ME/CFS patients exhibit altered T cell metabolism & cytokine associations

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations, by Alexandra H Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L Peterson, Marco Maynard, C Gunnar Gottschalk, and Maureen R Hanson in J Clin Invest. 2019. [First published December 12, 2019] https://doi.org/10.1172/JCI132185

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease.

ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients.

To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines.

We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects.

Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

 

Video: Dr Alexandra Mandarano explains the research in this paper.

NIH press release: Study finds differences in energy use by immune
cells in ME/CFS

Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.

“Our work demonstrates the importance of looking at particular types of immune cells that have different jobs to do, rather than looking at them all mixed together, which can hide problems specific to particular cells,” said Dr. Hanson. “Additional studies focusing on specific cell types will be important to unravel what’s gone wrong with immune defenses in ME/CFS.”

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Intimate partner violence & the risk of developing FM & CFS

Intimate partner violence and the risk of developing Fibromyalgia and Chronic Fatigue Syndrome, by Joht Singh Chandan, Tom Thomas, Karim Raza, Caroline Bradbury-Jones, Julie Taylor, Siddhartha Bandyopadhyay, Krishnarajah Nirantharakumar in Journal of Interpersonal Violence, December 6, 2019 [https://doi.org/10.1177/0886260519888515]

 

Research abstract:

Intimate partner violence (IPV) is a global public health issue with a variety of ill health consequences associated with exposure.

Due to the stimulation of chronic stress and inflammatory pathways, childhood abuse has been associated with the subsequent development of functional syndromes such as fibromyalgia and chronic fatigue syndrome (CFS). Although IPV in women appears to elicit similar biochemical responses, this association has not been tested thoroughly in IPV survivors. These functional syndromes are complex in etiology and any indication of their risk factors would benefit health care professionals managing this population. Therefore, we aimed to investigate the association between exposure to IPV with functional syndromes: fibromyalgia and CFS.

We conducted a retrospective open cohort study using “The Heath Improvement Network” database between January 1, 1995 and December 1, 2017. A total of 18,547 women who were exposed to IPV were each matched by age to four controls who were not exposed (n = 74,188). The main outcome measures were the risk of developing fibromyalgia and CFS.

These were presented as adjusted incidence rate ratios (aIRR) with 95% confidence intervals (CIs). We found that 97 women in the exposed group developed fibromyalgia (incidence rate [IR] = 1.63 per 1,000 person-years) compared to 239 women in the unexposed group (IR = 0.83 per 1,000 person-years). Following adjustment, this translated to an IRR of 1.73 (95% CI = [1.36, 2.22]).

Similarly, 19 women developed CFS in the exposed group (IR = 0.32 per 1,000 person-years), compared to 53 in the unexposed group (0.18 per 1,000 person-years), which translates to an aIRR of 1.92 (95% CI = [1.11, 3.33]).

Therefore, we have identified an association between a history of IPV in women and the development of these functional syndromes, which may provide more information to inform the biopsychosocial pathway precipitating the development of fibromyalgia and CFS.

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Press release: Domestic abuse survivors twice at risk of long-term illnesses

…the research shows that women who have experienced domestic abuse are almost twice as likely to develop fibromyalgia and chronic fatigue syndrome (CFS) than those who have not.

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Circulating levels of GDF15 in patients with ME/CFS

Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome, by A Melvin, E Lacerda, H M Dockrell, S O’Rahilly & L Nacul in Journal of Translational Medicine vol 17, no. 409 (2019)

 

Research abstract:

Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterised by fatigue and post-exertional malaise. Its pathogenesis is poorly understood. GDF15 is a circulating protein secreted by cells in response to a variety of stressors. The receptor for GDF15 is expressed in the brain, where its activation results in a range of responses. Among the conditions in which circulating GDF15 levels are highly elevated are mitochondrial disorders, where early skeletal muscle fatigue is a key symptom. We hypothesised that GDF15 may represent a marker of cellular stress in ME/CFS.

Methods:
GDF15 was measured in serum from patients with ME/CFS (n = 150; 100 with mild/moderate and 50 with severe symptoms), “healthy volunteers” (n = 150) and a cohort of patients with multiple sclerosis (n = 50).

Results:
Circulating GDF15 remained stable in a subset of ME/CFS patients when sampled on two occasions ~ 7 months (IQR 6.7–8.8) apart, 720 pg/ml (95% CI 625–816) vs 670 pg/ml (95% CI 598–796), P = 0.5. GDF15 levels were 491 pg/ml in controls (95% CI 429–553), 546 pg/ml (95% CI 478–614) in MS patients, 560 pg/ml (95% CI 502–617) in mild/moderate ME/CFS patients and 602 pg/ml (95% CI 531–674) in severely affected ME/CFS patients. Accounting for potential confounders, severely affected ME/CFS patients had GDF15 concentrations that were significantly increased compared to healthy controls (P = 0.01). GDF15 levels were positively correlated (P = 0.026) with fatigue scores in ME/CFS.

Conclusions:
Severe ME/CFS is associated with increased levels of GDF15, a circulating biomarker of cellular stress that appears which stable over several months.

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ME/CFS: investigating care practices pointed out to disparities in diagnosis & treatment across European Union

Myalgic encephalomyelitis/chronic fatigue Syndrome (ME/CFS): Investigating care practices pointed out to disparities in diagnosis and treatment across European Union
Elin B Strand, Luis Nacul, Anne Marit Mengshoel, Ingrid B Helland, Patricia Grabowski, Angelika Krumina, Jose Alegre-Martin, Magdalena Efrim-Budisteanu, Slobodan Sekulic, Derek Pheby, Giorgos K Sakkas, Carmen Adella Sirbu, F Jerome Authier, on behalf of the European Network on ME/CFS (EUROMENE) in PLoS ONE 14(12): e0225995, Dec 2019[https://doi.org/10.1371/journal.pone.0225995]

 

Research abstract:

ME/CFS is a chronic, complex, multisystem disease that often limits the health and functioning of the affected patients. Diagnosing patients with ME/CFS is a challenge, and many different case definitions exist and are used in clinical practice and research. Even after diagnosis, medical treatment is very challenging. Symptom relief and coping may affect how patients live with their disease and their quality of life. There is no consensus on which diagnostic criteria should be used and which treatment strategies can be recommended for patients.

The purpose of the current project was to map the landscape of the Euromene countries in respect of national guidelines and recommendations for case definition, diagnosis and clinical approaches for ME/CFS patients.

A 23 items questionnaire was sent out by email to the members of Euromene. The form contained questions on existing guidelines for case definitions, treatment/management of the disease, tests and questionnaires applied, and the prioritization of information for data sampling in research.

We obtained information from 17 countries. Five countries reported having national guidelines for diagnosis, and five countries reported having guidelines for clinical approaches. For diagnostic purposes, the Fukuda criteria were most often recommended, and also the Canadian Consensus criteria, the International Consensus Criteria and the Oxford criteria were used. A mix of diagnostic criteria was applied within those countries having no guidelines.

Many different questionnaires and tests were used for symptom registration and diagnostic investigation. For symptom relief, pain and anti-depressive medication were most often recommended. Cognitive Behavioral Therapy and Graded Exercise treatment were often recommended as disease management and rehabilitative/palliative strategies.

The lack of consistency in recommendations across European countries urges the development of regulations, guidance and standards. The results of this study will contribute to the harmonization of diagnostic criteria and treatment for ME/CFS in Europe.

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Identification of actin network proteins, talin-1 & filamin-A, in circulating extracellular vesicles as blood biomarkers for human ME/CFS

Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/ chronic fatigue syndrome, by Akiko Eguchi, Sanae Fukuda, Hirohiko Kuratsune, Junzo Nojima, Yasuhito Nakatomi, Yasuyoshi Watanabe, Ariel E Feldstein, in Brain, Behavior, and Immunity November 2019 [ https://doi.org/10.1016/j.bbi.2019.11.015]

 

Highlights

  • Circulating EV number was increased in ME/CFS patients correlating to CRP and BAP.
  • AUROC for circulating EVs was 0.802 allowing correct diagnosis in 90–94% of ME/CFS.
  • Proteins in actin skeletal regulation and EB virus infection were identified in ME/CFS patients.
  • Talin-1, filamin-A and 14-3-3 proteins were the most abundant proteins representing highly specific ME/CFS.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years.

Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS.

We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90–94% of ME/CFS cases.

From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers.

Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.

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Is CFS related to a crash of the brain attention mechanism – hypervigilance correlates with fatigue & pain scales among individuals with CFS

Is Chronic fatigue syndrom (CFS) related to a crash of the brain attention mechanism – Hypervigilance correlates with fatigue and pain scales among individuals with CFS, by Camilla Marylene Minani. Master thesis, Norwegian University of Science and Technology, 2019.

 

Research abstract:

Chronic fatigue syndrome (CFS) is a disabling condition. About 70–85% of those affected attribute their daily dysfunction to reduced cognitive abilities and muscle pains in various parts of the body.

Neuroimaging studies point to structural and functional abnormalities of the central nervous system, with no relationship to the reported fatigue and pain scales. This complicates the development of the diagnosis. Evidence shows that mental fatigue and pain affect the efficiency of cognitive control.

Event-related potentials (ERPs) recorded from the human scalp provide essential information about how the human brain normally processes information and about how this processing becomes abnormal in neurological or psychiatric disorders.

Method: A visual continuous performance task (vCPT) requires sustained attention to respond to relevant visual cues and refrain from responding to irrelevant stimuli. In this study, after completing the Chalder and pain inventory tests, a vCPT test was administered to 42 individuals complying with the Fukuda criteria of CFS diagnosis.

Event-related potentials (ERPs), which show direct brain response to stimuli, were retrieved and compared to a database of health 102 health individuals. A correlation and regression analysis of the ERPs was then conducted and compared to self-rated fatigue and pain inventory tests.

Results and Discussion: Compared to the database, an enhanced P3cue component reflected hyper-vigilance amongst unexplained chronic fatigue patients along with delayed motor response and reduced error-detection resources, indicating abnormalities in executive function. This suggests that CFS could be related to central sensitisation due to long-term stress exposure.

Full paper not available

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ME/CFS NICE guideline publication to be delayed

NICE has announced:

Please note that the publication date for the ME/CFS guideline is changing from 14th October 2020 to 9th December 2020.

This is to ensure that the committee have sufficient time to consider both the findings from the call for evidence, and from the two additional pieces of group work we have undertaken in children & young people with ME/CFS, and people with severe ME/CFS.

Consultation on the draft guideline will now run from 30th June 2020 to 11th August 2020.

 

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The effect of curcumin in patients with CFS/ME

The effect of curcumin in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis disparate responses in different disease severities, by C (Linda) MC van Campen and Frans C Visser in Pharmacovigil and Pharmacoepi  Vol 2 Issue 1, pages 6, Nov 19, 2019

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a chronic and often disabling disease. Although the exact pathophysiological mechanism of ME/CFS is unknown, immunological abnormalities may play an important role.

Curcumin is an herb with powerful anti-oxidative and anti-inflammatory properties. Therefore, we hypothesized that curcumin would have favorable effects on symptomatology in ME/CFS patients.

In an open trial among 65 ME/CFS participants, 6 stopped the use of curcumin because of side effects and 8 did not complete the end of study questionnaire. Before and 8 weeks after the use of curcumin complexed with phosphatidyl choline-, 500 mg bid, participants completed the CDC inventory for assessment of Chronic Fatigue Syndrome. The CDC questions (n=19) were scored and divided into 2 parts: the first being specific for CFS complaints (n=9), the second being scores of less specific symptoms (n=10); denoted as CDC other score.

Results showed that 8 weeks of curcumin significantly decreased the CDC CFS-related symptom scores and CDC other scores, especially in patients with mild disease.

Conclusion: in this open-labeled study 8 week curcumin use in a phosphatidyl choline complex reduced ME/CFS symptomatology, especially in patients with mild disease severity.

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Prevalence & treatment of CFS/ME & co-morbid severe health anxiety

Prevalence and treatment of Chronic Fatigue Syndrome/ME and co-morbid severe health Anxiety, by Jolene Daniels, Paul Salkovskis, Hannah Parker  in Journal of the International Neuropsychological Society, Nov 2019

 

Research abstract:

Background: Chronic Fatigue Syndrome/ME (CFS/ME) is a debilitating condition that affects 0.2–0.4% of the population.

Health focussed anxiety is common across medical conditions, and may be relevant in CFS/ME. This study sought to identify the prevalence and impact of health anxiety (HA) in CFS/ME and evaluate the effectiveness of Cognitive Behavioural Therapy for HA in CFS/ME.

Method: Cross sectional questionnaire methods and case-series design were used to achieve study aims.

Results: Analysis indicated that 41.9% of the CFS/ME clinic sample experienced threshold levels of health anxiety, which was associated with elevated symptom severity across several dimensions.  Stepwise multiple regression indicated physical functioning and depression accounted for 23.8% of variance in fatigue; depression, fatigue and HA, accounted for 32.9% of variance in physical functioning. Large effect sizes and clinically significant changes were generated in the treatment study.

Conclusion: HA is common in CFS/ME and likely to exacerbate fatigue and physical functioning. This study identifies HA as an important target for treatment, trial findings should be further replicated on a larger scale.

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Modification of immunological parameters, oxidative stress markers, mood symptoms, & well-being status in CFS patients after probiotic intake

Modification of immunological parameters, oxidative stress markers, mood symptoms, and well-being status in CFS patients after probiotic intake: observations from a pilot study, by Letizia Venturini, Sara Bacchi, Enrica Capelli, Lorenzo Lorusso, Giovanni Ricevuti, and Chiara Cusa in Oxidative Medicine and Cellular Longevity Vol 2019, 10 pages, 23 November 2019 [https://doi.org/10.1155/2019/1684198]

 

Research abstract:

The present study discusses about the effects of a combination of probiotics able to stimulate the immune system of patients affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

To this purpose, patients diagnosed according to Fukuda’s criteria and treated with probiotics were analyzed by means of clinical and laboratory evaluations, before and after probiotic administrations. Probiotics were selected considering the possible pathogenic mechanisms of ME/CFS syndrome, which has been associated with an impaired immune response, dysregulation of Th1/Th2 ratio, and high oxidative stress with exhaustion of antioxidant reserve due to severe mitochondrial dysfunction.

Immune and oxidative dysfunction could be related with the gastrointestinal (GI) chronic low-grade inflammation in the lamina propria and intestinal mucosal surface associated with dysbiosis, leaky gut, bacterial translocation, and immune and oxidative dysfunction.

Literature data demonstrate that bacterial species are able to modulate the functions of the immune and oxidative systems and that the administration of some probiotics can improve mucosal barrier function, modulating the release of proinflammatory cytokines, in CFS/ME patients.

This study represents a preliminary investigation to verifying the safety and efficacy of a certain combination of probiotics in CFS/ME patients.

The results suggest that probiotics can modify the well-being status as well as inflammatory and oxidative indexes in CFS/ME patients. No adverse effects were observed except for one patient, which displayed a flare-up of symptoms, although all inflammatory parameters (i.e., cytokines, fecal calprotectin, ESR, and immunoglobulins) were reduced after probiotic intake. The reactivation of fatigue symptoms in this patient, whose clinical history reported the onset of CFS/ME following mononucleosis, could be related to an abnormal stimulation of the immune system as suggested by a recent study describing an exaggerated immune activation associated with chronic fatigue.

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