The ME Association End of Week Research Round-up | 24 April 2020


Charlotte Stephens, Research Correspondent, ME Association.

We show below brief summaries of the research studies about ME/CFS that have been published in the last week, followed by the abstracts from those studies.

This information will be included in the monthly update to the central Research Index which is made freely available as a download at the end of every month.

You can also find the Index in the Research section of the website together with a list of Research Summaries from the ME Association that provide lay explanations of the more important and interesting work that has been published to date.

ME/CFS Research Published 17 – 23 April 2020

This week, 7 new research studies have been published, highlights include:

  • Researchers from the USA have been looking into miRNA (small molecules that regulate genes) expression in ME/CFS patients’ immune cells during an exercise challenge. They found changes in miRNA expression associated with inflammation and immune response. They are also the first research group to find differences in expression between males and females with ME/CFS in response to exercise, which could help to explain why females are more susceptible to ME/CFS.
  • A French research team looked at membrane excitability and oxidative stress in the muscles of ME/CFS patients during exercise and at rest. They found that ME/CFS patients have altered muscle membrane excitability during exercise and at rest. They also identified two distinct subgroups of patients within the ME/CFS cohort, which showed opposite changes in their biomarkers (one group had increased markers of oxidative stress, the other group did not).
  • Researchers from Berlin looked at specific gene variations known to be associated with susceptibility to autoimmune disease, in ME/CFS patients compared to controls. They found significant associations between two of the five gene variants and ME/CFS. However, the associations were only found in ME/CFS patients who reported an acute onset of disease following an infection. Both genes play a key role in regulating B and T cell activation (types of immune cells). This finding suggests that autoimmunity may play a role in patients with ME/CFS who had an infection-triggered onset.

ME/CFS Research references and abstracts

1. Cheema AK et al. (2020)
Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender‐specific changes in the microRNA expression profiling in ME/CFS.
Journal of Cellular and Molecular Medicine [Epub ahead of print].

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by medically unexplained debilitating fatigue with suggested altered immunological state. Our study aimed to explore peripheral blood mononuclear cells (PBMCs) for microRNAs (miRNAs) expression in ME/CFS subjects under an exercise challenge.

The findings highlight the immune response and inflammation links to differential miRNA expression in ME/CFS. The present study is particularly important in being the first to uncover the differences that exist in miRNA expression patterns in males and females with ME/CFS in response to exercise. This provides new evidence for the understanding of differential miRNA expression patterns and post‐exertional malaise in ME/CFS.

We also report miRNA expression pattern differences associating with the nutritional status in individuals with ME/CFS, highlighting the effect of subjects’ metabolic state on molecular changes to be considered in clinical research within the NINDS/CDC ME/CFS Common Data Elements.

The identification of gender‐based miRNAs importantly provides new insights into gender‐specific ME/CFS susceptibility and demands exploration of sex‐suited ME/CFS therapeutics.

2. Farragher JF et al. (2020)
Energy management education and occupation-related outcomes in adults with chronic diseases: A scoping review.
British Journal of Occupational Therapy [Epub ahead of print].

Abstract
Introduction: Fatigue is a pervasive symptom of chronic disease that often interferes with occupational performance. Our objective was to describe what is known about energy management education and occupation-related outcomes in adults with chronic diseases.

Methods: Seven electronic databases were searched for relevant literature published before August 2019. Eligible articles were full-text, available in English, and studied energy management education in adults with a chronic disease. The first author assessed article eligibility with validation from a second reviewer, extracted characteristics of included studies, and described them using descriptive statistics. A narrative synthesis of findings was conducted for each chronic disease population.

Results: Forty-four studies addressed eight different chronic disease populations. The most common program delivery format was face-to-face in a group setting (42%), 39% of programs were informed by a learning theory, and their median cumulative length was 8 hours.

Positive outcomes were associated with a specific, group-based energy management program in people with multiple sclerosis. The evidence on other energy management programs and in other chronic disease populations was more limited and inconclusive.

Conclusions: Further research is needed to understand the impact of energy management education in chronic disease populations beyond multiple sclerosis, and its impact on occupational performance.

3. Jammes Y et al. (2020)
Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome.
Journal of Translational Medicine 18 (1): 173.

Abstract
Background: In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.

Methods: Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS.

To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.

Results: Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.

Conclusions: Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS.

4. Malik S et al. (2020)
Cognitive–behavioural therapy combined with music therapy for chronic fatigue following Epstein-Barr virus infection in adolescents: a feasibility study.
BMJ Paediatrics Open 4 (1).

Abstract
​Background: Cognitive–behavioural therapy (CBT) is effective in chronic fatigue syndrome. However, CBT has not been investigated in post-infectious chronic fatigue (CF), nor is it known whether addition of therapeutic elements from other disciplines might be feasible. We studied the feasibility of a combined CBT and music therapy intervention for CF following Epstein-Barr virus (EBV) infection in adolescents.​

Methods: Adolescents (12–20 years old) participating in a post-infectious cohort study who developed CF 6 months after an acute EBV infection were eligible for the present feasibility study.

A combined CBT and music therapy programme (10 therapy sessions and related homework) was compared with care as usual in a randomised controlled design. Therapists and participants were blinded to outcome evaluation. Endpoints included physical activity (steps/day), symptom scores, recovery rate and possible harmful effects, but the study was underpowered regarding efficacy. Total follow-up time was 15 months.​

Results: A total of 43 individuals with post-infectious CF were included (21 intervention group, 22 control group). Seven individuals left the study during the first 3 months, leaving 15 in the intervention group and 21 in the control group at 3 months’ follow-up.

No harmful effects were recorded, and compliance with appointment was high. In intention-to-treat analyses, number of steps/day tended to decrease (difference=−1158, 95% CI −2642 to 325), whereas postexertional malaise tended to improve (difference=−0.4, 95% CI −0.9 to 0.1) in the intervention group at 3 months. At 15 months’ follow-up, there was a trend towards higher recovery rate in the intervention group (62% vs 37%).​

Conclusion: An intervention study of combined CBT and music therapy in postinfectious CF is feasible, and appears acceptable to the participants. The tendencies towards positive effects on patients’ symptoms and recovery might justify a full-scale clinical trial.

5. Staples A et al. (2020)
Pediatric-Onset Postural Orthostatic Tachycardia Syndrome in a Single Tertiary Care Center.
Journal of Child Neurology [Epub ahead of print].

Abstract
Aim: We characterize the pediatric postural orthostatic tachycardia syndrome (POTS) population seen at a single tertiary care referral center.

Method: Retrospective chart review of all pediatric POTS patients seen in our center between 2015 and 2017. Pediatric POTS was defined as chronic, at least 3 months, symptoms of orthostatic intolerance associated with excessive orthostatic tachycardia as determined by tilt table testing with orthostatic heart rate increment of ≥40 bpm within 5 minutes of head-up tilt or absolute orthostatic heart rate ≥130 bpm for patients 13 years old and younger and ≥120 bpm for those 14 years and older.

We looked at demographics, presenting symptoms, comorbidities, examination findings, investigation findings, treatment, and patient reported outcomes. Outcome measures were separated by patient report and group comparisons were made using 2-sample t tests or Mann-Whitney U tests for continuous variables and Fisher exact tests for categorical variables.

Results: One hundred thirty-four patients with pediatric onset POTS were identified. The mean age was 15 years. Seventy-nine percent of patients were female and 90% were white. The most common presenting symptoms included dizziness/lightheadedness (88%), syncope (54%), and palpitations (40%).

Many patients had significant comorbidities attributable to numerous bodily systems, most commonly headache syndromes (migraine 43%, nonspecific headache 22%, chronic daily headache 14%, and new daily persistent headache 5%) and chronic fatigue (60%).

Low vitamin D and insufficient iron stores were commonly seen. The majority of patients improved or had resolution of symptoms following treatment (70%).

When separated by outcome, statistically significant differences were found for glucose (patients whose symptoms resolved had higher median glucose), palpitations (patients whose symptoms resolved were less likely to have palpitations), constipation (patients whose symptoms were stable/worsened were more likely to have constipation), and unexplained pain (patients whose symptoms were stable/worsened were more likely to have unexplained pain).

Conclusions: Pediatric POTS is a chronic condition with a fairly good prognosis following appropriate treatment. It is associated with numerous comorbidities that necessitate multidisciplinary expert care.

6. Steiner S et al. (2020)
Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset.
Frontiers in Immunology 11: 578.

Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease.

In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases.

Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS.

The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p = 0.268).

This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.

7. Yin Z et al. (2020)
Acupuncture for Chronic Fatigue Syndrome: An Overview of Systematic Reviews.
Chinese Journal of Integrative Medicine [Epub ahead of print].

Abstract
Objective: To evaluate the quality of the existing studies and summarize evidence of important outcomes of meta-analyses/systematic reviews (MAs/SRs) of CFS.

Methods: Potentially eligible studies were searched in the following electronic databases from inception to 1 September, 2019: Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure (CNKI), WanFang Database (WF), Web of Science, Embase, PubMed and Cochrane Library. Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of evidence.

The methodological quality of the literature was evaluated by A Measure Tool to Assess Systematic Reviews-2 (AMSTAR-2) and the quality of the report was assessed by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The intra-class correlation coefficient was used to assess the consistency of the reviewers, with an overall intraclass correlation coefficient score of 0.967.

Results: Ten MAs/SRs were included. The overall conclusions were that acupuncture had good safety and efficacy in the treatment of CFS, but some of these results were contradictory.

The GRADE indicated that out of the 17 outcomes, high-quality evidence was provided in 0 (0%), moderate in 3 (17.65%), low in 10 (58.82%), and very low in 4 (23.53%). The results of AMSTAR-2 showed that the methodological quality of all included studies was critically low. The PRISMA statement revealed that 8 articles (80%) were in line with 20 of the 27-item checklist, and 2 articles (20%) matched with 10–19 of the 27 items.

Conclusion: We found that acupuncture on treating CFS has the advantage for efficacy and safety, but the quality of SRs/MAs of acupuncture for CFS need to be improved.

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