Human Herpesvirus-6 reactivation, mitochondrial fragmentation, & the coordination of antiviral & metabolic phenotypes in ME/CFS

Posted on 04/27/2020 by wames

Human Herpesvirus-6 reactivation, mitochondrial fragmentation, and the coordination of antiviral and metabolic phenotypes in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Philipp Schreiner, Thomas Harrer, Carmen Scheibenbogen, Stephanie Lamer, Andreas Schlosser, Robert K Naviaux and Bhupesh K Prusty in ImmunoHorizons April 1, 2020, 4 (4) 201-215 [doi.org/10.4049]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing.

To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A.

Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1.

Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, including pyruvate dehydrogenase, were strongly inhibited.

Adoptive transfer of U2-OS cell supernatants after reactivation of HHV-6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the associated antiviral state in the A549 cell assay.

Antiviral-immunity-in-ME/CFS (BK Prusty

In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metabolism.

Comment by Cort Johnson: Explaining ME/CFS? Prusty / Naviaux Study Ties Infections to Energy Breakdowns

EurekAlert: For ME/CFS patients, viral immunities come at a devastating, lifelong cost

UCSDSNews: For ME/CFS Patients, Viral Immunities Come at a Devastating, Lifelong Cost

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Altered muscle membrane potential & redox status differentiates two subgroups of patients with CFS

Posted on 04/27/2020 by wames

Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome, by Yves Jammes, Nabil Adjriou, Nathalie Kipson, Christine Criado, Caroline Charpin, Stanislas Rebaudet, Chloé Stavris, Régis Guieu, Emmanuel Fenouillet & Frédérique Retornaz in Journal of Translational Medicine vol 18, no: 173 (2020)

 

Research 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.

Trial registration Ethics Committee “Ouest II” of Angers (May 17, 2019) RCB ID: number 2019-A00611-56

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Self-isolating with ME – Tell your story for ME Awareness week

Posted on 04/25/2020 by wames

Self-isolating with ME

Tell your story for ME Awareness week

 

We’re hearing a lot about the joys and trials of being restricted to home when healthy or ‘at risk’. Many people with ME are however practised at ‘staying home’ (or being housebound) while feeling very ill.

ME Awareness week, 10-17 May 2020

 

Help WAMES tell what self-isolation means for people with ME.

How does your ME self-isolation experience compare with the Covid-19 experience?

  • View from my window – 2 years 2 months

    the struggle to understand what was wrong with you
    grieving for your lost life

  • learning to cope with new & frightening symptoms
    depending on others in new & unwelcome ways
  • the uncertainty about recovery
  • a changed relationship with your family and friends
  • your contact, or lack of it, with the outside world
  • how did you adapt & find a quality of life – hobbies, education, work

Isolated with ME – 2014-17

How has the C-19 lockdown affected you?

  • has it made life more difficult?
  • has it opened up new experiences?
  • brought back bad memories of being housebound in the past?
  • is this your first experience of being housebound?
  • is life less stressful, more lonely?
  • have people understood your experience better?

Tell us

  • in prose, rhyme, photos, or through the arts
  • one paragraph or photo, or a longer story
  • send as many contributions as you like
  • in English or Welsh
  • use your name or pseudonym
  • give us your permission to use your contributions to raise awareness
  • send to jan@wames.org.uk  or helpline@wames.org.uk
    Or via the online form www.wames.org.uk

There may never be a better time to communicate our experience.
So many people now know something of the frustrations of losing control of their future.
Or have watched others suffer.

Download this page in pdf

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Potential role of microbiome in CFS/ME

Posted on 04/24/2020 by wames

Potential role of microbiome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), by Guiseppe Lupo. PhD thesis, Università Cattolica del Sacro Cuore,  XXXII ciclo, a.a. 2018/19, Piacenza, 8 April 2020

 

Research abstract:

The Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), is a severe multisystemic disease characterized by immunological abnormalities and dysfunction of energy metabolism. Recent evidence suggest that there is a strong correlation between dysbiosis and pathological condition.

The present research investigated the composition of the intestinal and oral microbiota in CFS/ME patients in comparison to healthy controls and determined whether any observed differences could be useful for the identification of diagnostic biomarkers. The fecal and salivary bacterial composition in CFS/ME patients was investigated by Illumina sequencing of 16S rRNA gene amplicons.

The fecal microbiota of CFS/ME patients showed a significant reduction of Lachnospiraceae, particularly Anaerostipes, compared to the non-CFS/ME groups, and an increase of Phascolarctobacterium faecium and unclassified Ruminococcus. Bacteroides vulgatus, unclassified Bacteroides, Bacteroides uniformis and unclassified Barnesiella resulted significantly more abundant in CFS/ME patients. The oral microbiota of CFS/ME patients showed a significant increase of Rothia dentocariosa. The fecal metabolic profile of a subgroup of CFS/ME patients revealed an overall increase of SCFAs and indole derivatives compared to the non-CFS/ME groups, suggesting an increase in the fermentation processes.

Our results support the autoimmune hypothesis for CFS/ME condition and if confirmed by larger studies, the differences detected in the microbial profiles of CFS/ME patients may be used as markers for a more accurate diagnosis and for the development of specific therapeutic strategies.

Read more

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Unravelling ME/CFS: Gender‐specific changes in the microRNA expression profiling in ME/CFS

Posted on 04/23/2020 by wames

Unravelling ME/CFS: Gender‐specific changes in the microRNA expression profiling in ME/CFS by Amanpreet K Cheema, Leonor Sarria, Mina Bekheit, Fanny Collado, Eloy Almenar‐Pérez, Eva Martín‐Martínez, Jose Alegre, Jesus Castro‐Marrero, Mary A Fletcher, Nancy G Klimas,  Elisa Oltra, Lubov Nathanson in Journal of Cellular and Molecular Medicine 14 April 2020 [doi.org/10.1111/jcmm.15260]

 

Research 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.

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Acupuncture for CFS: an overview of systematic reviews

Posted on 04/22/2020 by wames

Acupuncture for Chronic Fatigue Syndrome: an overview of systematic reviews, by Zi-han Yin, Lin-jia Wang, Ying Cheng, Jiao Chen, Xiao-juan Hong, Ling Zhao, Fan-rong Liang in Chin. J. Integr. Med. (2020). [https://doi.org/10.1007/s11655-020-3195-3]

 

Review 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

Read full paper

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Autoimmunity-related risk variants in PTPN22 & CTLA4 are associated with ME/CFS with infectious onset

Posted on 04/22/2020 by wames

Autoimmunity-related risk variants in PTPN22 and CTLA4 are associated with ME/CFS with infectious onset, by Sophie Steiner, Sonya C Becker, Jelka Hartwig, Franziska Sotzny, Sebastian Lorenz, Sandra Bauer, Madlen Löbel, Anna B Stittrich, Patricia Grabowski and Carmen Scheibenbogen in Front. Immunol., 09 April 2020[doi.org/10.3389/fimmu.2020.00578]

 

Research abstract:

SNP model by David Eccles, Wiki commons

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.

Meet The Researchers: Carmen Scheibenbogen

 

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Processing of Laser-Evoked Potentials in patients with Chronic Whiplash-Associated Disorders, CFS & healthy controls: a case–control study

Posted on 04/20/2020 by wames

Processing of Laser-Evoked Potentials in patients with Chronic Whiplash-Associated Disorders, Chronic Fatigue Syndrome, and healthy controls: a case–control study, by Lisa Goudman, PhD, Liesbeth Daenen, PhD, Andre Mouraux, PhD, Jo Nijs, PhD, Patrick Cras, PhD, Nathalie Roussel, PhD, Maarten Moens, PhD, Iris Coppieters, PhD, Eva Huysmans, MSc, Margot De Kooning, PhD in Pain Medicine, 14 April 2020 [https://doi.org/10.1093/pm/pnaa068]

 

Research abstract:

Objective
Laser-evoked potentials (LEPs) are among the reliable neurophysiological tools to investigate patients with neuropathic pain, as they can provide an objective account of the functional status of thermo-nociceptive pathways. The goal of this study was to explore the functioning of the nociceptive afferent pathways by examining LEPs in patients with chronic whiplash-associated disorders (cWAD), patients with chronic fatigue syndrome (CFS), and healthy controls (HCs).

Design
Case–control study.

Setting
A single medical center in Belgium.

Subjects
The LEPs of 21 patients with cWAD, 19 patients with CFS, and 18 HCs were analyzed in this study.

Methods
All participants received brief nociceptive CO2 laser stimuli applied to the dorsum of the left hand and left foot while brain activity was recorded with a 32-channel electroencephalogram (EEG). LEP signals and transient power modulations were compared between patient groups and HCs.

Results
No between-group differences were found for stimulus intensity, which was supraliminal for Aδ fibers. The amplitudes and latencies of LEP wave components N1, N2, and P2 in patients with cWAD and CFS were statistically similar to those of HCs. There were no significant differences between the time–frequency maps of EEG oscillation amplitude between HCs and both patient populations.

Conclusions
EEG responses of heat-sensitive Aδ fibers in patients with cWAD and CFS revealed no significant differences from the responses of HCs. These findings thus do not support a state of generalized central nervous system hyperexcitability in those patients.

Read full paper

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Opposition to Oxford NHS Trust leaflet which confuses post Covid-19 fatigue with ME/CFS

Posted on 04/20/2020 by wames

The ME community requests Oxford NHS Trust leaflet be withdrawn

 

A collection of physicians, physiotherapists MPs and patient charities have written to Oxford Health NHS Foundation Trust to object to the content of a leaflet by their Psychosocial Response Group entitled Coping with the Coronavirus. It is one of a series of leaflets about Coronavirus and mental health, and has been adopted by other English NHS Trusts. (WAMES sincerely hopes no Welsh Trusts adopt it!)

“We, the undersigned, request immediate withdrawal of the Oxford Health NHS Foundation Trust leaflet “Coping with Coronavirus: Fatigue” for the following reasons:

  • The leaflet conflates post viral fatigue with myalgic encephalomyelitis (“ME”)
  • The leaflet purports to provide information for post-COVID-19 rehabilitation but is predominantly comprised of rehabilitation advice for ME / CFS
  • The information provided is incorrect or misleading
  • The advice provided is potentially detrimental to patients and may result in deterioration and exacerbation of disability”

The Oxford leaflet says this about recovering from Covid-19:

“Most of us will make a full recovery, but if you are still not back to your usual levels of energy, and you feel very tired and low, four months or more after you had the virus (or three months in children), then you may have post-viral fatigue.

Some people may go on to develop Chronic Fatigue Syndrome (CFS), sometimes also called Myalgic Encephalitis (ME), which is a condition which affects people in different ways. The main symptom is persistent fatigue (tiredness) and exhaustion which can be severe and disabling.”

It goes on to advise people not to rest too much and to avoid a ‘boom & bust’ approach to activity. The treatment for this? Pacing, activity management and Graded Exercise Therapy, and Cognitive Behavioural Therapy!

NB   The leaflet has now been removed from the Oxford site but is still online at another Trust site.

Why are patients and health professionals objecting?

The letter of objection asks for the withdrawal of the leaflet and offers an alternative, as soon as it is available, which would recommend:

“The emphasis should be on management of post Covid-19 fatigue and preventing the development of ME/CFS. This comes from effective management of post viral fatigue, in the form of paced activity, adequate sleep and nutrition. Inappropriate management may result in development of ME and reduces the likelihood of people being able to return to work36.

The recommended treatments of CBT and GET do not improve employment and illness benefit status. As a matter of fact, a systematic review of available data found that after CBT and GET more patients were unable to work and more were receiving illness benefits.

In brief, patients are advised to practice pacing techniques, which are a primary tool for managing energy and avoiding post exertional malaise. While some pacing guidance advocates a “quota-contingent” approach (undertaking activities according to an amount/distance/goal with the aim of improving function) for someone with ME, or recovering from a viral infection, this will ultimately push them beyond their limits and cause a symptom exacerbation and subsequent decline in abilities.”

Read the full letter 

Trial By Error: Oxford-NHS Recommends GET/CBT for Post-COVID “CFS” Patients

Dr David Tuller, a senior fellow in Public Health in Journalism at the University of Berkeley in the USA, and long time opponent of the discredited PACE trial, has announced his intention to challenge the Trust:

“I mean, really. Isn’t this 2020? The notion that there are “thoughts and beliefs” that “maintain” patients in a state of illness should have been discarded with the failure of PACE. I plan to ask the Oxford Health NHS Foundation Trust for references for the (mis)information provided in the pamphlet. I will also ask about  the role of the agency’s “psychosocial support group.”

Prof Tuller reports he has file a FOI request to find out more about the Psychosocial Response Group

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MCP-1 is increased in patients with CFS & FM, whilst several other immune markers are significantly lower than healthy controls

Posted on 04/20/2020 by wames

MCP-1 is increased in patients with CFS and FM, whilst several other immune markers are significantly lower than healthy controls, by Nina Groven, Egil Andreas Fors, Astrid Kamilla Stunes, Solveig Klæbo Reitan in Brain, Behavior, & Immunity – Health Vol 4, April 2020 [doi.org/10.1016/j.bbih.2020.100067]

 

Highlights:

  • MCP-1 is significantly increased in CFS and Fibromyalgia compared to controls.
  • CFS and Fibromyalgia share common features of inflammation.
  • Decreased IL-1β, IL-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3, IL-10 and IL-17A are found in both CFS and Fibromyalgia.

Abstract:

The role of the immune system in the pathogenesis of Fibromyalgia (FM) and Chronic fatigue syndrome (CFS) is not clear. We have previously reported increased levels of C-reactive protein (CRP) in these patient groups compared to healthy controls and wanted to further explore the levels of circulating immune markers in these populations.

The population consisted of three groups, 58 patients with FM, 49 with CFS and 54 healthy controls. All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university.

Plasma levels of Interferon (IFN)-γ, Interleukin (IL)-1β, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-β1, TGF-β2, TGF-β3 and Tumour Necrosis Factor (TNF)-α were analysed by multiplex. Differences between the three groups CFS, FM and controls, were analysed by Kruskal Wallis tests.

MCP-1 was significantly increased in both patient groups compared to healthy controls. IL-1β, Il-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3, IL-10 and IL17 all were significantly lower in the patient groups than healthy controls. IFN-γ was significantly lower in the FM group. For IL-8, IL-10 and IL-1ra there were no significant difference when controlled for multiple testing.

In conclusion, in our material MCP-1 seems to be increased in patients both with CFS and with FM, while several other immune markers are significantly lower in patients than controls.

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