Systematic review of fatigue severity in ME/CFS patients: insights from randomized controlled trials

Abstract Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness medically unexplained, affecting approximately 1% of the global population. Due to the subjective complaint, assessing the exact severity of fatigue is a clinical challenge, thus, this study aimed to produce comprehensive features of fatigue severity in ME/CFS patients. Methods We systematically extracted the data for fatigue levels of participants in randomized controlled trials (RCTs) targeting ME/CFS from PubMed, Cochrane Library, Web of Science, and CINAHL throughout January 31, 2024. We normalized each different measurement to a maximum 100-point scale and performed a meta-analysis to assess fatigue severity by subgroups of age, fatigue domain, intervention, case definition, and assessment tool, respectively. Results Among the total of 497 relevant studies, 60 RCTs finally met our eligibility criteria, which included a total of 7088 ME/CFS patients (males 1815, females 4532, and no information 741). The fatigue severity of the whole 7,088 patients was 77.9 (95% CI 74.7–81.0), showing 77.7 (95% CI 74.3–81.0) from 54 RCTs in 6,706 adults and 79.6 (95% CI 69.8–89.3) from 6 RCTs in 382 adolescents. Regarding the domain of fatigue, ‘cognitive’ (74.2, 95% CI 65.4–83.0) and ‘physical’ fatigue (74.3, 95% CI 68.3–80.3) were a little higher than ‘mental’ fatigue (70.1, 95% CI 64.4–75.8). The ME/CFS participants for non-pharmacological intervention (79.1, 95% CI 75.2–83.0) showed a higher fatigue level than those for pharmacological intervention (75.5, 95% CI 70.0–81.0). The fatigue levels of ME/CFS patients varied according to diagnostic criteria and assessment tools adapted in RCTs, likely from 54.2 by ICC (International Consensus Criteria) to 83.6 by Canadian criteria and 54.2 by MFS (Mental Fatigue Scale) to 88.6 by CIS (Checklist Individual Strength), respectively. Conclusions This systematic review firstly produced comprehensive features of fatigue severity in patients with ME/CFS. Our data will provide insights for clinicians in diagnosis, therapeutic assessment, and patient management, as well as for researchers in fatigue-related investigations.