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

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 (1, 2, 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 (10, 11). 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% (13, 14). 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. Methods 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 categorieshigh, moderate, low, or insufficientaccording 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 I 2 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. Results 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. 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). Appendix 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, 5