The ME Association ME/CFS Research Round-up

Emma Northwood, Research Correspondent, ME Association

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

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research.

This extensive library of research is updated at the end of each month and is correct to 02 November 2020. It is a free resource and available to anyone.

The Index provides an A-Z of published research studies and selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research in a particular area that you might be interested in, e.g. epidemiology, infection, neurology, post-exertional malaise etc.

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

ME/CFS Research Published 24th – 30th October 2020

Five new research studies were published, and we highlight two of them:

1. In this new study, Dr Cara Tomas and her team compared skeletal muscle cells from ME/CFS patients and controls, and identified differences in how the cells work.

“Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells…

“The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease…”

Tomas et al. – see abstract below

Dr Cara Tomas’s research has previously been funded through the MEA Ramsay Research Fund. An MEA Research Summary and interview about this new research will be coming soon.

2. A Phase III trial of rintatolimod (Ampligen) has been published. Rintatolimod is a drug that has been under investigation for several decades for use with ME/CFS but has not been approved.

In this study, a baseline duration of exercise on a treadmill was compared to duration of exercise after 40 weeks of ME/CFS sufferers taking rintatolimod or a placebo.

Statistically significant improvements in exercise duration was observed for ME/CFS sufferers who took rintatolimod (n=41) compared to those who took placebo (n=34).

This was only observed in a group of sufferers who had had symptoms for 2 to 8 years inclusive, and not in a combined group of <2 and >8-year sufferers.

It should be noted that the authors have equity holdings in the company that manufactures the drug rintatolimod and therefore may have a conflict of interest. 

ME/CFS Research References and Abstracts

1. Tomas C, Elson JL, Newton JL, Walker M.
Substrate utilisation of cultured skeletal muscle cells in patients with CFS
Sci Rep. 2020 Oct 26;10(1):18232

Abstract
Chronic fatigue syndrome (CFS) patients often suffer from severe muscle pain and an inability to exercise due to muscle fatigue. It has previously been shown that CFS skeletal muscle cells have lower levels of ATP and have AMP-activated protein kinase dysfunction.

This study outlines experiments looking at the utilisation of different substrates by skeletal muscle cells from CFS patients (n = 9) and healthy controls (n = 11) using extracellular flux analysis.

Results show that CFS skeletal muscle cells are unable to utilise glucose to the same extent as healthy control cells. CFS skeletal muscle cells were shown to oxidise galactose and fatty acids normally, indicating that the bioenergetic dysfunction lies upstream of the TCA cycle.

The dysfunction in glucose oxidation is similar to what has previously been shown in blood cells from CFS patients. The consistency of cellular bioenergetic dysfunction in different cell types supports the hypothesis that CFS is a systemic disease.

The retention of bioenergetic defects in cultured cells indicates that there is a genetic or epigenetic component to the disease. This is the first study to use cells derived from skeletal muscle biopsies in CFS patients and healthy controls to look at cellular bioenergetic function in whole cells.

2. Strayer DR, Young D, Mitchell WM.
Effect of disease duration in a randomized Phase III trial of rintatolimod, an immune modulator for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
PLoS One. 2020 Oct 29;15(10):e0240403.

Abstract
Background: Rintatolimod is a selective TLR3 agonist, which has demonstrated clinical activity for ME/CFS in Phase II and Phase III double-blind, placebo-controlled, randomized, multi-site clinical trials.

Methods and findings: A hypothesis-based post-hoc analysis of the Intent to Treat (ITT) population diagnosed with ME/CFS from 12 independent clinical sites of a Phase III trial was performed to evaluate the effect of rintatolimod therapy based on disease duration.

The clinical activity of rintatolimod was evaluated by exercise treadmill tolerance (ETT) using a modified Bruce protocol. The ITT population (n = 208) was divided into two subsets of symptom duration.

Patients with symptom duration of 2-8 years were identified as the Target Subset (n = 75); the remainder (<2 year plus >8 year) were identified as the Non-Target Subset (n = 133).

Placebo-adjusted percentage improvements in exercise duration and the vertical rise for the Target Subset (n = 75) were more than twice that of the ITT population.

The Non-Target Subset (n = 133) failed to show any clinically significant ETT response to rintatolimod when compared to placebo. Within the Target Subset, 51.2% of rintatolimod-treated patients improved their exercise duration by ≥25% (p = 0.003) despite reduced statistical power from division of the original ITT population into two subsets.

Conclusion/significance: Analysis of ETT from a Phase III trial has identified within the ITT population, a subset of ME/CFS patients with ≥2 fold increased exercise response to rintatolimod.

Substantial improvement in physical performance was seen for the majority (51.2%) of these severely debilitated patients who improved exercise duration by ≥25%.

This magnitude of exercise improvement was associated with clinically significant enhancements in quality of life. The data indicate that ME/CFS patients have a relatively short disease duration window (<8 years) to expect a significant response to rintatolimod under the dosing conditions utilized in this Phase III clinical trial.

These results may have direct relevance to the cognitive impairment and fatigue being experienced by patients clinically recovered from COVID-19 and free of detectable SARS-CoV-2.

3. Kim DY, Lee JS, Son CG.
Systematic Review of Primary Outcome Measurements for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in Randomized Controlled Trials
J Clin Med. 2020 Oct 28;9(11):E3463.

Abstract
Background: Due to its unknown etiology, the objective diagnosis and therapeutics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are still challenging. Generally, the patient-reported outcome (PRO) is the major strategy driving treatment response because the patient is the most important judge of whether changes are meaningful.

Methods: In order to determine the overall characteristics of the main outcome measurement applied in clinical trials for CFS/ME, we systematically surveyed the literature using two electronic databases, PubMed and the Cochrane Library, throughout June 2020. We analyzed randomized controlled trials (RCTs) for CFS/ME focusing especially on main measurements.

Results: Fifty-two RCTs out of a total 540 searched were selected according to eligibility criteria. Thirty-one RCTs (59.6%) used single primary outcome and others adapted ≥2 kinds of measurements.

In total, 15 PRO-derived tools were adapted (50 RCTs; 96.2%) along with two behavioral measurements for adolescents (4 RCTs; 7.7%). The 36-item Short Form Health Survey (SF-36; 16 RCTs), Checklist Individual Strength (CIS; 14 RCTs), and Chalder Fatigue Questionnaire (CFQ; 11 RCTs) were most frequently used as the main outcomes.

Since the first RCT in 1996, Clinical Global Impression (CGI) and SF-36 have been dominantly used each in the first and following decade (26.1% and 28.6%, respectively), while both CIS and Multidimensional Fatigue Inventory (MFI) have been the preferred instruments (21.4% each) in recent years (2016 to 2020).

Conclusions: This review comprehensively provides the choice pattern of the assessment tools for interventions in RCTs for CFS/ME. Our data would be helpful practically in the design of clinical studies for CFS/ME-related therapeutic development.

4. Kujawski S, Cossington J, Słomko J, Dawes H, Strong JW, Estevez-Lopez F, Murovska M, Newton JL, Hodges L, Zalewski P.
Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients
J Clin Med. 2020 Oct 26;9(11):E3436.

Abstract
Purpose: The purpose of this study was to assess differences in the physiological profiles of completers vs. non-completers following a structured exercise programme (SEP) and the ability to predict non-completers, which is currently unknown in this group.

Methods: Sixty-nine patients met the Fukuda criteria. Patients completed baseline measures assessing fatigue, autonomic nervous system (ANS), cognitive, and cardiovascular function.

Thirty-four patients completed a home-based SEP consisting of 10-40 min per day at between 30 and 80% actual HR max. Exercise intensity and time was increased gradually across the 16 weeks and baseline measures were repeated following the SEP.

Results: Thirty-five patients discontinued, while 34 completed SEP.

For every increase in sympathetic drive for blood pressure control as measured by the taskforce, completion of SEP decreased by a multiple of 0.1. For a 1 millisecond increase in reaction time for the simple reaction time (SRT), the probability for completion of SEP also decreases by a multiple of 0.01. For a one beat HRmax increase, there is a 4% increase in the odds of completing SEP.

Conclusion: The more sympathetic drive in the control of blood vessels, the longer the reaction time on simple visual stimuli and the lower the HRmax during physical exercise, then the lower the chance of SEP completion in ME/CFS.

5. Brodwall EM, Pedersen M, Asprusten TT, Wyller VBB.
Pain in adolescent chronic fatigue following Epstein-Barr virus infection
Scand J Pain. 2020 Oct 25;20(4):765-773. 

Abstract
Objectives: Acute Epstein-Barr virus (EBV) infection is a trigger of Chronic Fatigue (CF) and Chronic Fatigue Syndrome (CFS).

The aim of this cross-sectional study was to investigate pain symptoms and pressure pain thresholds in fatigued and non-fatigued adolescents six months after acute EBV-infection, and in healthy controls.

This study is part of the CEBA-project (CF following acute EBV infection in adolescents).

Methods: A total of 195 adolescents (12-20 years old) that had undergone an acute EBV infection six months prior to assessment were divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score.

The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of seventy healthy controls was included.

Symptoms were mapped with questionnaires. Pressure pain thresholds were measured through pressure algometry. One way ANOVA were used for between-group analyses. Linear regression analyses were used to explore associations between Pediatric Quality of Life (dependent variable), pain symptoms and other variables within the EBV (CF+) group.

Results: The EBV CF+ group had significantly higher scores for pain symptoms as compared with the EBV CF- group and healthy controls, but pressure pain threshold did not differ significantly.

The number of pain symptoms as well as pain severity were strongly and independently associated with quality of life.

Conclusions: CF and CFS following acute EBV-infection in adolescents is characterized by high pain symptom burden, which in turn is associated with a decline in quality of life.

Pain in CF and CFS is of considerable clinical importance and should be a focal point for further investigation and intervention in these patient groups.

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