ME/CFS as a hyper-regulated immune system driven by an interplay between regulatory T cells & chronic human herpesvirus infections

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as a hyper-regulated immune system driven by an interplay between regulatory T cells and chronic human herpesvirus infections, by Nuno Sepúlveda,  Jorge Carneiro,  Eliana M Lacerda and  Luis C Nacul in Front. Immunol. 21 Nov 2019 [https://doi.org/10.3389/fimmu.2019.02684]

 

Hypothesis & theory article abstract:

Conceptual scheme of the cross-regulation model

Autoimmunity and chronic viral infections are recurrent clinical observations in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a complex disease with an unknown cause.

Given these observations, the regulatory CD4+ T cells (Tregs) show promise to be good candidates for the underlying pathology due to their known capacity to suppress the immune responses not only to body components but also against infections. Here we discussed the overlooked role of these cells in the chronicity of Human Herpes Virus 6 (HHV6), Herpes Simplex 1 (HSV1) and Epstein-Barr virus (EBV), as often reported as triggers of ME/CFS.

Using simulations of the Cross-regulation model for the dynamics of Tregs, we illustrated that mild infections might lead to a chronically activated immune responses under control of Tregs if the responding clone has a high autoimmune potential. Such infections promote persistent inflammation and possibly fatigue.

We then hypothesized that ME/CFS is a condition characterized by a predominance of this type of infections under control of Tregs. In contrast, healthy individuals are hypothesized to trigger immune responses of a virus-specific clone with a low autoimmune potential.

According to this hypothesis, simple model simulations of the CD4+ T-cell repertoire could reproduce the increased density and percentages of Tregs observed in patients suffering from the disease when compared to healthy controls. A deeper analysis of Tregs in the pathogenesis of ME/CFS will help to assess the validity of this hypothesis.

A Never-Ending Immune Battle in ME/CFS? The Regulatory T-cell / Herpesvirus Hypothesis

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A systematic review of natural killer cells profile & cytotoxic function in ME/CFS

A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome, by Natalie Eaton-Fitch, Stanley du Preez, Hélène Cabanas, Donald Staines & Sonya Marshall-Gradisnik in Systematic Reviews vol 8, no: 279 (2019)

 

Review abstract:

Background:
Compromised natural killer (NK) cell cytotoxic function is a well-documented and consistent feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Other outcomes evaluated in NK cells of ME/CFS patients, however, remain equivocal. The aim of this study was to conduct a systematic review of the literature regarding NK cell phenotype, receptor expression, cytokine production and cytotoxicity in ME/CFS patients and determine the appropriateness as a model for ME/CFS.

Methods:
Medline (EBSCOHost), Scopus, EMBASE and PubMed databases were systematically searched to source relevant papers published between 1994 and March 2018. This review included studies examining NK cells’ features in ME/CFS patients compared with HC following administration of specific inclusion and exclusion criteria. Secondary outcomes included genetic analysis in isolated NK cells or quality of life assessment. Quality assessment was completed using the Downs and Black checklist in addition to The Joanna Briggs Institute checklist.

Results:
Seventeen eligible publications were included in this review. All studies were observational case control studies. Of these, 11 investigated NK cell cytotoxicity, 14 investigated NK cell phenotype and receptor profiles, three examined NK cell cytokine production, six investigated NK cell lytic protein levels and four investigated NK cell degranulation. Impaired NK cell cytotoxicity remained the most consistent immunological report across all publications. Other outcomes investigated differed between studies.

Conclusion:
A consistent finding among all papers included in this review was impaired NK cell cytotoxicity, suggesting that it is a reliable and appropriate cellular model for continued research in ME/CFS patients. Aberrations in NK cell lytic protein levels were also reported. Although additional research is recommended, current research provides a foundation for subsequent investigations. It is possible that NK cell abnormalities can be used to characterise a subset of ME/CFS due to the heterogeneity of both the illness itself and findings between studies investigating specific features of NK function.

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The longitudinal effects of seated isometric yoga on blood biomarkers, autonomic functions, & psychological parameters of patients with CFS

The longitudinal effects of seated isometric yoga on blood biomarkers, autonomic functions, and psychological parameters of patients with chronic fatigue syndrome: a pilot study, by Takakazu Oka, Tokusei Tanahashi, Battuvshin Lkhagvasuren, & Yu Yamada in BioPsychoSocial Medicine vol 13, no: 28 (2019)

 

Research abstract:

Background:
In a previous randomized controlled trial, we found that practicing seated isometric yoga regularly for 2 months improved the fatigue of patients with chronic fatigue syndrome (CFS) who are resistant to conventional therapy. The aim of this pilot study was to investigate the possible mechanisms behind this finding by comparing blood biomarkers, autonomic nervous function, and psychological indices before versus after an intervention period of seated isometric yoga practice.

Methods:
Fifteen patients with CFS who did not show satisfactory improvements after at least 6 months of conventional therapy practiced seated isometric yoga (biweekly 20-min sessions with a yoga instructor and daily practice at home) for 2 months. The longitudinal effects of seated isometric yoga on fatigue, blood biomarkers, autonomic function, and psychological state were investigated by comparing the following parameters before and after the intervention period: Fatigue severity was assessed by the Chalder fatigue scale (FS) score. Levels of the blood biomarkers cortisol, DHEA-S, TNF-α, IL-6, prolactin, carnitine, TGF-β1, BDNF, MHPG, HVA, and α-MSH were measured. The autonomic nervous functions assessed were heart rate (HR) and HR variability. Psychological indices included the 20-item Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale (HADS).

Results:
Practicing seated isometric yoga for 2 months resulted in significant reductions in the Chalder FS (P = 0.002) and HADS-depression (P = 0.02) scores. No significant changes were observed in any other parameter evaluated. The change in Chalder FS score was not correlated with the change in HADS-depression score. However, this change was positively correlated with changes in the serum TNF-α levels (P = 0.048), the high frequency component of HR variability (P = 0.042), and TAS-20 scores (P = 0.001).

Conclusions:
Regular practice of seated isometric yoga for 2 months reduced the fatigue and depressive symptom scores of patients with CFS without affecting any other parameters we investigated. This study failed to identify the markers responsible for the longitudinal fatigue-relieving effect of seated isometric yoga. However, considering that the reduced fatigue was associated with decreased serum TNF-α level and TAS-20 scores, fatigue improvement might be related to reduced inflammation and improved alexithymia in these patients.

Trial registration:
University Hospital Medical Information Network (UMIN CTR) UMIN000009646. Registered Dec 27, 2012.

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Developing & pretesting a new patient reported outcome measure for paediatric CFS/ME

Developing and pretesting a new patient reported outcome measure for paediatric Chronic Fatigue Syndrome/Myalgic Encephalopathy (CFS/ME): cognitive interviews with children, by Roxanne M. Parslow, Alison Shaw, Kirstie L Haywood, Esther Crawley in Journal of Patient-Reported Outcomes Vol 3, p 67 [First Online 09 November 2019]

 

Research abstract:

Background:
There is a lack of patient derived, child specific outcome measures to capture what health outcomes are important to children with Chronic Fatigue Syndrome/ Myalgic Encephalopathy (CFS/ME). We developed a new Patient Reported Outcome Measure (PROM) for paediatric CFS/ME through qualitative research with children. This study aimed to pre-test the new measure through cognitive interviews with children with CFS/ME.

Methods:
Cognitive interviews were undertaken in children’s homes or over Skype. The Three-Step Test-Interview (TSTI) method was used to assess the quality of the draft PROM with children with CFS/ME to identify problems with initial content and design and test modifications over subsequent interview rounds. Children were purposively sampled from a single specialist paediatric CFS/ME service in England.

Results:
Twenty-four children and their parents took part. They felt the new measure captured issues relevant to their condition and preferred it to the generic measures they completed in clinical assessment. Changes were made to item content and phrasing, timeframe and response options and tested through three rounds of interviews.

Conclusions:
Cognitive interviews identified problems with the draft PROM, enabling us to make changes and then confirm acceptability in children aged 11-18. Further cognitive interviews are required with children 8-10 years old to examine the acceptability and content validity and provide evidence for age related cut offs of the new PROM to meet FDA standards. This study demonstrates the content validity of the new measure as relevant and acceptable for children with CFS/ME. The next stage is to undertake a psychometric evaluation to support the reduction of items, confirm the structure of the PROM and provide evidence of the data quality, reliability and validity.

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Survey of severe ME – help inform the NICE guidelines

Survey of severe ME

Dr Keith Geraghty & Manchester University are conducting a study to better understand the needs and views of patients with severe ME/CFS.

This project has been commissioned by the National Institute of Health and Care Excellence (NICE) to  provide them with up-to-date information that might help inform the NICE Guideline Committee as they to undertake a review of treatment guidelines for this illness.

Who is eligible to take part?

  • adults aged 18 and over, living in England & Wales.
  • they want to hear from you if you consider you have been severely affected / limited by ME.
  • If that was in the past and you have improved, they still want to hear from you.

About the questionnaire

  • Short deadline to meet NICE’s requirements: 20th November
  • Available online only, but you can preview the questions here
  • It could take 45 mins to complete but you can save pages to pace yourself.

If you change your mind

You are able to opt out of this study within 2 weeks after you complete the online survey. After this time your data may form part of a report or dataset that cannot be changed. You can have your personal details deleted at anytime.

More information & to take part in the survey: https://t.co/aas8FKNq4C

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A logistic regression analysis of risk factors in ME/CFS pathogenesis

A logistic regression analysis of risk factors in ME/CFS pathogenesis, by Eliana M Lacerda, Keith Geraghty, Caroline C Kingdon, Luigi Palla & Luis Nacul in BMC Neurology vol 19, no: 275 (2019)

 

Research abstract:

Background:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whose exact cause remains unclear. A wide range of risk factors has been proposed that helps understanding potential disease pathogenesis. However, there is little consistency for many risk factor associations, thus we undertook an exploratory study of risk factors using data from the UK ME/CFS Biobank participants. We report on risk factor associations in ME/CFS compared with multiple sclerosis participants and healthy controls.

Methods:
This was a cross-sectional study of 269 people with ME/CFS, including 214 with mild/moderate and 55 with severe symptoms, 74 people with multiple sclerosis (MS), and 134 healthy controls, who were recruited from primary and secondary health services. Data were collected from participants using a standardised written questionnaire. Data analyses consisted of univariate and multivariable regression analysis (by levels of proximity to disease onset).

Results:
A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls. Being single (OR = 4.41, P <= 0.001), having lower income (OR = 3.71, P <= 0.001), and a family history of anxiety is associated with a higher risk of ME/CFS compared to healthy controls only (OR = 3.77, P < 0.001). History of frequent colds (OR = 6.31, P < 0.001) and infections before disease onset (OR = 5.12, P = 0.005), being single (OR = 3.66, P = 0.003) and having lower income (OR = 3.48, P = 0.001), are associated with a higher risk of ME/CFS than MS. Severe ME/CFS cases were associated with lower age of ME/CFS onset (OR = 0.63, P = 0.022) and a family history of neurological illness (OR = 6.1, P = 0.001).

Conclusions:
Notable differences in risk profiles were found between ME/CFS and healthy controls, ME/CFS and MS, and mild-moderate and severe ME/CFS. However, we found some commensurate overlap in risk associations between all cohorts. The most notable difference between ME/CFS and MS in our study is a history of recent infection prior to disease onset. Even recognising that our results are limited by the choice of factors we selected to investigate, our findings are consistent with the increasing body of evidence that has been published about the potential role of infections in the pathogenesis of ME/CFS, including common colds/flu.

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Differentiating post-polio syndrome from ME & CFS

Differentiating post-polio syndrome from myalgic encephalomyelitis and chronic fatigue syndrome, by Lauren Klebek, Madison Sunnquist & Leonard A Jason in Fatigue: Biomedicine, Health & Behavior.  Published online: 06 Nov 2019 [doi.org/10.1080/21641846.2019.1687117]

 

Research abstract:

Background: 

Overlapping and concomitant symptoms among similar chronic illnesses have created difficulties for diagnosis and further treatment. Three such chronically fatiguing illnesses, Post-polio syndrome (PPS), Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS) fall under this category.

Purpose: 

The aim of this study is to examine and distinguish between core symptoms found in these illnesses (i.e. muscle pain/weakness, fatigue or exhaustion, and autonomic symptoms) via three methods of analysis (DePaul Symptom Questionnaire 2 (DSQ-2), Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and machine learning techniques).

Results: 

Items assessing onset and severity for individuals who reported having PPS were found to have experienced an onset of PPS related symptoms roughly 30 years after the onset of Polio. Items found in the DSQ-2, SF-36 compared all illness groups and found that participants with ME/CFS were more functionally impaired across symptoms than those with PPS. Across all analyses, three domains most commonly differentiated the illnesses (neurocognitive, Post-exertional malaise, and neuroendocrine).

Conclusion: 

Examining functional impairment amongst chronically fatiguing illnesses using multiple methods of analysis can be an important factor in distinguishing similar illnesses. These findings support further analysis of analogous symptomatology among other chronic illnesses to assist in diagnosis.

Read the full paper

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Video lecture by Dr Lucinda Bateman: Upright activity & exercise intolerance: critical concepts in the evaluation of chronic fatigue

Upright activity and exercise intolerance: critical concepts in the evaluation of chronic fatigue, by Dr Lucinda Bateman

 

Dr Bateman talks to doctors.  Duration 56 minutes.

Topics covered:

  • how she assesses and diagnoses patients with ME/CFS
  • the questionnaires she gets them to fill in before they see her include the whole of the SF-36 (Rand-36) questionnaire, not just physical function, the fibromyalgia impact questionnaire, questions about hours of upright activity (feet on floor) on good and bad days
  • Post exertional malaise – what it is, and some research relating to it
  • the importance of staying within the energy envelope and some research that showed that those patients who successfully managed their activity to stay within their envelope stabilised and gradually improved over time, and those who didn’t got worse.
  • orthostatic intolerance including 10 minute stand test and pulse, blood pressure and pulse pressure changes.
  • cognitive problems

Dr Lucinda Bateman has run a clinic for patients with ME/CFS and Fibromyalgia in Utah, USA since 2000: Bateman Horne Center

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Rethinking the standard of care for ME/CFS

Rethinking the standard of care for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Fred Friedberg, Madison Sunnquist, Luis Nacul in Journal of General Internal Medicine, Published online: 21 October 2019 [doi.org/10.1007/s11606-019-05375-y ]

 

Article abstract:

For over two decades, the standard of care for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been cognitive behavior therapy (CBT) and graded exercise therapy (GET). Both interventions had been recommended by the US Centers for Disease Control and the UK NICE guidelines.1

Behavioral intervention as the clinical standard was given a considerable boost by the 5 million–pound PACE trial, a large multi-arm randomized trial of CBT and GET launched in 2007.2 This British government–funded trial was intended to definitively answer whether such interventions were beneficial in ME/CFS. In their 2011 and 2013 publications, the PACE trial authors announced with widespread publicity that 22% of their patients had “recovered” and 59–61% had clinically improved across the CBT and GET interventions.2, 3

More generally, multiple literature reviews have reported that these therapies are not only effective at improving fatigue and, to a lesser extent, physical function in ME/CFS but also safe.4, 5, 6 It would seem obvious then that good clinical care of these patients would include these behavioral interventions. But, a closer look at these trials has generated many concerns about their applicability to these patients. This perspective critically examines their findings and more generally discusses the behavioral intervention literature in ME/CFS. Finally, we briefly describe a pragmatic clinical approach for these often-marginalized patients.

CARING FOR ME/CFS PATIENTS

In clinical practice, many individuals presenting with the common symptom of persistent fatigue may benefit from activity-based behavioral interventions, e.g., Friedberg et al.26 However, persistent fatigue is not equivalent to the multi-symptom debilitating illness of ME/CFS. Despite the lack of approved treatments or a fully articulated standard of medical care, there are still many actions physicians can take to help these underserved patients. First, practitioners can acknowledge the biomedical reality of the illness and their belief that the patient is genuinely ill. Next, clinicians can help patients to better manage a major illness challenge: how to minimize debilitating post-exertional malaise by learning to stay within their energy envelope.36

The energy envelope delineates the amount of energy that a ME/CFS patient has available to perform all activities.37 The size of this energy envelope can vary from day to day and between patients with some patients lacking energy for basic activities of daily living. When patients exceed their limited energy levels, they experience post-exertional worsening of symptoms and functioning. Medical providers can teach patients how to recognize their own personal energy limits and use pacing (dividing symptom-producing activities into smaller parts with interspersed rest intervals) to stay within those limits.34, 37 Once pacing is effectively used, some patients may be able to use an individualized exercise plan to increase available energy and functioning while avoiding post-exertional worsening.34, 36

Practitioners can also help patients with appropriate pharmacological and non-pharmacological treatments.38, 39 This includes treatments for unrefreshing sleep, e.g., trazodone and low-dose tricyclic antidepressants, and sleep hygiene measures.

In addition, pain can be addressed with low-dose naltrexone40 and anti-epileptics, e.g., gabapentin, and orthostatic intolerance can be treated with fludrocortisone and salt loading. Comorbidities can be managed using standard of care. Drugs should usually be started at low doses because patients can be sensitive to medications. If needed, patients can be referred to counseling to improve coping with the severe impacts of ME/CFS on quality of life.

For optimal patient care, we recommend a ME/CFS specialist or a specialist center supported by a multi-disciplinary team. Unfortunately, few of these practitioners or centers are available, which highlights the need for provider education and training regarding this illness. Realistically, when specialists are not available, care is best provided by the generalist (internal medicine or family doctor) working as part of a multidisciplinary team including expertise (as available) in immunology, infectious disease, cardiology or neurology, psychology, occupational therapy, and social work. With this interprofessional approach, practitioners can lessen harms while helping patients improve their health, function, and quality of life to the extent possible.

Further information on clinical management may be found in the following sources: a free practitioner’s guide to ME/CFS,34 a clinically focused review, 41 and a pragmatic clinical paper.36

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Is a diagnostic blood test for CFS on the horizon?

Is a diagnostic blood test for chronic fatigue syndrome on the horizon?, by
Michael Maes, Laura Andres & Gerwyn Morris in Expert Review of Molecular Diagnostics, Published online: 18 Oct 2019 [https://doi.org/10.1080/14737159.2020.1681976]

 

Expert opinion

Most if not all biomarkers of ME/CFS are pathway biomarkers although a few etiologic or predisposing biomarkers were delineated. These biomarkers indicate the multiple immune, oxidative, and metabolic pathways that underpin the pathophysiology of ME/CFS.

However, until now, no diagnostic, treatment or staging biomarkers could be developed and, therefore, future research should develop those types of biomarkers employing data mining models with biomarkers of the pathways described herein as input variables. Moreover, pathway-phenotype algorithms should be modeled which may be used to diagnose biomarker-validated symptom dimensions including disabling fatigue, cognitive impairments, post-exertional malaise, fibromyalgia-like symptoms, and irritable bowel syndrome.

All in all, a new ME/CFS diagnostic blood test useful to make the diagnosis of ME/CFS is not yet on the horizon. The way forward is to develop adequate diagnostic criteria based on machine learning and to combine biomarkers and clinical phenotypes into pathway-phenotypes using machine learning techniques.

Read the authors’ review of the research into biomarkers so far.

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