Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Updated Systematic Evidence Review A DRAFT Systematic Evidence Review prepared for: Centers for Disease Control and Prevention December 7, 2020 Investigators: Roger Chou, MD, FACP Marian McDonagh, Pharm.D. Jessica C. Griffin, MS Sara Grusing, BA Pacific Northwest Evidence-based Practice Center Roger Chou, MD, Director Marian McDonagh, PharmD, Co-Director Copyright © 2020 by Oregon Health & Science University Portland, Oregon 97239. All rights reserved. Structured Abstract Objectives. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can have profound effects on function and quality of life. This report updates a 2014 Agency for Healthcare Research Quality (AHRQ)-funded review in order to synthesize the evidence on evaluation and management of ME/CFS. It also expands upon the prior AHRQ review by including children as well as adults, evaluating harms as well as benefits of diagnosis, and evaluating effects of treatment on depression, anxiety, sleep quality, pain, and other symptoms associated with ME/CFS in addition to fatigue, function, and quality of life. Data Sources. MEDLINE (1988 to January 2019), PsycINFO (1988 to January 2019), Embase (through January 2019) and the Cochrane Library (through January 2019); supplemented by review of reference lists and the 2014 AHRQ review. Review Methods. Articles were selected for review if they included: 1) evaluation of patients with fatigue, 2) diagnosis of ME/CFS, or 3) treatments (pharmacological, nonpharmacological, dietary, or complementary and alternative therapies) of ME/CFS. We abstracted data on the frequency of non-ME/CFS conditions in patients presenting with fatigue; benefits and harms of diagnosis of ME/CFS versus non-diagnosis; and benefits and harms of treatments. Two investigators reviewed abstracts and full-text articles for inclusion based on predefined criteria. Risk of bias was assessed using predefined criteria. Discrepancies were resolved through discussion and consensus, with a third investigator if needed. Random effects meta-analyses were conducted on trials of exercise and cognitive therapy; where evidence was unsuitable for combining, it was synthesized qualitatively. The strength of evidence was assessed using methods recommended by the AHRQ Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Results. We identified 4,951 potentially relevant articles, selected 636 for full-text review, and included 72 studies in 91 publications (1 systematic review and 5 observational studies on diagnosis and 66 trials of treatments). A systematic review of patients with fatigue or tiredness in primary care settings found that the most common non-ME/CFS conditions were depression (18.5%), serious somatic diseases (4.3%), anemia (2.8%), and malignancy (0.6%). In specialty settings of patients referred for evaluation of possible ME/CFS, the most common non-ME/CFS conditions were psychological (15% to 51%) and sleep disorders (6% to 30%). No study evaluated benefits or harms of ME/CFS diagnosis versus non-diagnosis. Sixty-six trials evaluated treatments for ME/CFS. Thirty-three trials were included in the prior AHRQ report and 33 trials were new since the prior report. CBT and exercise therapy were associated with improved fatigue, function, and other outcomes versus inactive control therapies, but the magnitude of effects based on average benefits was small to moderate. These trials demonstrated unexplained statistical heterogeneity in pooled estimates and contained methodological limitations. Additionally, the applicability of findings to patients with severe ME/CFS diagnosed using more current, specific case definitions was uncertain. Other pharmacological, nonpharmacological, dietary, and complementary and alternative therapies were ineffective, or evidence of effectiveness was too limited to guide clinical practice. Reporting of harms across trials was suboptimal, with limited evidence that exercise and CBT were not associated with increased risk of serious adverse events or worsening of symptoms. In Management of ME/CFS DRAFT Systematic Review Pacific Northwest Evidence-based Practice Center ii adolescents with ME/CFS, limited evidence found CBT (family based or involving parents) associated with improved function and school attendance versus inactive therapies, but differences were not statistically significant. Limitations. Treatment trials had methodological limitations. Most interventions and comparisons were evaluated in few trials, most trials used older ME/CFS case definitions, and there was limited information on how key characteristics and subgroups of patients impacted outcomes. There was unexplained statistical heterogeneity in meta-analyses, study inclusion was restricted to English language publications and formal methods for determining small sample effects were not performed due to small numbers of studies. Conclusions. Evidence on effective treatments for ME/CFS remains limited. Although graded exercise and CBT were more effective than inactive control therapies (usual care, usual specialist care, or an attention control) in improving fatigue, function, and other outcomes, the magnitude of effects was small to moderate and methodological and other limitations (imprecision, inconsistency, uncertain generalizability) precluded strong conclusions. Other therapies were not shown to be effective or require additional evidence to verify effectiveness. Non-ME/CFS conditions were common in patients presenting with fatigue. Management of ME/CFS DRAFT Systematic Review Pacific Northwest Evidence-based Practice Center iii Contents Introduction ..................................................................................................................................... 1 Background ..................................................................................................................................... 1 Purpose ............................................................................................................................................ 5 Methods........................................................................................................................................... 5 Topic Development and Refinement .......................................................................................... 5 Data Sources and Searches ......................................................................................................... 6 Process for Study Selection ........................................................................................................ 6 Inclusion criteria ..................................................................................................................... 6 Data Extraction and Data Management ...................................................................................... 7 Risk of Bias of Individual Studies Assessment .......................................................................... 7 Assessing Research Applicability ............................................................................................... 8 Data Synthesis ............................................................................................................................. 8 Grading the Body of Evidence for Each Key Question ............................................................ 10 Peer Review and Public Commentary ...................................................................................... 10 Results ........................................................................................................................................... 11 Results of Literature Searches .................................................................................................. 11 Key Question 1. In patients undergoing evaluation for possible ME/CFS, what is the frequency of non-ME/CFS conditions? .................................................................................... 12 Key Points ................................................................................................................................. 12 Detailed Synthesis ..................................................................................................................... 12 Key Question 2. What are the benefits and harms of diagnosing ME/CFS vs. non-diagnosis? 16 Key Points ................................................................................................................................. 16 Detailed Synthesis ..................................................................................................................... 16 Key Question 3. What are the benefits and harms of therapeutic interventions for patients with ME/CFS and how do they vary by patient subgroups?............................................................. 17 Key Question 3a. Interventions for treating ME/CFS Key Question 3b. Interventions for treating symptoms commonly present in persons with ME/CFS (poor sleep, orthostatic intolerance, pain, fatigue, cognitive problems, depression, multiple chemical sensitivity, gastrointestinal symptoms, urinary symptoms, etc.) ................................................................. 17 Key Points ................................................................................................................................. 17 Exercise Therapy .................................................................................................................