Biomedical insights that inform the diagnosis of ME/CFS

Posted on 02/24/2020 by wames

Biomedical insights that inform the diagnosis of ME/CFS, by Brett A Lidbury, & Paul R Fisher, in Diagnostics 2020, 10(2), 92; [doi.org/10.3390/diagnostics10020092] (This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)

 

Editorial announcing the publication of a new book:

Prof Brett A Lidbury

It is well known that myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), whether considered as separate diseases or as the one chronic syndrome, continue to generate debate. Discussions on language, definitions and theoretical parameters continue, but whatever your position, one can now agree that ME and/or CFS (referred to hereafter as ME/CFS) is a disease with a physiological basis, rooted in biochemical and molecular dysfunction in the cells of sick individuals, and not attitudes that can be alleviated by psychological therapies. As a result, biomedical imperatives must now become the focus of research enquiry in order to find clinically translatable answers as soon as possible.

Prof Paul R Fisher

 

This book is intended as a landmark volume to mark this shift in thinking and to consolidate recent fundamental discoveries and biomedical insights as pathways towards tangible diagnostics, and eventual ME/CFS treatments.

Australian researchers, with their collaborators locally and abroad, have been at the forefront of discovery in the biomedical realm, and this book draws together fundamental and applied insights that have emerged from scientific and clinical enquiry.

The consolidation of up-to-date insights into ME/CFS was catalysed by a conference (https://www.emerge.org.au/symposium#.XbIv2iVS-3c) in March 2019 (Geelong, Australia), hosted by Emerge Australia, and several chapters in this volume are based on presentations from this meeting.

Section I—Reviews, Commentaries and Opinions

Section II—Research Results—Biomedical Insights and Diagnostics

Read full editorial – a pdf

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IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS

Posted on 02/24/2020 by wames

IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS, by Jelka Hartwig, Franziska Sotzny, Sandra Bauer, Harald Heidecke, Gabriela Riemekasten, Duska Dragund, Christian Meisel, Claudia Dames, Patricia Grabowski, Carmen Scheibenbogen in Brain, Behavior, & Immunity – Health, 5 February 2020, [doi.org/10.1016/j.bbih.2020.100047]

Highlights:

  • IgG physiologically stimulates β2 AdR signaling.
  • β2 AdR activation by IgG is attenuated in ME/CFS patients.
  • First evidence that IgG from ME/CFS patients differentially modulates β2 AdR ligand signaling.

Abstract:

β2 AdR

Background:
There is emerging evidence of a network of natural autoantibodies against GPCR which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients.

Methods:
We comparatively analyzed the effects of polyclonal IgG on β2 AdR signaling and immune cell function in vitro. 16 IgG fractions were isolated from serum of 5 ME/CFS patients with elevated (CFS AABhigh) and 5 with normal levels (CFS AABnorm) of β2 AdR autoantibodies, and from 6 healthy controls (HC). The effect of each IgG on β-arrestin recruitment and cAMP production in β2 AdR and M3/4R reporter cell lines was studied. Further effect of each IgG on human monocyte cytokine production and on T cell proliferation in vitro was analyzed. In addition, studies on cytokine production in β2 AdR wild type and knockout mice splenocytes incubated with IgG fractions were performed.

Results:
We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AABhigh had no effect. The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice. In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes.

Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28. IgG fractions from CFS AABhigh patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AABnorm had an intermediate effect. We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.

Conclusions:
We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.

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Investigation into cognitive behavioural therapy for CFS/ME

Posted on 02/20/2020 by wames

Investigation into cognitive behavioural therapy for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis, by Catherine E Clark . DClinPsych Thesis, Canterbury Christ Church, April 2019

 

Thesis abstract:

Background:

In the UK, CBT is currently recommended as an intervention for CFS/ME. Physical and psychological outcomes of CBT for CFS/ME vary across studies, as does the CBT model adopted. There is some evidence to suggest that some participants experience improved psychological and physical outcomes post CBT. However, the specific nature of these changes and the factors facilitating them is not well understood. This was therefore the focus of the current study.

Methodology:

Semi-structured interviews were conducted with 13 service users who had engaged in CBT aimed at improved management of their condition. Interviews were analysed using a grounded theory methodology, in order to build a theory of participants’ experiences.

Results:

The theory suggests that CBT led to participants feeling more able to cope with CFS/ME. This was due to both a shift in perspective arising from the therapy room and taking a more adaptive approach to daily life. The theory also suggested that participants experienced increased acceptance of the condition, which facilitated further adaptive changes.

Discussion:

Findings extend existing literature in suggesting that CBT aimed to improve management of CFS/ME may result in improved coping and reduced distress, independently of changes in fatigue. Clinical and research implications are discussed.

Thesis summary:

Section A is a systematic review exploring service users’ and their families’ experiences of psycho-social interventions for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). A thematic analysis was completed on the qualitative literature to explore the experience of interventions, the intervention components perceived as helpful and unhelpful and facilitators and barriers to benefitting from interventions. Resulting themes are discussed and study methodologies critiqued. Clinical and research implications are discussed.

Section B presents the results of a grounded theory study of cognitive behavioural therapy (CBT) for CFS/ME, specifically focused on the changes experienced by service users and the therapy components and conditions perceived to facilitate these. Semi-structured interviews were conducted with 13 service users recruited via a specialist CFS/ME service.

In contrast to the NICE guidelines, the model of CBT delivered in this service was not one of ‘reconditioning’ in which service users are supported to increase their activity; instead the goal was better adjustment to CFS/ME to improve quality of life. A theorised model of the therapeutic process is discussed, in which CBT led to participants feeling more able to cope with CFS/ME and experience increased acceptance of the condition. Clinical and research implications are discussed.

Read full thesis

 

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An isolated complex V inefficiency & dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients

Posted on 02/20/2020 by wames

An isolated complex V inefficiency and dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients, by Daniel Missailidis, Sarah J Annesley, Claire Y Allan, Oana Sanislav, Brett A Lidbury, Donald P Lewis and Paul R Fisher in J. Mol. Sci. 2020, 21(3), 1074; [doi.org/10.3390/ijms21031074]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition.

Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells.

We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays.

As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged.

Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated.

 

A short guide to mitochondria and complex V (you’ll need to sign in)

Mitochondria-Powering the Cell-Science Video

“The Cellular Equivalent of Chronic Fatigue” Found in ME/CFS – the work of Paul Fisher

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News & views in ME/CFS: the role of co-morbidity & novel treatments

Posted on 02/19/2020 by wames

News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments, by F Comhaire, JP Deslypere in Medical Hypotheses Vol 134, January 2020, 109444 [doi.org/10.1016/j.mehy.2019.109444]

 

Research abstract:

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure.

There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy.

Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

Extract from materials & methods:

Sixty four (64) consecutive patients participated in a prospective pragmatic open-label trial. They had been diagnosed to suffer from ME/CFS by certified expert university centres, and consulted at the private clinic of one of the authors (FC). All patients underwent a thorough and systematic evaluation at intake. This included history taking and completion of the fatigue severity score (FSS) [12], propaedeutic physical examination, echography, blood analysis including immunological and endocrinological tests with postprandial C-peptide measurement [13] and essays for the detection of infections, NeuroSPECT fusion imaging of cerebral blood supply [14] and quantitative electro-encephalography (sLORETA) [15].

Patients were offered the option to start a treatment trial with a nutraceutical composed of sodium dichloroacetate, Vitamin B1, Alpha lipoic acid, and Ubiquinone Q10 as described earlier [4]. Six weeks after the intake consultation, patients came back to discuss the results of the examinations, to report on their experience with the nutraceutical, and to complete the FSS once again.

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Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells & extracellular vesicles in ME/CFS

Posted on 02/17/2020 by wames

Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Eloy Almenar-Pérez, Leonor Sarría, Lubov Nathanson & Elisa Oltra in Scientific Reports vol 10, no: 2064 (2020)

 

Research abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystemic disease of unknown etiology, affecting thousands of individuals worldwide. Its diagnosis still relies on ruling out medical problems leading to unexplained fatigue due to a complete lack of disease-specific biomarkers.

Our group and others have explored the potential value of microRNA profiles (miRNomes) as diagnostic tools for this disease. However, heterogeneity of participants, low numbers, the variety of samples assayed, and other pre-analytical variables, have hampered the identification of  disease-associated miRNomes.

In this study, our team has evaluated, for the first time, ME/CFS miRNomes in peripheral blood mononuclear cells (PBMCs) and extracellular vesicles (EVs) from severely ill patients recruited at the monographic UK ME biobank to assess, using standard operating procedures (SOPs), blood fractions with optimal diagnostic power for a rapid translation of a miR-based diagnostic method into the clinic.

Our results show that routine creatine kinase (CK) blood values, plasma EVs physical characteristics (including counts, size and zeta-potential), and a limited number of differentially expressed PBMC and EV miRNAs appear significantly associated with severe ME/CFS (p < 0.05).

Gene enrichment analysis points to epigenetic and neuroimmune dysregulated pathways, in agreement with previous reports. Population validation by a cost-effective approach limited to these few potentially discriminating variables is granted.

 

Comment: MEA Summary Review: Assessing diagnostic value of microRNAs from PMBC’s and EV’s in ME/CFS  11 February 2020

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Legitimizing ME/CFS: indications of change over a decade (US)

Posted on 02/17/2020 by wames

Legitimizing myalgic encephalomyelitis/chronic fatigue syndrome: indications of change over a decade, by Fred Friedberg in Fatigue: Biomedicine, Health & Behavior, February 5, 2020

 

Research abstract:

This commentary identifies recent scientific and clinical milestones that appear to have increased legitimization of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

These milestones include government-funded reports recognizing the seriousness of ME/CFS, new initiatives for biomedical research sponsored by the US National Institutes of Health, official endorsement of the ME/CFS name, publication of practitioner primers, and the launch of a new peer-review fatigue journal.

These positive developments are tempered by ongoing illness challenges including patient stigma, absence of diagnostic markers, a lack of established treatments, and a dearth of researchers and knowledgeable, interested clinicians.

 

Read full article

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Cochrane review of exercise therapy for CFS: appointment of advisory group lead

Posted on 02/17/2020 by wames

Cochrane library blog post, 13 Feb 2020: Appointment of lead to independent advisory group

 

In October 2019, Cochrane announced its commitment to a full update the Cochrane Review Exercise therapy for chronic fatigue syndrome. The statement noted plans for: “a comprehensive review of the protocol, which will be developed in consultation with an independent advisory group that we intend to convene. This group will involve partners from patient-advocacy groups from different parts of the world who will help us to embed a patient-focused, contemporary perspective on the review question, methods and findings.”

Cochrane is now pleased to announce that Hilda Bastian has been appointed to lead the independent advisory group. Hilda has been a health consumer advocate and researcher, and has held many roles with healthcare bodies. She is also author of the popular PLoS blog “Absolutely Maybe”, which looks at the uncertainties in medicine, and reported on the contents and conduct of the Cochrane Review Exercise therapy for chronic fatigue syndrome. Her knowledge and understanding of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and the methodology of systematic reviews, saw broad support for her blog posts from consumers and researchers alike.

Read full blog post

 

Read the comments and criticisms of the existing review

Hilda Bastian is a scientist, blogger, health consumer advocate and cartoonist. Read more about her.

Read Hilda’s past blogs:

Consumer-Contested Evidence: Why the ME/CFS Exercise Dispute Matters So Much
Posted February 8, 2019

It’s a Start: The Amended Version of the Cochrane Review on Exercise and CFS
Posted October 3, 2019

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Suicide is a concern for the chronic invisible illness community

Posted on 02/14/2020 by wames

Suicide is a concern for the chronic invisible illness community, by Cathy L Pederson in Journal of Health Science & Education Vol 4, #1, p 176, January 28, 2020

 

Commentary:

Rates of suicidal ideation, attempts, and completion are alarmingly high in chronic invisible illness communities. Suicide is the second leading cause of death for people with myalgic encephalomyelitis/chronic fatigue syndrome [1], with 20% of patients dying by suicide [2]. In postural orthostatic tachycardia syndrome, approximately 50% are at high risk for suicide, with 15-18% reporting past suicide attempts, and 13% stating that they will likely make a future suicide attempt [3,4].

In the fibromyalgia community, 33% report suicidal ideation [5], while 4% of people with hypermobile Ehlers-Danlos syndrome attempt suicide [6]. Finally, 1,200 chronic Lyme disease patients die by suicide in the United States annually [7]. Clearly, the chronic invisible illness community is highly affected by suicidal ideation.

There are several reasons that people with chronic invisible illness are at particularly high risk of suicide. Nearly half of the risk factors for suicide – major physical illness, sense of isolation, hopelessness, job or financial loss, loss of relationships, and lack of good health care – are prevalent in this population. Common symptoms for many with chronic illnesses have also been linked with increased suicide risk, including functional disability [8], chronic pain [9], and sleep disturbance [10]. However, most people with chronic illnesses do not have a mental health diagnosis [11].

Read full article

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Potential benefits of a ketogenic diet to improve response & recovery from physical exertion in people with ME/CFS

Posted on 02/11/2020 by wames

Potential benefits of a ketogenic diet to improve response and recovery from physical exertion in people with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a feasibility study, by Jo Cossington, Dr Shelly Coe, Yaomeng Liu, Helen Dawes in International Journal of Sport, Exercise and Health Research 2019; 3(2): 33-39

 

Research abstract:

Background:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) affects approximately 250,000 people in the UK. The condition varies in severity causing long-term physical and cognitive fatigue which is not alleviated by rest. Whilst the pathology is not understood, recent evidence suggests metabolic abnormalities may be associated with the manifestation of symptoms, particularly involving the metabolism of glucose and energy production.

The use of ketone bodies as an alternative energy substrate may be beneficial to people with ME/CFS, in order to by-pass the glycolytic pathway, enhance energy production and reduce fatiguing outcomes.

Study Design and Methods:

Using a pragmatic collective case study with repeated measures methodology we investigated the feasibility of following a ketogenic diet and potential effects of the high fat, low carbohydrate diet on response to physical activity in people with ME/CFS (n=3) and healthy controls (n=3) using a submaximal exercise stress test both with and without dietary intervention. Exercise tolerance (mins), rate of oxygen consumption (VO2) to workload (75W), respiratory exchange ratio (RER), rate of perceived effort (RPE) and lactate response were measured throughout and descriptive statistics performed.

Results:

We found that the ketogenic diet was followed, with compliance higher in the pwME/CFS. Variations in response following the ketogenic diet was observed across individuals in minutes performed, VO2, HR, RER, and RPE post diet but the KD only limited exercise capacity in the control individuals. Individuals responded differently to the KD but group trends have been reported as means and standard deviation. The KD resulted in a decrease in RER at submax in the controls with a mean change of 0.07 from baseline (0.86 ± 0.1) to post intervention (0.79 ± 0.1) compared to a mean change of 0.02 in the ME/CFS from baseline (1.03 ± 0.1) to post intervention (1.01 ± 0.1).

A decrease in VO2 (L/min) at submax showed a mean change of 0.06 (L/min) in the pwME/CFS at baseline (1.34 ± 0.1) to post intervention (1.27 ± 0.2) compared to a mean change of 0.07 (L/min) in the controls at baseline (1.40 ± 0.3) to post intervention (1.33 ± 0.2). HR (bpm) at submax decreased in all individuals, with a mean change of 4 (bpm), with pwME/CFS at baseline (139 ± 8.2) to post intervention (135 ± 14) and control individuals at baseline (107 ± 7.8) to intervention (103 ± 3.2). RPE at submax decreased in the pwME/CFS from baseline (6 ± 1.0) to post intervention (5 ± 2.1) whereas the controls increased from baseline (2 ± 1.0) to post intervention (3 ± 1.5).

Conclusion:

Our observations suggest individualised but metabolic flexibility in healthy individuals is achievable via dietary manipulation showing the ability to switch from glucose to fats under controlled conditions. The different response in substrate utilisation in individuals with ME/CFS suggests that potential metabolic abnormalities may be present in ME/CFS. Further investigation is now warranted in order to assess whether the KD is beneficial for people with ME/CFS.

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