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


Charlotte Stephens, Research Correspondent, ME Association.

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

It’s is a convenient way to locate and read the most recent research or research that was published decades ago.

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).

They are 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 research reviews that we have published.

ME/CFS Research Published in July 2019

1. Al-Rawaf et al. (2019)
MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome.
Pain Practice [Epub ahead of print]

Abstract
Numerous experimental models have shown that microRNAs play an important role in regulating pain-processing in clinical pain disorders. In this study, we evaluated a set of micro-RNAs as diagnostic biomarkers of pain intensity in adolescents with chronic fatigue syndrome (CFS). We then correlated the expression of these microRNAs with the levels of inflammatory markers and pain-related comorbidities in adolescents with CSF and healthy controls (HCs).

A total of 150 adolescents, aged 12-18 years, participated in this study between April 2016 and April 2017. The participants were classified into two groups: adolescents with CFS (n=100) and HCs (n=50). RT-PCR was used to evaluate the expression of miR-558, miR-146a, miR-150, miR-124, and miR-143. Immunoassay analysis was used to assess the levels of immune inflammatory markers IL-6, TNF-α, and COX-2.

Adolescents with CFS showed significantly higher pain thresholds than comparable non-fatigued HCs. Also, enjoy of life and relation to others as the life domains, showed lower pain interference in CFS patients. Differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143 was significantly down regulated and notably interfered with pain intensity and frequency in patients with CFS. Also, the expression of these miRNAs was significantly correlated with that of IL-6, TNF-α, and COX-2, which have been shown to mediate pain intensity in patients with CFS. Girls with CSF showed significantly decreased expression levels of these miRNAs compared with the levels of boys with CSF. Girls with CSF also showed increased expression of inflammatory pain-related markers IL-6, TNF-α, and COX-2, compared with the levels of boys with CSF

The intensity and consequences of pain were influenced by differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143, which was directly associated with higher expression of immune inflammatory related genes TNFα, IL-6, and COX-2 in adolescences with CFS. Further studies of larger patient cohorts will help clarify the role of miRNAs in the pathogenesis of CFS. This article is protected by copyright. All rights reserved.

2. Comerford B and Podell R (2019)
Medically Documenting Disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Cases.
Frontiers in Paediatrics 7: 231.

Abstract
The following research relates to disability claims made in America:
Patients with severe myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS) experience debilitating physical and cognitive symptoms, which often result in the need to file disability claims. A significant number of ME/CFS patients are children or adolescents. 

ME/CFS patients often turn to physicians who are not trained to recognize and diagnose ME/CFS, and who might or might not understand that ME/CFS is a multi-system primarily physical illness. Such misperceptions can adversely affect the doctor-patient relationship, the clinical outcomes, as well as the results of disability claims.

According to the National Academies of Science, Engineering and Medicine, “Between 836,000 and 2.5 million Americans suffer from myalgic encephalomyelitis/chronic fatigue syndrome… This disease is characterized by profound fatigue, cognitive dysfunction, sleep abnormalities, autonomic manifestations, pain, and other symptoms that are made worse by exertion of any sort. ME/CFS can severely impair patients’ ability to conduct their normal lives.”

The prevalence of MECFS among children and adolescents has been estimated variously as between 0.11 and 4% (1). A large percentage of children and adolescents with ME/CFS suffer from orthostatic intolerance due to one or both of these syndromes: Neurally Mediated Hypotension (NMH) and Postural Orthostatic Tachycardia Syndrome (POTS). These elements of ME/CFS often respond well to proper treatment (2, 3).

3. Kashi A et al. (2019)
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS.
Diagnostics 9 (3): 82.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure.

A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common.

A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation.

This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics. 

4. Kenyon J et al. (2019)
A Retrospective Outcome Study of 42 Patients with Chronic Fatigue Syndrome, 30 of Whom had Irritable Bowel Syndrome. Half were treated with oral approaches, and half were treated with Faecal Microbiome Transplantation.
Human Microbiome Journal [Epub ahead of print].

Abstract
This retrospective study was conducted by The Dove Clinic for Integrated Medicine, Hampshire.
The gut microbiome comprises the community of microorganisms in the intestinal tract. Research suggests that an altered microbiome may play a role in a wide range of disorders including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

42 participants with ME/ CFS with Irritable Bowel Syndrome (IBS) were allocated into one of two groups, 21 were treated with standard oral approaches, which centred around various nutritional remedies, probiotics, prebiotics, dietary advice and lifestyle advice.

The second group who had mostly failed using oral approaches, were treated with Faecal Microbiome Transplantation (FMT). Each patient received 10 Implants, each from a different screened donor, and the Implants were processed under anaerobic conditions. The transplant is delivered via a paediatric rectal catheter, which is inserted through the anus to reach the lower part of the sigmoid colon.

The results were assessed on a percentage basis before and after treatment, 0% being no improvement, 100% being maximum improvement. An exact non-parametric Mann-Whitney (one-tailed) test was used to compare medians from those on FMT compared with those receiving oral approaches only. On clinical experience over many years, the only way to judge improvement in Chronic Fatigue Syndrome as there is no test for Chronic Fatigue Syndrome, is my [stet] clinical assessment.

The median for the FMT group was found to be significantly higher compared to the oral treatment group (Mann-Whitney U=111.5, p=.003). Therefore, the FMT group improved to a greater extent (z=-2.761).

This study shows that FMT is a safe and a promising treatment for CFS associated with IBS. Adequately powered randomised controlled trials should be carried out to assess the effectiveness of FMT in patients with CFS and IBS.

5. Komaroff A (2019)
Advances in Understanding the Pathophysiology of Chronic Fatigue Syndrome.
JAMA [Epub ahead of print].

Abstract
When does an illness become a disease? When the underlying biological abnormalities that cause the symptoms and signs of the illness are clarified.

The illness now called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was first described in the mid-1980s. At that time, nothing was known about its underlying biology. Indeed, because many standard laboratory test results were normal, some clinicians explained to patients that “there is nothing wrong.” There was, of course, an alternative explanation: the standard laboratory tests might not have been the right tests to identify the underlying abnormalities.

Over the past 35 years, thousands of studies from laboratories in many countries have documented underlying biological abnormalities involving many organ systems in patients with ME/CFS, compared with healthy controls: in short, there is something wrong.

Moreover, most of the abnormalities are not detected by standard laboratory tests. In 2015, the Institute of Medicine of the National Academy of Sciences concluded that ME/CFS “is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients,” affects up to an estimated 2.5 million people in the United States, and generates direct and indirect expenses of approximately $17 billion to $24 billion annually.1

Over the past several years, the National Institutes of Health (NIH) has expanded its research efforts directed toward this disease. It has initiated an unusually comprehensive multisystem study at the NIH Clinical Center, funded 3 extramural ME/CFS research centers and 1 data coordinating center, awarded supplemental support to 7 existing grants, and held regular telebriefings on the illness (as has the Centers for Disease Control and Prevention).

A 2-day conference at the NIH in April 2019 highlighted recent progress. New research was presented that both reinforced and expanded on previous reports. Equally important, several plausible models were proposed that could explain many of the abnormalities that have been described.

6. Larrimore C et al. (2019)
Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and the Emerging Osteopathic Approach: A Narrative Review.
Journal of American Osteopathic Association 119 (7): 446-455.

Abstract
This review was conducted by The Institute for Neuro Immune Medicine at the Dr Kiran C. Patel College of Osteopathic Medicine at Nova Southeastern University, Florida.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating syndrome of unknown origin, characterized by profound postexertional malaise and fatigue, unrefreshing sleep, cognitive impairments, immune dysfunction, pain, autonomic dysfunction, and neuroendocrine symptoms.

Although ME/CFS is well documented within the medical literature, it remains difficult to diagnosis and manage. Some of the current challenges include an absence of diagnostic markers, differing diagnostic criteria, and an overall lack of awareness within the medical community. As a result, patients are often frustrated by the difficulties in acquiring a diagnosis and from the overall lack of available treatments.

In an effort to increase awareness, this review discusses disease pathophysiology, clinical presentation, and treatment options, while also highlighting the benefits of an osteopathic approach.

7. Lidbury B et al. (2019)
Rethinking ME/CFS Diagnostic Reference Intervals via Machine Learning, and the Utility of Activin B for Defining Symptom Severity.
Diagnostics 9 (3).

Abstract
Biomarker discovery applied to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling disease of inconclusive aetiology, has identified several cytokines to potentially fulfil a role as a quantitative blood/serum marker for laboratory diagnosis, with activin B a recent addition. We explored further the potential of serum activin B as a ME/CFSbiomarker, alone and in combination with a range of routine test results obtained from pathology laboratories.

Previous pilot study results showed that activin B was significantly elevated for the ME/CFS participants compared to healthy (control) participants. All the participants were recruited via CFS Discovery and assessed via the Canadian/International Consensus Criteria. A significant difference for serum activin B was also detected for ME/CFS and control cohorts recruited for this study, but median levels were significantly lower for the ME/CFS cohort.

Random Forest (RF) modelling identified five routine pathology blood test markers that collectively predicted ME/CFS at ≥62% when compared via weighted standing time (WST) severity classes. A closer analysis revealed that the inclusion of activin B to the panel of pathology markers improved the prediction of mild to moderate ME/CFS cases. Applying correct WST class prediction from RFA modelling, new reference intervals were calculated for activin B and associated pathology markers, where 24-h urinary creatinine clearance, serum urea and serum activin B showed the best potential as diagnostic markers.

While the serum activin B results remained statistically significant for the new participant cohorts, activin B was found to also have utility in enhancing the prediction of symptom severity, as represented by WST class.

8. McGregor N et al. (2019)
Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases.
Diagnostics 9 (3).  

Abstract
Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period.

Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group.

The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly.

Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event.

These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation.

These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.

9. Missailidis D et al. (2019)
Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Diagnostics 9 (3).

Abstract
The underlying molecular basis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”), and variably presenting multi-system symptoms, ME/CFS is a complex disease, which demands a concerted biomedical investigation from disparate fields of expertise. 

ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work.

Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is mostly comprised of disturbances to immunological and inflammatory pathways, autonomic and neurological dysfunction, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiota disturbances.

It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift.

Due to the variability of non-overlapping symptom presentation or precipitating events, such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition.

Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

10. Ohba T et al. (2019)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Induced by Repeated Forced Swimming in Mice.
Biological and Pharmaceutical Bulletin 42 (7).

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients.

Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS.

To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA).

In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group.

DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS

11. Silvestre I et al. (2019)
Mitochondrial alterations in NK lymphocytes from ME/CFS patients.
The Journal of Immunology 202 (1): 126.39.

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by profound fatigue, flu-like symptoms, trouble concentrating, and autonomic problems, all of which worsen after exertion.

ME/CFS patients have impaired natural killer (NK) cell activity. NK lymphocytes are a critical first defense against viruses and cancer. ME/CFS patients have difficulties controlling viral infections and many develop non-Hodgkin’s lymphoma.

Mitochondrial metabolism is crucial for immune cell function. Mitochondria dysfunction has been previously reported in ME/CFS, but it is not known whether the NK cells of these patients have altered mitochondrial metabolism that affect their activity and contribute to ME/CFS pathogenesis. More importantly, there is currently no efficient method to diagnose ME/CFS or assess efficacy of therapeutic interventions.

The Bioenergetic Health Index (BHI) has been developed as promising and reliable surrogate readout of human health by measuring the bioenergetic status of immune cells. Variations in bioenergetic function in patient’s immune cells can reflect both metabolic stress and the mutable role of these cells in ME/CFS immunity and pathogenesis.

In our study, we observed that the two main energy-generating mitochondrial pathways, oxidative phosphorylation and glycolysis (bioenergetics parameters), are deregulated in ME/CFS NK cells and in PBMCs. Moreover, we observed alterations in the morphology and membrane potential of the mitochondria of NK cells. These mitochondrial features can affect NK cell function and contribute to the severity of disease.

To date, this is the first metabolism assessment of NK cells in ME/CFS and as potential new diagnostic tool for the disease.

12. Sweetman E et al. (2019)
Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Diagnostics 9 (3).

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. 

ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians.

There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness.

Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2-3 years that promise new leads towards an effective clinical diagnostic test that may have a general application.

Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness.

These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.

13. Sunnquist M et al. (2019)
The development of a short form of the DePaul Symptom Questionnaire.
Rehabilitation Psychology [Epub ahead of print].

Abstract
The DePaul Symptom Questionnaire (DSQ) is a widely used instrument that assesses common symptoms of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS).

The DSQ has strong psychometric properties; however, it consists of 99 items, and the energy limitations and cognitive difficulties experienced by individuals with ME and CFS may hinder their ability to easily complete the questionnaire. The current study examined symptom prevalence and discriminative ability to develop a short form of the DSQ (DSQ-SF).

The resulting short form questionnaire consists of 14 items that were highly prevalent among individuals with ME and CFS. Additionally, the items demonstrated the ability to differentiate individuals with ME and CFS from adult controls and, to a lesser extent, individuals with multiple sclerosis.

The DSQ-SF may serve as an effective, brief screening tool for symptoms of ME and CFS.

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