421
Treatment of Myalgic Encephalomyelitis/Chronic Fatigue syndrome: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop
Posted on July 30, 2015
M.E. Beth Smith†, DO; Elizabeth Haney†, MD; Heidi D. Nelson†¶, MD, MPH
†Pacific Northwest Evidence-based practice Center, Oregon Health & Science University and ¶Providence Cancer Center, Providence Health and Services Oregon, Portland, Oregon
Conflict of Interest: None Declared
We thank the authors for their comments and Dr. Speedy for sharing his personal experience. Regarding Dr. White’s comments about the harms of exercise, we acknowledge that exercise testing is distinct from graded exercise programs. However, both forms of exercise may be considered harmful by patients. To clarify the results of the Moss-Morris trial, while 44% of participants in the intervention group declined repeat exercise testing, 20% declined because of their perception of harm.1 Also, although the Cochrane review did not identify harms of exercise, the authors drew similar conclusions to ours stating that, “limited information makes it difficult to draw firm conclusions about the safety of exercise therapy.” 2
To address Dr. Chu’s comment about safety data in the Nunez trial, we agree that a decline in physical function and pain were reported in the intervention group. However, the trial reported within-group differences, not between-group differences,3 which are necessary to support results of comparisons of interventions in the trial.
Dr. Chu’s comment regarding the importance of analyzing data based on case definitions used for inclusion to trials is consistent with our approach. For example, in the trials of cognitive behavioral therapy (CBT) using the SF-36 physical function item as an outcome measure, the two studies using Oxford criteria indicated improvement, while the two using CDC criteria reported no improvement.4 We also agree with Dr. White’s comment that combining counseling and CBT trials in a meta-analysis may dilute the effectiveness of each individually, which is why our meta-analysis included only trials of CBT.
The studies referenced by Drs. Chu and Kirby, regarding the effectiveness of CBT and graded exercise therapy (GET) and predictors of outcomes, were excluded from our analysis because they included participants with chronic fatigue rather than ME/CFS.5,6 Of the fatigued participants, 31% met criteria for CFS (CDC Fukuda). Although CFS participants had more fatigue and functional impairment compared to other participants, no case definitions were compared and outcomes for the CFS participants based on intervention were not evaluated.
(1) Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol 2005; 10: 245–59.
(2) Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews 2015, Issue 2. Art. No.: CD003200.
(3) Nunez M, Ferna´ndez-Sola J, Nunez E, Ferna´ndez-Huerta JM, Godas-Sieso T, Gomez-Gil E. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011;30:381-9.
(4) 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;162:841-850. doi:10.7326/M15-0114
(5) L. Ridsdale, M. Hurley, M. King, P. McCrone1 and N. Donaldson
The effect of counselling, graded exercise and usual care for people with chronic fatigue in primary care: a randomized trial
Psychological Medicine (2012), 42, 2217–2224.
(6) Darbishire L, Seed P, Risdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005; 186 (4) 350-351
Between-group difference in Nunez et al. trial/ differences in outcomes from GET depending on symptoms
Posted on December 15, 2015
Lily Chu, MD, MSHS
Independent consultant, Burlingame, CA
Conflict of Interest: I am involved in ME/CFS research.
I thank Smith et al. for replying to my prior letter. I am writing again to clarify two points.

1) In their paper, Nunez et al. (1) analyzed both within-group and between-group differences. At trial initiation, intervention and control groups started out with similar SF-36 pain scores (27.09±24.22 vs. 27.41±19.04). Under the heading of “Between-group differences,” the researchers wrote, “At 12-months, SF-36 pain dimension scores were significantly lower in the intervention group [ME/CFS patients who received graded exercise therapy (GET) and cognitive behavioral therapy (CBT)] (21.81±21.43 vs. 29.34±21.58 [control group], p=0.040).” For the SF-36, a lower score denotes a decreased level of function. In the discussion section they reiterated this point, writing, “Between-group analysis showed that the intervention group had worse SF-36 bodily pain dimension scores at 12 months.”

2) In an accompanying paper (3) to the one I previously cited (2), Risdale et al. showed, in subgroup analysis, that among a group of chronically fatigued subjects assigned to graded exercise therapy, those fitting Fukuda criteria were much less likely to recover by the end of the trial compared to those who did not (19% vs. 65%). The symptom criteria for entry into their study was fatigue as “a main or important problem” for at least 3 months.(2) I bring up these two papers because they show the wide differences in outcomes from GET depending on what symptoms are present in a patient.

Although Risdale et al. did not directly compare subjects fitting Oxford criteria with those fitting Fukuda criteria, their studies’ results suggest that patients fitting Oxford criteria, which require no other symptoms except chronic fatigue, might respond differently to GET than those fitting Fukuda criteria, which requires at least 4 other specific symptoms besides chronic fatigue. Thus, combining trials of GET using Oxford criteria with those using Fukuda criteria could lead to inaccurate conclusions.

References:

(1) Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta JM, Godás-Sieso T. Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. Clin Rheumatol. 2011 Mar;30(3):381-9.

(2) Darbishire L, Seed P, Risdale L. Predictors of outcome following treatment for chronic fatigue. Br J Psychiatry. 2005; 186 (4) 350-351.

(3) Ridsdale L, Darbishire L, Seed PT. Is graded exercise better than cognitive behaviour therapy for fatigue? A UK randomized trial in primary care. Psychol Med. 2004 Jan;34(1):37-49.

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