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

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.

[Interdisciplinary, collaborative D-A-CH (Germany, Austria and Switzerland) consensus statement concerning the diagnostic and treatment of myalgic encephalomyelitis/chronic fatigue syndrome]. / Interdisziplinäres, kollaboratives D-A-CH Konsensus-Statement zur Diagnostik und Behandlung von Myalgischer Enzephalomyelitis/Chronischem Fatigue-Syndrom.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe, chronic multisystemic disease which, depending on its severity, can lead to considerable physical and cognitive impairment, loss of ability to work and the need for nursing care including artificial nutrition and, in very severe cases, even death.The aim of this D-A-CH (Germany, Austria, Switzerland) consensus statement is 1) to summarize the current state of knowledge on ME/CFS, 2) to highlight the Canadian Consensus Criteria (CCC) as clinical criteria for diagnostics with a focus on the leading symptom post-exertional malaise (PEM) and 3) to provide an overview of current options and possible future developments, particularly with regard to diagnostics and therapy. The D-A-CH consensus statement is intended to support physicians, therapists and valuer in diagnosing patients with suspected ME/CFS by means of adequate anamnesis and clinical-physical examinations as well as the recommended clinical CCC, using the questionnaires and other examination methods presented. The overview of the two pillars of therapy for ME/CFS, pacing and symptom-relieving therapy options, is intended not only to provide orientation for physicians and therapists, but also to support decision-makers from healthcare policy and insurance companies in determining which therapy options should already be reimbursable by them at this point in time for the indication ME/CFS.

The effect of massage on patients with chronic fatigue syndrome: A systematic review and meta-analysis.

BACKGROUND: Chronic fatigue syndrome (CFS) is a long-term and complex chronic disease that seriously affects the physical and mental health and quality of life of patients. Massage, as one of the methods in traditional Chinese medicine, can treat both symptoms and root causes and is widely used to treat CFS. The main purpose is to systematically evaluate the impact of massage therapy on the efficacy and safety of CFS patients, providing a reference for clinical practice. METHODS: By searching for literature published in PubMed, Cochrane Library, Web of Science, Embase, Wanfang Database, VIP Database, and China National Knowledge Infrastructure Database until November 2023, randomized controlled trial studies were selected according to the established inclusion and exclusion criteria. The Cochrane system evaluation manual was used to evaluate the quality of the included studies, and RevMan5.4 software was used for meta-analysis. RESULTS: 32 randomized controlled trials were included, with a total of 2594 CFS patients. Meta-analysis showed that the total score of the fatigue scale (FS-14) in the treatment group, MD = -1.59, 95% CI (-1.84, -1.34), P < .00001; Physical fatigue score, MD = -1.30, 95% CI (-1.60, -1.00), P < .00001; Mental fatigue score, MD = -0.84, 95% CI (-0.99, -0.72), P < .0001]; Effective rate [RR = 1.23, 95% CI (1.19,1.28), P < .00001]; all indicators were superior to the control group, Only one study reported adverse reactions, including local swelling, skin bruising, and nausea. CONCLUSION: Our research findings suggest that massage therapy has a significant therapeutic effect on CFS, avoiding adverse reactions and improving fatigue symptoms. Therefore, massage therapy for chronic fatigue syndrome should be further promoted and applied.

Comparing effectiveness of physiotherapy versus drug management on fatigue, physical functioning, and episodic disability for myalgic encephalomyelitis in post-COVID-19 condition: a study protocol of randomized control trial.

BACKGROUND: Physiotherapy interventions effectively improved fatigue and physical functioning in non-COVID patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). There is a research gap on the effectiveness of physiotherapy interventions versus drug management on ME/CFS in post-COVID-19 conditions (PCC). METHODS: We planned a three-arm prospective randomized control trial on 135 PCC cases with ME/CFS who are diagnosed between 20 November 2023 and 20 May 2024 from a population-based cohort. The study aims to determine the effectiveness of physiotherapy interventions as adapted physical activity and therapeutic exercise (APTE) provided in institution-based care versus telemedicine compared with drug management (DM). Participants will be assigned to three groups with the concealed location process and block randomization with an enrollment ratio of 1:1:1. The post-treatment evaluation will be employed after 2 months of interventions, and follow-up will be taken after 6 months post-intervention. The Chalder fatigue scale will measure the primary outcome of fatigue. SF-36 and the disability-adjusted life years (DALYs) will measure the secondary outcome of physical functioning and episodic disability. DISCUSSION: This study will address the research gap to determine the appropriate approach of physiotherapy or drug management for ME/CFS in PCC cases. The future direction of the study will contribute to developing evidence-based practice in post-COVID-19 condition rehabilitation. TRIAL REGISTRATION: The trial is registered prospectively from a primary Clinical Trial Registry side of WHO CTRI/2024/01/061987. Registered on 29 January 2024.

Research progress in the treatment of chronic fatigue syndrome through interventions targeting the hypothalamus-pituitary-adrenal axis.

Chronic fatigue syndrome (CFS) causes great harm to individuals and society. Elucidating the pathogenesis of CFS and developing safe and effective treatments are urgently needed. This paper reviews the functional changes in the hypothalamus-pituitary-adrenal (HPA) axis in patients with CFS and the associated neuroendocrine mechanisms. Despite some controversy, the current mainstream research evidence indicates that CFS patients have mild hypocortisolism, weakened daily variation in cortisol, a weakened response to the HPA axis, and an increase in negative feedback of the HPA axis. The relationship between dysfunction of the HPA axis and the typical symptoms of CFS are discussed, and the current treatment methods are reviewed.

IA-PACS-CFS: a double-blinded, randomized, sham-controlled, exploratory trial of immunoadsorption in patients with chronic fatigue syndrome (CFS) including patients with post-acute COVID-19 CFS (PACS-CFS).

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severely debilitating condition which markedly restricts activity and function of affected people. Since the beginning of the COVID-19 pandemic ME/CFS related to post-acute COVID-19 syndrome (PACS) can be diagnosed in a subset of patients presenting with persistent fatigue 6 months after a mostly mild SARS-CoV-2 infection by fulfillment of the Canadian Consensus Criteria (CCC 2003). Induction of autoimmunity after viral infection is a mechanism under intensive investigation. In patients with ME/CFS, autoantibodies against thyreoperoxidase (TPO), beta-adrenergic receptors (ß2AR), and muscarinic acetylcholine receptors (MAR) are frequently found, and there is evidence for effectiveness of immunomodulation with B cell depleting therapy, cyclophosphamide, or intravenous immunoglobulins (IVIG). Preliminary studies on the treatment of ME/CFS patients with immunoadsorption (IA), an apheresis that removes antibodies from plasma, suggest clinical improvement. However, evidence from placebo-controlled trials is currently missing. METHODS: In this double-blinded, randomized, sham-controlled, exploratory trial the therapeutic effect of five cycles of IA every other day in patients with ME/CFS, including patients with post-acute COVID-19 chronic fatigue syndrome (PACS-CFS), will be evaluated using the validated Chalder Fatigue Scale, a patient-reported outcome measurement. A total of 66 patients will be randomized at a 2:1 ratio: 44 patients will receive IA (active treatment group) and 22 patients will receive a sham apheresis (control group). Moreover, safety, tolerability, and the effect of IA on patient-reported outcome parameters, biomarker-related objectives, cognitive outcome measurements, and physical parameters will be assessed. Patients will be hospitalized at the clinical site from day 1 to day 10 to receive five IA treatments and medical visits. Four follow-up visits (including two visits at site and two visits via telephone call) at month 1 (day 30), 2 (day 60), 4 (day 120), and 6 (day 180; EOS, end of study visit) will take place. DISCUSSION: Although ME/CFS including PACS-CFS causes an immense individual, social, and economic burden, we lack efficient therapeutic options. The present study aims to investigate the efficacy of immunoadsorption and to contribute to the etiological understanding and establishment of diagnostic tools for ME/CFS. TRIAL REGISTRATION: Registration Number: NCT05710770 . Registered on 02 February 2023.

Effect of electroacupuncture on behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome. / ç”µé’ˆå¯¹æ ¢æ€§ç–²åŠ³ç»¼åˆå¾å¤§é¼ è¡Œä¸ºå­¦åŠæµ·é©¬ç‚Žæ€§å› å­çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on the changes of behavior and hippocampal inflammatory factors in rats with chronic fatigue syndrome (CFS), so as to explore its possible mechanisms in the treatment of CFS. METHODS: Twenty-seven SD rats were randomly divided into control, model and electroacupuncture (EA) groups (n=9 rats in each group). The CFS model was established by multi-factor compound stress stimulation method. Rats of the EA group received EA (10 Hz) at "Shenting" (GV24) penetrating "Baihui" (GV20), "Dazhui" (GV14) for 15 min, twice a day for 14 days. The general conditions, Morris water maze test, open field test, the exhausted running platform were conducted for determining the rats' locomotor and learning-memory activities. H.E. staining was used to observe the morphological structure of neurons in hippocampal CA1 region. The contents of interleukin (IL)-10, IL-17 and transforming growth factor (TGF) ß1 in hippocampus and serum of rats were detected by ELISA, and the positive expressions of IL-10, IL-17 and TGF-ß1 in hippocampal CA1 region were detected by immunofluorescence staining. RESULTS: Compared with the control group, the score of general condition was increased (P<0.05), the escape latency was prolonged (P<0.05), the number of crossing the original platform was decreased (P<0.05), the numbers of crossing the grid and entering the central area were increased (P<0.05), and the exhaustive treadmill time was shortened (P<0.05) in the model group. The contents of IL-10 in the hippocampus and serum were decreased (P<0.05), while IL-17 and TGF-ß1 contents were increased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was decreased (P<0.05), while the intensity of IL-17 and TGF-ß1 were increased (P<0.05). After treatment, compared with the model group, the score of general condition was decreased (P<0.05), the escape latency was shortened (P<0.05), the number of crossing the original platform was increased (P<0.05), the numbers of crossing the grid and entering the central area were decreased (P<0.05), and the exhaustive treadmill time was prolonged (P<0.05) in the EA group. The contents of IL-10 in the hippocampus and serum were increased (P<0.05), while IL-17 and TGF-ß1 levels were decreased (P<0.05). The immunofluorescence intensity of IL-10 in the hippocampus was increased (P<0.05), while the intensity of IL-17 and TGF-ß1 were decreased (P<0.05). H.E. staining showed that in the model group, the number of neurons in the hippocampus decreased, with disordered arrangement and loose structure, and a small numbers of neuronal nuclei were missing. The degree of tissue damage of the EA group was milder than that of the model group. CONCLUSIONS: EA can alleviate fatigue and spatial learning and memory impairment in CFS rats, which may be related to the regulation of peripheral and central inflammation.

Graded exercise therapy compared to activity management for paediatric chronic fatigue syndrome/myalgic encephalomyelitis: pragmatic randomized controlled trial.

The MAGENTA pragmatic parallel groups randomized controlled trial compared graded exercise therapy (GET) with activity management (AM) in treating paediatric myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). Children aged 8-17 years with mild/moderate ME/CFS and presenting to NHS specialist paediatric services were allocated at random to either individualised flexible treatment focussing on physical activity (GET, 123 participants) or on managing cognitive, school and social activity (AM, 118 participants) delivered by NHS therapists. The primary outcome was the self-reported short-form 36 physical function subscale (SF-36-PFS) after 6 months, with higher scores indicating better functioning. After 6 months, data were available for 201 (83%) participants who received a mean of 3.9 (GET) or 4.6 (AM) treatment sessions. Comparing participants with measured outcomes in their allocated groups, the mean SF-36-PFS score changed from 54.8 (standard deviation 23.7) to 55.7 (23.3) for GET and from 55.5 (23.1) to 57.7 (26.0) for AM giving an adjusted difference in means of -2.02 (95% confidence interval -7.75, 2.70). One hundred thirty-five participants completed the mean SF-36-PFS at 12 months, and whilst further improvement was observed, the difference between the study groups remained consistent with chance. The two study groups showed similar changes on most of the secondary outcome measures: Chalder Fatigue, Hospital Anxiety and Depression Scale: Depression, proportion of full-time school attended, a visual analogue pain scale, participant-rated change and accelerometer measured physical activity, whether at the 6-month or 12-month assessment. There was an isolated finding of some evidence of an improvement in anxiety in those allocated to GET, as measured by the Hospital Anxiety and Depression Scale at 6 months, with the 12-month assessment, and the Spence Children's Anxiety scale being aligned with that finding. There was weak evidence of a greater risk of deterioration with GET (27%) than with AM (17%; p = 0.069). At conventional UK cost per QALY thresholds, the probability that GET is more cost-effective than AM ranged from 18 to 21%. Whilst completion of the SF-36-PFS, Chalder Fatigue Scale and EQ-5D-Y was good at the 6-month assessment point, it was less satisfactory for other measures, and for all measures at the 12-month assessment.  Conclusion: There was no evidence that GET was more effective or cost-effective than AM in this setting, with very limited improvement in either study group evident by the 6-month or 12-month assessment points.  Trial registration: The study protocol was registered at www.isrctn.com (3rd September 2015; ISRCTN 23962803) before the start of enrolment to the initial feasibility phase.

Management of severe ME/CFS in children and young people in the UK: a British Paediatric Surveillance Unit study.

OBJECTIVE: Severe myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) in children and young people (CYP) is a little-understood condition which significantly impacts education, development and quality of life. We used data from a population-wide surveillance study to explore the screening investigation, referral and management of suspected cases of paediatric severe ME/CFS. METHODS: A British Paediatric Surveillance Unit (BPSU) study reported cases of CYP with suspected severe ME/CFS between February 2018 and February 2019. Paediatricians reporting cases to BPSU and allied healthcare professionals in two large specialist paediatric ME/CFS centres were invited to complete questionnaires for CYP meeting the surveillance case definition. The study focused primarily on CYP with confirmed severe ME/CFS and the extent to which their care met NICE (The National Institute for Health and Care Excellence) recommendations but also considered separately those with probable or possible severe ME/CFS. RESULTS: This study includes a total of 92 CYP with suspected severe ME/CFS; 33 meeting criteria for severe ME/CFS and an additional 59 classified as probable or possible severe ME/CFS. For 16 possible cases, incomplete investigation to exclude alternative diagnoses prevented confirmation of a severe ME/CFS diagnosis. Only 21 of 33 (64%) confirmed severe ME/CFS cases had been referred to specialist services. The management provided varied considerably between patients and four received nothing at all. Of the management provided, the most frequent approaches were medication (67%), activity management (61%) and physiotherapy (61%). Domiciliary assessments and support, and social services referrals were received by 12% and 6% of confirmed severe cases. Similar proportions of management approaches were seen in probable/possible severe ME/CFS. CONCLUSION: Full investigation is frequently incomplete in CYP with suspected severe ME/CFS and recommendations for referral and management are poorly implemented, in particular the needs of CYP who are unable to leave their home might be poorly met.

Heat treatment in health and disease: How water-filtered infrared-A (wIRA) irradiation affects key cellular mechanisms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy donors.

Heat treatment or hyperthermia is a promising therapy for many diseases, especially cancer, and can be traced back thousands of years. Despite its long history, little is known about the cellular and molecular effects of heat on human cells. Therefore, we investigated the impact of water-filtered infrared-A (wIRA) irradiation (39 °C, 60 min) on key cellular mechanisms, namely autophagy, mitochondrial function and mRNA expression, in human fibroblasts and peripheral blood mononuclear cells (PBMCs) from healthy donors and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients. Our results show an induction of autophagy in healthy fibroblasts and PBMCs from healthy donors and ME/CFS patients. ME/CFS patients have higher mitochondrial function compared to healthy donors. The wIRA treatment leads to a slight reduction in mitochondrial function in PBMCs from ME/CFS patients, thereby approaching the level of mitochondrial function of healthy donors. Furthermore, an activation of the mRNA expression of the autophagy-related genes MAP1LC3B and SIRT1 as well as for HSPA1, which codes for a heat shock protein, can be observed. These results confirm an impact of heat treatment in human cells on key cellular mechanisms, namely autophagy and mitochondrial function, in health and disease, and provide hope for a potential treatment option for ME/CFS patients.

Disentangling pain and fatigue in chronic fatigue syndrome: a resting state connectivity study before and after cognitive behavioral therapy.

BACKGROUND: Fatigue is a central feature of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), but many ME/CFS patients also report comorbid pain symptoms. It remains unclear whether these symptoms are related to similar or dissociable brain networks. This study used resting-state fMRI to disentangle networks associated with fatigue and pain symptoms in ME/CFS patients, and to link changes in those networks to clinical improvements following cognitive behavioral therapy (CBT). METHODS: Relationships between pain and fatigue symptoms and cortico-cortical connectivity were assessed within ME/CFS patients at baseline (N = 72) and after CBT (N = 33) and waiting list (WL, N = 18) and compared to healthy controls (HC, N = 29). The analyses focused on four networks previously associated with pain and/or fatigue, i.e. the fronto-parietal network (FPN), premotor network (PMN), somatomotor network (SMN), and default mode network (DMN). RESULTS: At baseline, variation in pain and fatigue symptoms related to partially dissociable brain networks. Fatigue was associated with higher SMN-PMN connectivity and lower SMN-DMN connectivity. Pain was associated with lower PMN-DMN connectivity. CBT improved SMN-DMN connectivity, compared to WL. Larger clinical improvements were associated with larger increases in frontal SMN-DMN connectivity. No CBT effects were observed for PMN-DMN or SMN-PMN connectivity. CONCLUSIONS: These results provide insight into the dissociable neural mechanisms underlying fatigue and pain symptoms in ME/CFS and how they are affected by CBT in successfully treated patients. Further investigation of how and in whom behavioral and biomedical treatments affect these networks is warranted to improve and individualize existing or new treatments for ME/CFS.

Nutrition and Chronobiology as Key Components of Multidisciplinary Therapeutic Interventions for Fibromyalgia and Associated Chronic Fatigue Syndrome: A Narrative and Critical Review.

Fibromyalgia (FM) is often accompanied by chronic fatigue syndrome (CFS). It is a poorly understood disorder that mainly affects women and leads to chronic pain, fatigue, and insomnia, among other symptoms, which decrease quality of life. Due to the inefficiency of current pharmacological treatments, increasing interest is being directed towards non-pharmacological multicomponent therapies. However, nutrition and chronobiology are often overlooked when developing multicomponent therapies. This narrative and critical review explore the relevance of nutritional and chronobiological strategies in the therapeutic management of FM and the often-associated CFS. Reviewed literature offers scientific evidence for the association of dietary habits, nutrient levels, body composition, gut microbiota imbalance, chronobiological alterations, and their interrelation with the development and severity of symptoms. This review highlights the key role of nutrition and chronobiology as relevant and indispensable components in a multidisciplinary approach to FM and CFS.

The novel application of the Lightning Process to treat Long COVID in primary care - Case report.

As a result of the COVID-19 pandemic, Long COVID (LC) is now prevalent in many countries. Little evidence exists regarding how this chronic condition should be treated, but guidelines suggest for most people it can be managed symptomatically in primary care. The Lightning Process is a trademarked positive psychology focused self-management programme which has shown to be effective in reducing fatigue and accompanying symptoms in other chronic conditions including Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Here we outline its novel application to two patients with LC who both reported improvements in fatigue and a range of physical and emotional symptoms post-treatment and at 3 months follow-up.

Applying Lessons From Rheumatology to Better Understand Long COVID.

Long COVID can sometimes be attributed to organ damage and well-characterized pathophysiology, but more often there is no evidence of organ damage or abnormal biomarkers. This is most evident in patients with mild to moderate initial SARS-CoV-2 infection who were not hospitalized. Their persistent symptoms are strikingly similar to those of fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome, including fatigue, post-exertional malaise, myalgias/arthralgias, and sleep and cognitive disturbances in 50% to 100% of cases. Analogous pathophysiologic pathways in fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and long COVID include host-microbial interactions in the absence of direct tissue invasion and absence of systemic autoimmunity, with evidence for immune dysregulation as well as autonomic, peripheral, and central nervous system dysfunction. Current treatment of long COVID has been based on multidisciplinary management recommended for FM and ME/CFS and has been formalized and made widely available by funding for nationwide long COVID clinics. Long COVID and its treatment should be distinguished by the presence or absence of organ damage. The acknowledged role of patient engagement in research and open dialogue regarding work and disability noted in long COVID may have meaningful impact on patients with FM and ME/CFS. Hopefully, advances in basic long COVID research will aid in understanding FM and ME/CFS, and rheumatologists should thus be involved in such research and patient care.

Patient perspectives of recovery from myalgic encephalomyelitis/chronic fatigue syndrome: An interpretive description study.

AIMS AND OBJECTIVES: Myalgic encephalomyelitis (ME), also called chronic fatigue syndrome (CFS), is characterised by persistent fatigue, postexertional malaise, and cognitive dysfunction. It is a complex, long-term, and debilitating illness without widely effective treatments. This study describes the treatment choices and experiences of ME/CFS patients who have experienced variable levels of recovery. METHOD: Interpretive description study consisting of semi-structured qualitative interviews with 33 people who met the US Centers for Disease Control (2015) diagnostic criteria for ME/CFS and report recovery or symptom improvement. RESULTS: Twenty-six participants endorsed partial recovery, and seven reported full recovery from ME/CFS. Participants reported expending significant time and energy to identify, implement, and adapt therapeutic interventions, often without the guidance of a medical practitioner. They formulated individualised treatment plans reflecting their understanding of their illness and personal resources. Most fully recovered participants attributed their success to mind-body approaches. CONCLUSION: Patients with ME/CFS describe independently constructing and managing treatment plans, due to a lack of health system support. Stigmatised and dismissive responses from clinicians precipitated disengagement from the medical system and prompted use of other forms of treatment.

Does the effect of cognitive behavior therapy for chronic fatigue syndrome (ME/CFS) vary by patient characteristics? A systematic review and individual patient data meta-analysis.

Debate is ongoing on the efficacy of cognitive behavior therapy (CBT) for myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). With an individual patient data (IPD) meta-analysis we investigated whether the effect of CBT varied by patient characteristics. These included post-exertional malaise (PEM), a central feature of ME/CFS according to many. We searched for randomized controlled trials similar with respect to comparison condition, outcomes and treatment-protocol. Moderation on fatigue severity (Checklist Individual Strength, subscale fatigue severity), functional impairment (Sickness Impact Profile-8) and physical functioning (Short Form-36, subscale physical functioning) was investigated using linear mixed model analyses and interaction tests. PROSPERO (CRD42022358245). Data from eight trials (n = 1298 patients) were pooled. CBT showed beneficial effects on fatigue severity (ß = -11.46, 95% CI -15.13 to -7.79); p < 0.001, functional impairment (ß = -448.40, 95% CI -625.58 to -271.23); p < 0.001; and physical functioning (ß = 9.64, 95% CI 3.30 to 15.98); p < 0.001. The effect of CBT on fatigue severity varied by age (pinteraction = 0.003), functional impairment (pinteraction = 0.045) and physical activity pattern (pinteraction = 0.027). Patients who were younger, reported less functional impairments and had a fluctuating activity pattern benefitted more. The effect on physical functioning varied by self-efficacy (pinteraction = 0.025), with patients with higher self-efficacy benefitting most. No other moderators were found. It can be concluded from this study that CBT for ME/CFS can lead to significant reductions of fatigue, functional impairment, and physical limitations. There is no indication patients meeting different case definitions or reporting additional symptoms benefit less from CBT. Our findings do not support recent guidelines in which evidence from studies not mandating PEM was downgraded.