Biomarker research: Skewing of the B cell receptor repertoire in ME/CFS

Posted on 07/09/2021 by wames

Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/ chronic fatigue syndrome, by Wakiro Sato, Hirohiko Ono, Takaji Matsutani, Masakazu Nakamura, Isu Shin, Keiko Amano, Ryuji Suzuki, Takashi Yamamura in Brain, Behavior, and Immunity, Vol 95, July 2021, Pages 245-255

 

Highlights

  • ME/CFS is characterized by skewed B cell receptor gene usage.
  • Upregulation of specific IGHV genes correlated to infection-related episodes at onset.
  • Plasmablasts of ME/CFS patients upregulated interferon response genes.
  • B cell receptor repertoire analysis can provide a useful diagnostic marker in ME/CFS.

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system.

By CNX OpenStax - http://cnx.org/contents/GFy_h8cu@10.53:rZudN6XP@2/Introduction, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=49935883

Structure of the B cell receptor

Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire.

Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts.

Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.

From the Discussion:

In conclusion, we demonstrated that specific BCR IGH usage is selectively upregulated in ME/CFS patients compared with HCs. Among the upregulated genes, IGHV3-30/3-30-3 are associated with an infection-related episode before disease onset, with relatively short disease duration and with the expression of type 1 IFN response genes in PB. BCR repertoire analysis could be developed as a powerful tool to help diagnose ME/CFS. It may also be used to predict the efficacy of B cell-targeted therapy, which is effective in a subgroup of patients.

NCNP: Discovery of Immune Biomarkers for Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) based on B cell receptor repertoire analysis

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Bioenergetic & proteomic profiling of immune cells in ME/CFS patients

Posted on 07/08/2021 by wames

Bioenergetic and proteomic profiling of immune cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients: an exploratory study, by Paula Fernandez-Guerra, Ana C Gonzalez-Ebsen, Susanne E Boonen, Julie Courraud, Niels Gregersen, Jesper Mehlsen, Johan Palmfeldt, Rikke K J Olsen, Louise Schouborg Brinth in Biomolecules 2021 Jun 29;11(7):961 [doi: 10.3390/biom11070961]

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous, debilitating, and complex disease. Along with disabling fatigue, ME/CFS presents an array of other core symptoms, including autonomic nervous system (ANS) dysfunction, sustained inflammation, altered energy metabolism, and mitochondrial dysfunction.

Here, we evaluated patients’ symptomatology and the mitochondrial metabolic parameters in peripheral blood mononuclear cells (PBMCs) and plasma from a clinically well-characterised cohort of six ME/CFS patients compared to age- and gender-matched controls.

We performed a comprehensive cellular assessment using bioenergetics (extracellular flux analysis) and protein profiles (quantitative mass spectrometry-based proteomics) together with self-reported symptom measures of fatigue, ANS dysfunction, and overall physical and mental well-being.

This ME/CFS cohort presented with severe fatigue, which correlated with the severity of ANS dysfunction and overall physical well-being. PBMCs from ME/CFS patients showed significantly lower mitochondrial coupling efficiency. They exhibited proteome alterations, including altered mitochondrial metabolism, centred on pyruvate dehydrogenase and coenzyme A metabolism, leading to a decreased capacity to provide adequate intracellular ATP levels.

Overall, these results indicate that PBMCs from ME/CFS patients have a decreased ability to fulfill their cellular energy demands.

From study Discussion (4):

…in this study, we aimed to recruit a homogenous group of ME/CFS patients and applied strategies for personalised medicine by performing many tests in a few individuals to shed light on molecular mechanisms of disease in these individuals.

Despite the small sample size, our data indicate a dysregulated mitochondrial metabolism centred on PDH and CoA metabolism, which supports findings from other and larger ME/CFS cohorts [29].

Interestingly, between 35 and 40% of ME/CFS patients experience significant improvement in their health when treated with dichloroacetate, a well-known activator of PDH [74,75]. These open-label studies need further follow-up; however, together with the present study and the previous metabolomics and proteomic studies of independent ME/CFS cohorts, they support dysregulated mitochondrial metabolism as an important feature of ME/CFS pathology.

To some degree, abnormalities in bioenergetics parameters of blood cells have shown to correlate with the severity of ME/CFS symptoms [31,76]. Similarly, coupling efficiency correlated with symptom severity and disease duration in our cohort of ME/CFS patients.

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Female patients with ME/CFS or idiopathic chronic fatigue: comparison of responses to a 2-day CPET protocol

Posted on 07/07/2021 by wames

Female patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: comparison of responses to a Two-Day Cardiopulmonary Exercise Testing protocol, by C Linda M C van Campen, Frans C Visser in Healthcare (Basel) 2021 Jun 5;9(6):682 [doi: 10.3390/healthcare9060682] This article belongs to the Special Issue Sport and Exercise Medicine

 

Research abstract

Introduction:

Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a female population and hypothesized a different pattern of response would be present during the 2nd day CPET.

Methods:

Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities.

Results:

Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload.

Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations.

Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls, [suggesting that despite fatigue complaints of similar severity, a different disease is present and ICF might be trainable, whereas ME/CFS is not. – comment from full paper]

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Medical care situation of people with ME/CFS in Germany

Posted on 07/06/2021 by wames

Medical care situation of people with Myalgic Encephalomyelitis /Chronic Fatigue Syndrome in Germany, by Laura Froehlich, Daniel B.R. Hattesohl, Leonard A. Jason, Carmen Scheibenbogen, Uta Behrends, Manuel Thoma in Medicina Vol 57, #7, p 646, June 23, 2021 [doi.org/10.3390/medicina57070646] This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis

 

Research abstract

Background and Objective:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe illness with the hallmark symptom of Post-Exertional Malaise (PEM).

Currently, no biomarkers or established diagnostic tests for ME/CFS exist. In Germany, it is estimated that over 300,000 people are affected by ME/CFS. Research from the United States and the UK shows that patients with ME/CFS are medically underserved, as they face barriers to medical care access and are dissatisfied with medical care.

The first aim of the current research was to investigate whether patients with ME/CFS are medically underserved in Germany in terms of access to and satisfaction with medical care. Second, we aimed at providing a German-language version of the DePaul Symptom Questionnaire Short Form (DSQ-SF) as a tool for ME/CFS diagnostics and research in German-speaking countries.

Materials and Methods:

The current research conducted an online questionnaire study in Germany investigating the medical care situation of patients with ME/CFS. The questionnaire was completed by 499 participants who fulfilled the Canadian Consensus Criteria and reported PEM of 14 h or longer.

Results:

Participants frequently reported geographic and financial reasons for not using the available medical services. Furthermore, they reported low satisfaction with medical care by the physician they most frequently visited due to ME/CFS. The German version of the DSQ-SF showed good reliability, a one-factorial structure and construct validity, demonstrated by correlations with the SF-36 as a measure of functional status.

Conclusions:

Findings provide evidence that patients with ME/CFS in Germany are medically underserved. The German-language translation of the DSQ-SF provides a brief, reliable and valid instrument to assess ME/CFS symptoms to be used for research and clinical practice in German-speaking countries. Pathways to improve the medical care of patients with ME/CFS are discussed.

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Comparing idiopathic chronic fatigue & ME/CFS in males: response to 2-day CPET protocol

Posted on 07/06/2021 by wames

Comparing Idiopathic Chronic Fatigue and Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) in males: response to Two-Day Cardiopulmonary Exercise Testing protocol, by C Linda M C van Campen, Frans C Visser in Healthcare (Basel). 2021 Jun 5;9(6):683 [doi: 10.3390/healthcare9060683]

 

Research abstract:

(1) Introduction:

Multiple studies have shown that peak oxygen consumption is reduced in the majority of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) patients, using the gold standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols.

We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET.

(2) Methods:

We compared 25 male patients with ICF who had completed a 2-day CPET protocol to an age-/gender-matched group of 26 male ME/CFS patients.

Measures of oxygen consumption (VO2), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities.

(3) Results:

Baseline characteristics for both groups were similar for age, body mass index (BMI), body surface area, (BSA), and disease duration.

A significant difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs. zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001).

ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO2 and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload.

(4) Conclusion:

This study confirms that male ME/CFS patients have a reduction in exercise capacity in response to a second-day CPET. These results are similar to published results in male ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.

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Systematic review of mind-body interventions to treat ME/CFS

Posted on 07/05/2021 by wames

Systematic review of mind-body interventions to treat Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Samaneh Khanpour Ardestani, Mohammad Karkhaneh, Eleanor Stein, Salima Punja, Daniela R. Junqueira, Tatiana Kuzmyn, Michelle Pearson, Laurie Smith, Karin Olson, Sunita Vohra in Medicina Vol 57, #7, p 652, June 24, 2021 [doi.org/10.3390/medicina57070652] This article belongs to the Special Issue ME/CFS: Causes, Clinical Features and Diagnosis

 

Review abstract:

Background and Objectives

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic condition distinguished by disabling fatigue associated with post-exertional malaise, as well as changes to sleep, autonomic functioning, and cognition. Mind-body interventions (MBIs) utilize the ongoing interaction between the mind and body to improve health and wellbeing.

Purpose

To systematically review studies using MBIs for the treatment of ME/CFS symptoms.

Materials and Methods

MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane CENTRAL were searched (inception to September 2020). Interventional studies on adults diagnosed with ME/CFS, using one of the MBIs in comparison with any placebo, standard of care treatment or waitlist control, and measuring outcomes relevant to the signs and symptoms of ME/CFS and quality of life were assessed for inclusion.

Characteristics and findings of the included studies were summarized using a descriptive approach.

Results

12 out of 382 retrieved references were included. Seven studies were randomized controlled trials (RCTs) with one including three reports (1 RCT, 2 single-arms); others were single-arm trials. Interventions included mindfulness-based stress reduction, mindfulness-based cognitive therapy, relaxation, Qigong, cognitive-behavioral stress management, acceptance and commitment therapy and isometric yoga.

The outcomes measured most often were fatigue severity, anxiety/ depression, and quality of life. Fatigue severity and symptoms of anxiety/depression were improved in nine and eight studies respectively, and three studies found that MBIs improved quality of life.

Conclusions

Fatigue severity, anxiety/depression and physical and mental functioning were shown to be improved in patients receiving MBIs. However, small sample sizes, heterogeneous diagnostic criteria, and a high risk of bias may challenge this result. Further research using standardized outcomes would help advance the field.

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Central autonomic network disturbance in ME/CFS

Posted on 07/02/2021 by wames

Central autonomic network disturbance in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: a pilot study, by Mark Zinn, Marcie L Zinn, Leonard A Jason in NeuroRegulation Vol 8, #2, pp 73-86, June 30 2021

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease of the central nervous system known to be associated with multiple behavioral symptoms (fatigue, low stamina, dizziness, etc.) combined with autonomic nervous system (ANS) dysfunction, thus implicating the central autonomic network (CAN).

Post-exertional malaise (PEM) is a core feature of ME/CFS, characterized by a pathological reduction in stamina in response to performing minor physical or mental tasks, often lasting at least 24 hours.

Exact low-resolution electromagnetic tomography (eLORETA) allows non-invasive investigation of cortical regions of interest that may contribute to better understanding of the role of the brain disturbances in behavioral manifestations of PEM.

This pilot study therefore aimed to use eLORETA to characterize changes in current density in cortical structures related to the CAN following submaximal isometric handgrip exercise in 7 patients with ME/CFS and 6 neurotypical healthy controls (HCs). Resting EEG was recorded at pre-, post- handgrip, and 24 hours later. Findings showed that hand grip dynamometersignificant differences occurred immediately post-test, which were most pronounced after 24 hours, particularly in the low alpha (8-10 Hz) and low beta (13-18 Hz) frequency sub-bands. Together, the present findings offer support for EEG source localization techniques to investigate PEM. If confirmed, this study could provide a useful instrument for functional diagnosis and evaluation of treatment outcomes.

 

Phoenix rising: Central Autonomic Network Disturbance in People with ME: A Conversation with Dr. Mark Zinn      Aug 2021

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Doctors with ME – new professional association

Posted on 06/30/2021 by wames

Doctors with ME

 

Recently launched is the global professional association for medical practitioners, scientists and researchers with myalgic encephalomyelitis.

The DwME mission and vision:

To improve patient outcomes worldwide by empowering medics, scientists, and policymakers with up to date practices and scientific rigour, fostering collaboration between professionals, the industries they serve, patients and the public.

To build a future where every surgery, hospital, agency, insurance provider and employer is enabled with accurate information that supports their patients, clients, shareholders and wider stakeholders.

Led by doctors with ME

  • Dr KN Hng – founder
  • Dr Nina Muirhead – director
  • Dr Keith Geraghty – director
  • Dr Richard Ramyar – business & strategy advisor

Honorary fellows:

  • Prof Jonathan Edwards – UK
  • Prof Leonard Jason – USA
  • Prof Anthony Komaroff – USA
  • Prof Ian Lipkin – USA
  • Prof Alain Moreau – Canada
  • Prof Derek Pheby – UK
  • Prof Chris Ponting – UK
  • Prof Ron Tompkins – USA
  • Dr Lucinda Bateman – USA
  • Tom Kindlon – Ireland
  • Dr Karl Morten – UK
  • Dr Charles Shepherd – UK
  • Dr David Strain – UK
  • Dr Nigel Speight – UK
  • Dr David Tuller – USA

Find out more about what DwME will be doing and how they will do it.

Like them on Facebook: https://www.facebook.com/doctorswithme/

Follow them on twitter @doctorswithme

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Research: Whole-body cryotherapy & static-stretching exercises in CFS patients

Posted on 06/28/2021 by wames

Changes in the allostatic response to whole-body cryotherapy and static-stretching exercises in Chronic Fatigue Syndrome patients vs. healthy individuals, by Sławomir Kujawski, Anna M Bach, Joanna Slomko, Derek FH Pheby, Modra Murovska, Julia L Newton, Paweł Zalewski in Journal of Clinical Medicine Vol 10, no. 13, p 2795 25 June 2021

 

Research abstract:

This study represents a comparison of the functional interrelation of fatigue and cognitive, cardiovascular and autonomic nervous systems in a group of Chronic Fatigue Syndrome (CFS) patients compared with those in healthy individuals at different stages of analysis: at baseline and after changes induced by whole-body cryotherapy (WBC) combined with a static-stretching (SS) program.

The study included 32 patients (Fukuda criteria) and 18 healthy controls. Fatigue, cognitive, cardiovascular and autonomic function and arterial stiffness were measured before and after 10 sessions of WBC with SS.

In the patients, a disturbance in homeostasis was observed. The network relationship based on differences before and after intervention showed comparatively higher stress and eccentricity in the CFS group: 50.9 p/m 56.1 vs. 6.35 p/m 8.72, p=0.002, r=0.28; and 4.8 p/m 0.7 vs. 2.4 p/m 1, p<0.001, r=0.46, respectively.

Before and after intervention, in the CFS group increased fatigue was related to baroreceptor function, and baroreceptor function was in turn related to aortic stiffness, but no such relationships were observed in the control group. Differences in the network structure underlying the interrelation among the four measured criteria were observed in both groups, before the intervention and after ten sessions of whole cryotherapy with a static stretching exercise.

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Insights from ME/CFS may help unravel the pathogenesis of post-acute COVID-19 syndrome

Posted on 06/28/2021 by wames

Insights from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome may help unravel the pathogenesis of post-acute COVID-19 syndrome, by Anthony L Komaroff, W Ian Lipkin in Trends in Molecular Medicine, 7 June 2021 [doi.org/10.1016/j.molmed.2021.06.002]

 

Highlights:

  • In some people, the aftermath of acute coronavirus disease 2019 (COVID-19) is a lingering illness with fatigue and cognitive defects, known as post–COVID-19 syndrome or ‘long COVID.’
  • Post–COVID-19 syndrome is similar to postinfectious fatigue syndromes triggered by other infectious agents and to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition that patients often report is preceded by an infectious-like illness.
  • ME/CFS is associated with underlying abnormalities of the central and autonomic nervous systems, immune dysregulation, disordered energy metabolism, and redox imbalance. It is currently unclear if the same abnormalities will be identified in post–COVID-19 syndrome.
  • The USA and other developed nations have committed considerable support for research on post–COVID-19 illnesses.

Review abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause chronic and acute disease. Postacute sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys, and brain that may produce a variety of symptoms. PASC also includes a post–coronavirus disease 2019 (COVID-19) syndrome (‘long COVID’) with features that can follow other acute infectious diseases and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Here we summarize what is known about the pathogenesis of ME/CFS and of ‘acute’ COVID-19, and we speculate that the pathogenesis of post–COVID-19 syndrome in some people may be similar to that of ME/CFS.

We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and we suggest a research agenda for both ME/CFS and post–COVID-19 syndrome.

Comment from Health rising: Experts Assert Insights From ME/CFS Needed to Understand Long COVID

We’re just beginning to learn about long COVID, but some possible connections have shown up. Besides the wide overlap in symptoms, the mixed results from attempts to find evidence of the virus in the central nervous system suggest that it’s the “host response to the virus and microvascular damage” occurring from that – rather than the direct effects of the virus – that is probably causing symptoms. Indeed, they believe the virus probably does much of its damage via its effects on the vascular system (blood vessels). The widespread “microinfarcts” found in COVID-19 could be contributing to the cognitive problems found.

These findings alone present plenty of potential overlap with ME/CFS and fibromyalgia, with several studies suggesting the microcirculation, in particular, has been disturbed.

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