ME Association June Summary of ME/CFS Published Research | 05 July 2019

July 5, 2019

Charlotte Stephens, Research Correspondent, ME Association.

ME Association Index of Published ME/CFS Research

The Index of Published ME/CFS Research has now been updated to take account of the research that has been published during the month of June 2019.

The Index is a useful way to locate and then read all relevant research on ME/CFS. It’s free to download and comes with an interactive contents table.

This is an A-Z list of all the most important ME/CFS research studies (and selected key documents and articles), listed by subject matter and author, with links to PubMed or the relevant Journal.

You can also find the index in the Research section of the website together with all the summary reviews that have been published.

ME/CFS research abstracts from studies published in June 2019

1. Ballantine R, et al. (2019)
Gravity-induced exercise intervention in an individual with chronic fatigue syndrome/myalgic encephalomyeltis and postural tachycardia syndrome: a case report.
International Journal of Therapy and Rehabilitation 26 (5).

Chronic fatigue syndrome/myalgic encephalomyeltis is a condition of complex nature, characterised by unexplained disabling fatigue and a combination of non-specific accompanying symptoms. Individuals with chronic fatigue syndrome/myalgic encephalomyeltis frequently present with debilitating orthostatic symptoms, which may fall under the umbrella of postural tachycardia syndrome. Postural tachycardia syndrome is underpinned by autonomic nervous system dysfunction.

The gravitational deconditioning that occurs in those severely affected by chronic fatigue syndrome/myalgic encephalomyeltis alongside postural tachycardia syndrome has been suggested as a key focus for interventions in this group. This case report documents the evaluation and rationale behind a novel gravity-induced exercise intervention to improve the symptoms of a 44-year-old female severely affected by chronic fatigue syndrome/myalgic encephalomyeltis and postural tachycardia syndrome, who had been bedbound for 10–15 years.

An exercise intervention was designed to challenge and therefore improve key areas of autonomic nervous system regulation in the presence of gravity. It contained seven different exercises conducted once a month in a class over a 6-month period. Fatigue impact score, activity levels and heart rate upon standing, as detected by an active stand test, improved during the exercise intervention and at follow up.

Gravity-induced exercise intervention can have a positive effect on an individual severely affected by Chronic fatigue syndrome/myalgic encephalomyeltis alongside postural tachycardia syndrome.

2. Bohne V and Bohne O (2019)
Suggested Pathology of Systemic Exertion Intolerance Disease: Impairment of the E3Subunit or Crossover of Swinging Arms of the E2 Subunit of the Pyruvate Dehydrogenase Complex Decreases Regeneration of Cofactor Dihydrolipoic Acid of the E2 Subunit.
Medical Hypothesis [Epub ahead of print]

Systemic Exertion Intolerance Disease (SEID) or myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) has an unknown aetiology, with no known treatment and a prevalence of approximately 22 million individuals (2%) in Western countries. Although strongly suspected, the role of lactate in pathology is unknown, nor has the nature of the two most central symptoms of the condition – post exertional malaise and fatigue.

The proposed mechanism of action of pyruvate dehydrogenase complex (PDC) plays a central role in maintaining energy production with cofactors alpha-lipoic acid (LA) and its counterpart dihydrolipoic acid (DHLA), its regeneration suggested as the new rate limiting factor. Decreased DHLA regeneration due to impairment of the E3 subunit or crossover of the swinging arms of the E2 subunit of PDC have been suggested as a cause of ME/CFS/SEID resulting in instantaneous fluctuations in lactate levels and instantaneous offset of the DHLA/LA ratio and defining the condition as an LA deficiency with chronic instantaneous hyperlactataemia with explicit stratification of symptoms.

While instantaneous hyperlactataemia has been suggested to account for the PEM, the fatigue was explained by the downregulated throughput of pyruvate and consequently lower production of ATP with the residual enzymatic efficacy of the E3 subunit or crossover of the E2 as a proposed explanation of the fatigue severity.

Functional diagnostics and visualization of instantaneous elevations of lactate and DHLA has been suggested. Novel treatment strategies have been implicated to compensate for chronic PDC impairment and hyperlactataemia.

This hypothesis potentially influences the current understanding and treatment methods for any type of hyperlactataemia, fatigue, ME/CFS/SEID, and conditions associated with PDC impairment.

3. Castro-Marrero J et al. (2019)
Unemployment and work disability in individuals with chronic fatigue syndrome/myalgic encephalomyelitis: a community-based cross-sectional study from Spain.
BMC Public Health 19: 840.

Background: Few reports have examined the association between unemployment and work disability in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). This study explored the key determinants of work disability in a CFS/ME cohort.

Methods: A community-based prospective study included 1086 CFS/ME patients aged 18–65 years. Demographic and clinical characteristics and outcome measures were recorded. Multiple linear regression analysis was performed to identify key risk indicators of work disability.

Results: Four hundred and fifty patients with CFS/ME were employed (41.4%) and 636 were unemployed (58.6%). Older age at pain onset (OR: 1.44; 95% CI: 1. 12–1.84, autonomic dysfunction (OR: 2.21; 95% CI: 1.71–2.87), neurological symptom (OR: 1.66; 95% CI: 1. 30–2.13) and higher scores for fatigue (OR: 2.61; 95% CI: 2.01–3.39), pain (OR: 2.09; 95% CI: 1.47–2.97), depression (OR: 1.98; 95% CI: 1. 20–3.26), psychopathology (OR: 1.98; 95% CI: 1.51–2.61) and sleep dysfunction (OR: 1.47; 95% CI: 1. 14–1.90) were all associated with a higher risk of work disability due to illness.

Conclusions: Using an explanatory approach, our findings suggest that unemployment is consistently associated with an increased risk of work disability due to CFS/ME, although further more rigorous research is now needed to help in targeting interventions at the workplace.

4. Dibnah B et al. (2019)
Investigating the role of TGF-B and fatigue in Chronic Fatigue Syndrome.
Annals of the Rheumatic Diseases 78 (2).

Background: Chronic fatigue syndrome (CFS) is estimated to affect up to 5% of people in Europe and is more common in women than men. It is characterised by unexplained fatigue, post-exertional malaise and a range of other symptoms. Recent studies indicate potential immune dysfunction in CFS, specifically regarding cytokines and the adaptive behavioural response.

Objectives: This study aims to investigate serum transforming growth factor-beta (TGF-β) and the expression of the TGF-β Receptor 1 (TGFBR1) and TGF-β Receptor 2 (TGFBR2) genes, in relation to the fatigue associated with CFS.

Methods: Serum active and total TGF-β concentrations were measured in 117 CFS patients and 40 HCs using a TGF-β responsive luciferase bioassay. Expression levels of TGFBR1 and TGFBR2 were analysed using quantitative PCR. Fatigue was measured using the fatigue impact scale (FIS)1. FIS was categorised into three groups; ‘mild’ (0-80), ‘moderate’ (81-120) and ‘severe’ (121-160). Linear and ordinal regressions were performed on the continuous FIS and FIS categories respectively.

Results: Serum TGF-β concentrations in the CFS group did not differ significantly compared with the HC group (p=0.58). TGF-β concentrations showed no correlation with disease duration but there was a trend towards decreased TGF-β with increasing symptom duration. There were no significant differences between the levels of TGFBR1 and TGFBR2 in any of the fatigue groups, or between HCs. Active TGF-β concentrations were significantly elevated in the ‘severe’ FIS group compared to the ‘mild’ FIS group (p=0.04). Active/total TGF-β levels were significantly higher in the ‘severe’ FIS group than the ‘mild’ and ‘moderate’ FIS groups (p=0.02, p=0.03 respectively).

Conclusion: These data suggest no differences in serum concentrations of TGF-β or expression of TGFBR1 and TGFBR2, between the HC and CFS groups. It also suggests no differences in expression levels of TGFBR1/2 between any of the CFS fatigue groups. However, active/total TGF-β levels were increased in more severely fatigued patients based on FIS. This finding could be due to higher levels of circulating TGF-β, or increased amounts of TGF-β activation. Further work is necessary to confirm this finding in a larger cohort of CFS patients, and to explore how this increase in TGF-β relates to fatigue.

5. Garner R and Baraniuk J (2019)
Orthostatic intolerance in chronic fatigue syndrome.
Journal of Translational Medicine 17: 185.

Background: Orthostatic intolerance (OI) is a significant problem for those with chronic fatigue syndrome (CFS). We aimed to characterize orthostatic intolerance in CFS and to study the effects of exercise on OI.

Methods: CFS (n = 39) and control (n = 25) subjects had recumbent and standing symptoms assessed using the 20-point, anchored, ordinal Gracely Box Scale before and after submaximal exercise. The change in heart rate (ΔHR ≥ 30 bpm) identified Postural Orthostatic Tachycardia Syndrome (POTS) before and after exercise, and the transient, exercise-induced postural tachycardia Stress Test Activated Reversible Tachycardia (START) phenotype only after exercise.

Results: Dizziness and lightheadedness were found in 41% of recumbent CFS subjects and in 72% of standing CFS subjects. Orthostatic tachycardia did not account for OI symptoms in CFS. ROC analysis with a threshold ≥ 2/20 on the Gracely Box Scale stratified CFS subjects into three groups: No OI (symptoms < 2), Postural OI (only standing symptoms ≥ 2), and Persistent OI (recumbent and standing symptoms ≥ 2).

Conclusions: Dizziness and Lightheadedness symptoms while recumbent are an underreported finding in CFS and should be measured when doing a clinical evaluation to diagnose orthostatic intolerance. POTS was found in 6 and START was found in 10 CFS subjects. Persistent OI had symptoms while recumbent and standing, highest symptom severity, and lability in symptoms after exercise.

6. Groven N et al. (2019)
Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls.
Brain, Behaviour and Immunity [Epub ahead of print]

Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are both chronic disorders that have a devastating effect on the lives of the affected patients and their families. Both conditions have overlapping clinical features that partly resemble those of inflammatory disorders. The etiology is still not understood, and it is suggested that the immune system might be a contributing factor. So far, the results are inconclusive.

The purpose of this study was to compare the two conditions and investigate the level of the inflammatory marker high-sensitivity CRP (hsCRP) in CFS and FM patients compared to healthy controls. Female participants aged 18–60 years were enrolled in this study. The group consisted of 49 CFS patients, 57 FM patients, and 54 healthy controls.

hsCRP levels were significantly higher for both the CFS and the FM groups compared to healthy controls when adjusting for age, smoking, and BMI (p < .001). There was no difference between the two patient groups. The level of hsCRP was affected by BMI but not by age and smoking.

Patients with CFS and FM have higher concentrations of hsCRP compared to healthy controls. This remains significant even after adjusting for BMI. CFS and FM cannot be distinguished from each other on the basis of hsCRP in our study.

7. Lien K et al. (2019)
Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome.
Physiological Reports 7 (11).

Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO2) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa]) is unknown.

We studied 18 female patients (18–50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18–50 years) who underwent repeated CPETs 24 h apart (CPET1 and CPET2) with [Laa] measured every 30th second.

VO2 at peak exercise (VO2peak) was lower in patients than in controls on CPET1 (P < 0.001) and decreased in patients on CPET2 (P < 0.001). However, the difference in VO2peak between CPETs did not differ significantly between groups. [Laa] per PO was higher in patients during both CPETs (Pinteraction < 0.001), but increased in patients and decreased in controls from CPET1 to CPET2 (Pinteraction < 0.001). Patients had lower VO2(P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO2production increases relative to VO2), but relative intensity (%VO2peak) and [Laa] at GET did not differ significantly from controls on CPET1. Patients had a reduction in VO2 (P = 0.02) and PO (P = 0.01) at GET on CPET2, but no significant differences in %VO2peak and [Laa] at GET between CPETs. Controls had no significant differences in VO2, PO or %VO2peak at GET between CPETs, but [Laa] at GET was reduced on CPET2 (P = 0.008).

In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME/CFS while it lowers [Laa] in healthy subjects.

8. McPhee G et al. (2019)
Monitoring treatment harm in myalgic encephalomyelitis/chronic fatigue syndrome: A freedom-of-information study of National Health Service specialist centres in England.
Journal of Health Psychology [Epub ahead of print].

The use of graded exercise therapy and cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome has attracted considerable controversy. This controversy relates not only to the disputed evidence for treatment efficacy but also to widespread reports from patients that graded exercise therapy, in particular, has caused them harm.

We surveyed the National Health Service-affiliated myalgic encephalomyelitis/chronic fatigue syndrome specialist clinics in England to assess how harms following treatment are detected and to examine how patients are warned about the potential for harms. We sent 57 clinics standardised information requests under the United Kingdom's Freedom of Information Act. Data were received from 38 clinics.

Clinics were highly inconsistent in their approaches to the issue of treatment-related harm. They placed little or no focus on the potential for treatment-related harm in their written information for patients and for staff. Furthermore, no clinic reported any cases of treatment-related harm, despite acknowledging that many patients dropped out of treatment.

In light of these findings, we recommend that clinics develop standardised protocols for anticipating, recording, and remedying harms, and that these protocols allow for therapies to be discontinued immediately whenever harm is identified.

9. Murga I and Lafuente JV (2019)
From neurasthenia to post-exertion disease: Evolution of the diagnostic criteria of chronic fatigue syndrome/myalgic encephalomyelitis.
Atencion Primaria [Epub ahead of print]

Changes in the terminology and diagnostic criteria for chronic fatigue syndrome/myalgic encephalomyelitis are explained in this paper. This syndrome is a complex and controversial entity of unknown origins. It appears in the medical literature in 1988, although clinical pictures of chronic idiopathic fatigue have been identified since the nineteenth century with different names, from neurasthenia, epidemic neuromyasthenia, and benign myalgic encephalomyelitis up to the current proposal of disease of intolerance to effort (post-effort). All of them allude to a chronic state of generalised fatigue of unknown origin, with limitations to physical and mental effort, accompanied by a set of symptoms that compromise diverse organic systems.

The International Classification of Diseases (ICD-10) places this syndrome in the section on neurological disorders (G93.3), although histopathological findings have not yet been found to clarify it. Multiple organic alterations have been documented, but a common biology that clarifies the mechanisms underlying this disease has not been established. It is defined as a neuro-immune-endocrine dysfunction, with an exclusively clinical diagnosis and by exclusion. Several authors have proposed to include CFS/ME within central sensitivity syndromes, alluding to central sensitisation as the common pathophysiological substrate for this, and other syndromes.

The role of the family doctor is a key figure in the disease, from the detection of those patients who present a fatigue of unknown nature that is continuous or intermittent for more than 6 months, in order to make an early diagnosis and establish a plan of action against a chronic disease with high levels of morbidity in the physical and mental sphere.

OBJECTIVE: To carry out a bibliographic review of the terminology and diagnostic criteria of the chronic fatigue syndrome/myalgic encephalomyelitis, in order to clarify the pathology conceptually, as a usefulness in the diagnosis of Primary Care physicians.

10. Neale FK et al. (2019)
Illness duration, mood and symptom impact in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis?
Archives of Disease in Childhood [Epub ahead of print].

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling condition that affects 0.4% to 2.4% of adolescents in the UK. Previous studies have reported high levels of anxiety, depression and worry among adolescents with CFS/ME. In adult studies, concerns have been raised about delays in accessing specialist CFS/ME services and the impact of delays on patients’ health and well-being.

In this study, we aimed first to assess the prevalence of self-reported anxiety/depression, worry and degree of symptom impact among our patient population of adolescents with CFS/ME. We then investigated whether longer illness duration was associated with higher prevalence of self-reported anxiety/depression, worry and symptom impact at initial assessment.

11. Pederson M (2019)
Chronic Fatigue Syndrome and chronic pain conditions – vitally protective systems gone wrong.
Scandinavian Journal of Pain [Epub ahead of print]

Chronic Fatigue Syndrome (CFS) and chronic pain syndromes represent major health problems in society. These conditions are disabling and strongly associated with low quality of life. Even though CFS and chronic pain are separate conditions, they have strikingly much in common.

Both pain and fatigue are important sensations with protective value in an acute situation. It can be life-threatening not to be aware of them. However, as these symptoms become chronic, their protective roles decrease and instead they become health problems.

Our understanding of the perception of pain and fatigue has shifted through the years, from a dualistic biomedical point of view to a holistic biopsychosocial understanding. This combined with the increasing evidence of how our brain works in a predictive/anticipatory manner, gives a deeper understanding of why treatments like cognitive behavior therapies and stress relief therapies can help these patients recover to better health.

12. Rasouli O et al. (2019)
Neuropsychological dysfunction in chronic fatigue syndrome and the relation between objective and subjective findings.
Neuropsychology 33 (5): 658-669.

Objective: This study aimed to explore the relationship between self-reported cognitive difficulties, objective neuropsychological test performances, and subjective health complaints in chronic fatigue syndrome (CFS) and to examine the degree of impaired cognitive functions.

Method: A total of 236 consecutively recruited outpatients, 18-62 years of age, completed the tests. Self-administered questionnaires were used for assessing fatigue, pain, depression, anxiety and subjective cognitive complaints (Everyday Memory Questionnaire [EMQ]). Also, neuropsychological tests, that is, Stroop I-IV, California Verbal Learning Test-Second Edition (CVLT-II) learning and delay, Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Letter Number (L-N) Sequencing, and the Paced Auditory Serial Addition Task were performed to examine whether these objective measures correlated with subjective complaints and were compared with normative data.

Results: There was a trend of association (p < .05) between the unadjusted EMQ with Stroop IV (inhibition and shifting attention), the CVLT-II learning and delay (verbal learning and memory), and the WAIS-III L-N Sequencing (working memory), but none were statistically significant at the .001 level. The EMQ was positively associated with fatigue, pain, and depression (p < .001). The PASAT (working memory) was negatively associated with pain (p < .001). Between 21% and 38% of the patients performed below the 1.5-SD cutoff for clinically significant impairment on the Stroop tests.

Conclusion: The self-reported cognitive performance was not strongly associated with the objective cognitive performances on any domains in patients with CFS. Patients with higher fatigue, pain, and depression levels reported greater subjective cognitive difficulties, as well as higher pain related to lower objective working memory function. The CFS patients had problems mainly in the domains of psychomotor speed and attention measured by the objective neuropsychological tests.

13. Sharpe M and Greco M (2019)
Chronic fatigue syndrome and an illness-focused approach to care: controversy, morality and paradox.
Medical Humanities [Epub ahead of print]

Contemporary medicine distinguishes between illness and disease. Illness refers to a person's subjective experience of symptoms; disease refers to objective bodily pathology. For many illnesses, medicine has made great progress in finding and treating associated disease. However, not all illnesses are successfully relieved by treating the disease. In some such cases, the patient's suffering can only be reduced by treatment that is focused on the illness itself.

Chronic disabling fatigue is a common symptom of illness, for which disease-focused treatment is often not effective, but for which illness-focused treatments (psychological or behavioural) often are.

In this article, we explore a controversy surrounding illness-focused treatments for fatigue. We do this by contrasting their acceptance by people whose fatigue is associated with a disease (using the example of cancer-related fatigue) with their controversial rejection by some people whose fatigue is not associated with an established disease (chronic fatigue syndrome or CFS, sometimes called ME (myalgic encephalomyelitis)). In order to understand this difference in acceptability we consider the differing moral connotations of illness and disease and then go on to examine the limitations of the concepts of illness and disease themselves.

We conclude that a general acceptance of illness-focused treatments by all who might benefit from them will require a major long-term change in thinking about illness, but that improvements to the care of individual patients can be made today.

14. Solomon-Moore E et al. (2019)
Physical activity patterns among children and adolescents with mild-to-moderate chronic fatigue syndrome/myalgic encephalomyelitis.
BMJ Paediatrics Open 3 (1).

Objective: Chronic fatigue syndromemyalgic encephalomyelitis (CFS/ME) is relatively common among children and adolescents; however, little is known about the physical activity levels and patterns of this population. The aim of this study was to examine the underlying patterns of physical activity among youth with mild-to-moderate CFS/ME. Cross-sectional associations between physical activity patterns with self-reported physical function, pain, fatigue, anxiety and depression were also examined.

Methods: Baseline cross-sectional data from the Managed Activity Graded Exercise iN Teenagers and pre-Adolescents randomised controlled trial. Children and adolescents (aged 8–17 years) diagnosed with mild-to-moderate CFS/ME who wore an accelerometer for at least three valid weekdays. Latent profile analysis was used to identify physical activity patterns. Linear regression models examined associations between physical activity classes and self-reported physical function, pain, fatigue, anxiety and depression.

Results: 138 children and adolescents (72.5% females) had valid data. Overall, participants did less than half the government recommended level of physical activity for children and adolescents, but not all were inactive: three (2.2%) did more than 1 hour of physical activity every day, and 13 (9.4%) achieved an average of 60 min a day. Adolescents (≥12 years) were less active than younger children, but activity levels were similar between genders. Three latent classes emerged from the data: ‘active’, ‘light’ and ‘inactive’. Compared with being ‘inactive’, being in the ‘light’ class was associated with greater self-reported physical function (10.35, 95% CI 2.32 to 18.38) and lower fatigue (−1.60, 95% CI −3.13 to −0.06), while being ‘active’ was associated with greater physical function (15.26, 95% CI 0.12 to 30.40), but also greater anxiety (13.79, 95% CI 1.73 to 25.85).

Conclusions: Paediatricians need to be aware that physical activity patterns vary widely before recommending treatment.

15. Son C (2019)
Differential diagnosis between “chronic fatigue” and “chronic fatigue syndrome”.
Integrative Medicine Research 8 (2): 89-91.


16. Yang T et al. (2019)
The clinical value of cytokines in chronic fatigue syndrome.
Journal of Translational Medicine 17 (1): 213.

Chronic fatigue syndrome (CFS) is a heterogeneous disorder with uncertain pathogenesis. Without effective therapy, CFS is characterized by disabling fatigue, depression, memory loss, and somatic discomfort. This comprehensive and impartial review aimed to assess the available evidence and examined the potential clinical value of using cytokines for the monitoring of CFS and as targets for the treatment of CFS.

Inflammatory reactions and immune modulation are considered to contribute to the pathophysiology of CFS, and it is well documented that cytokines present in both blood and cerebrospinal fluid (CSF) are closely associated with the progression and severity of CFS. However, pathophysiological and methodological limitations prevent using circulating cytokines as independent diagnostic indices. Moreover, there is no evidence to support the use of CSF cytokines as independent diagnostic indices. Nevertheless, a comprehensive evaluation of changes in circulating and CSF cytokines may improve clinical understanding of the pathophysiology of patients with CFS, aiding in the establishment of an appropriate diagnosis.

Importantly, the available evidence does not support the value of cytokines as therapeutic targets. We believe that an improved understanding of cytokine-related mechanisms will be helpful to explore new cytokine-related therapeutic targets.

17. Zhang Q et al. (2019)
Acupuncture for chronic fatigue syndrome: a systematic review and meta-analysis.
Acupuncture in Medicine [Epub ahead of print].

Objective: To evaluate evidence for the efficacy of acupuncture for chronic fatigue syndrome (CFS).

Methods: Randomized controlled trials (RCTs) comparing acupuncture with sham acupuncture, other interventions that may have a therapeutic effect, or no intervention, for the treatment of CFS, were searched for in the following databases up to March 2018: Pubmed; Embase; the Cochrane Library; Web of Science; Wanfang database; China National Knowledge Infrastructure (CNKI); Chinese Biomedicine (CBM) database; and VIP database. Risk of bias was determined using the Cochrane tool. Meta-analyses were performed using RevMan V.5.3 software. The GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) was adopted for levels of evidence.

Results: Sixteen studies with 1346 subjects were included. Most studies had low methodological quality. Meta-analyses showed a favourable effect of acupuncture on overall response rate compared with sham acupuncture (four studies, 281 participants, RR=2.08, 95% CI 1.4 to 3.1, I2=64%, low certainty) and Chinese herbal medicine (three studies, 290 participants, RR=1.17, 95% CI 1.07 to 1.29, I2=0%, low certainty). Acupuncture also appeared to significantly reduce fatigue severity measured by Chalder's Fatigue Scale and the Fatigue Severity Scale compared with other types of control.

Conclusion: Our review indicated that acupuncture was more effective than sham acupuncture and other interventions (Chinese herbal medicine, mainly), but no firm conclusion could be reached owing to limited data, poor quality and potentially exaggerated effect size evaluation. Further large, rigorously designed and reported RCTs are required.

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