Research Roundup: ME/CFS Research Published 1-7 March 2022

March 11, 2022


The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight the studies that have particularly caught our interest and follow these with the full list of publications together with their abstracts (summaries).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

Audio Commentary by Katrina Pears

ME/CFS Research Published 1 – 7 March 2022 

There has been an interesting mix of papers this week, with seven new ME/CFS studies and sixteen studies on Long Covid.  

We have highlighted two of the studies below:  

Paper two (2) is on the use of dietary supplements- coenzyme Q10 (coQ10) plus selenium. The study showed a number of benefits in taking these supplements for ME/CFS patients with: 

  • improvements in fatigue and quality of life, 
  • increased total antioxidant capacity, 
  • reduced lipoperoxide levels, 
  • decreased circulating cytokine levels. 

This paper is behind a paywall so we cannot evaluate the full strength of this study, but we do know that this study was small and only used 27 patients, and there were no controls, making it a weak study. This study shows the need for a fully double blinded trial to be conducted to fully confirm any benefits from taking CoQ10 plus selenium.  

I feel it is likely that these findings will be reproduced in future trails as previously larger studies have also reported benefits of taking CoQ10, such as a recent study by Castro-Marrero et al., 2021, although this looked at using NADH as well.  

Future studies are also needed to understand the pathomechanisms involved in taking these supplements, to explain why these trials are showing benefits. (Please note: the ME association does not endorse supplements, there is currently not enough evidence to support their use for managing symptoms. Please consult your doctor before taking any supplements. We have a range of leaflets available on supplements). 

Paper three (3) while not directly on ME/CFS could have important implications on the pathology of the disease as this study using mice shows that viral infections can lead to autoimmune diseases. There is a growing body of evidence for ME/CFS being an autoimmune disease (see a previous conference report covering this topic). 

This latest study shows that mechanisms involved in roseolovirus infection (a type of herpes virus) could play a fundamental role. This particular virus can infect the thymus which is a fundamental organ in the immune system where T cells mature, these recognise foreign antigens. As well as this the thymus eliminates T cells that are prone to attack the body’s own cells. This virus has been shown to weaken this function leading to more disruptive T cells circulating in the blood and the increased risk of autoimmune disease.  

The findings from this study are exciting, but this is likely to be only a very small part of the jigsaw: 

  • Roseolovirus is common and most people will be infected by this virus at some point but most people do not develop autoimmune diseases. 
  • The study was conducted in mice which are genetically and physiologically similar to humans but they adapt to their environments differently making them less reliable as a model for human disease. 
  • It is likely that there are other factors at play that make some people more susceptible, such as genetic and environmental factors. 

I feel the findings from this study warrant further investigation, especially to establish whether the thymus has a fundamental role in autoimmune disease, and whether these findings relate solely to roseolovirus. 

You may also be interested in reading: 

  • Paper four (4) which is on evaluating the diagnostic criteria for ME/CFS and the abstract gives a good summary overview of the findings. 
  • Paper five (5) on the lasting immunological imprint (IM) left by Epstein- Barr infection (EBV). (This paper is not directly on ME/CFS, but EBV is a common risk factor for development of ME/CFS). 

ME/CFS Research References and Abstracts  

1. Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

A.M. Helliwell, P.A. Stockwell, C.D. Edgar, A. Chatterjee, W.P. Tate 
medRxiv [preprint] 

Abstract 

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity throughout the ongoing illness. Patients experience relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but the dynamic changes specific to each individual patient are unknown. Precision medicine can determine how each patient responds individually during variations in their long-term illness. We apply precision medicine here to map genomic changes in two selected ME/CFS patients through a relapse recovery cycle. 

Results: DNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) from two patients and a healthy age/gender matched control in a longitudinal study to capture a patient relapse. Reduced representation DNA methylation sequencing profiles were obtained from each time point spanning the relapse recovery cycle. Both patients throughout the time course showed a significantly larger methylome variability (10-20 fold) compared with the control. During the relapse changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated respectively with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions occurring during the relapse. 

Conclusions Severe health relapses in ME/CFS patients result in functionally important changes in their DNA methylomes that, while differing among patients, lead to similar compromised physiology. DNA methylation that is a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency. 

2. Does Dietary Coenzyme Q10 plus Selenium Supplementation Ameliorate Clinical Outcomes by Modulating Oxidative Stress and Inflammation in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? 

Castro-Marrero J, Domingo JC, Cordobilla B, Ferrer R, Giralt M, Sanmartin-Sentañes R, Alegre-Martin J.  
Antioxid Redox Signal. 2022 Mar 1. [Epub ahead of print.] 

Abstract 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neuroinflammatory, multifaceted chronic disorder of unknown cause. Accumulating data indicates a link between a redox imbalance, mitochondrial dysfunction, and inflammation status in ME/CFS. CoQ10 and selenium as effective antioxidant and anti-inflammatory agents have shown potential clinical implications in chronic diseases; however, their therapeutic benefits on ME/CFS remain elusive.  

This open-label exploratory study aimed to evaluate the effectiveness of combined CoQ10 plus selenium supplementation on clinical features and circulating biomarkers in ME/CFS.  

Twenty-seven ME/CFS patients received an oral combination of 400 mg of CoQ10 and 200 µg of selenium daily for 8-weeks.  

The primary endpoint was patient-reported changes in outcome measures from baseline to 8 weeks post-intervention. Secondary endpoint included changes in circulating biomarkers from baseline to each participant.  

After an 8-week intervention, a significant improvement was found for overall fatigue severity (p = 0.021) and global quality of life (p = 0.002), while there was no significant effect on the sleep disturbances (p = 0.480) among participants.  

After 8-weeks' intervention, there was significantly increased total antioxidant capacity, and there were reduced lipoperoxides levels from the participants (p < 0.0001 for both). Circulating cytokine levels decreased significantly (p < 0.01 for all), but with no significant changes on the CRP, FGF21, and NT-proBNP biomarkers after supplementation.  

Based on these findings, we hypothesized that long-term supplementation of combined CoQ10 and selenium may indicate a potentially beneficial synergistic effect in ME/CFS. 

3. Disruption of thymic central tolerance by infection with murine roseolovirus induces autoimmune gastritis 

Tarin M. Bigley, Liping Yang, Liang-I Kang, Jose B. Saenz, Francisco Victorino, Wayne M. Yokoyama 
J Exp Med 7 March 2022; 219 (3): e20211403. 

Abstract 

Infections with herpesviruses, including human roseoloviruses, have been proposed to cause autoimmune disease, but defining a causal relationship and mechanism has been difficult due to the ubiquitous nature of infection and development of autoimmunity long after acute infection.  

Murine roseolovirus (MRV) is highly related to human roseoloviruses. Herein we show that neonatal MRV infection induced autoimmune gastritis (AIG) in adult mice in the absence of ongoing infection.  

MRV-induced AIG was dependent on replication during the neonatal period and was CD4+ T cell and IL-17 dependent. Moreover, neonatal MRV infection was associated with development of a wide array of autoantibodies in adult mice.  

Finally, neonatal MRV infection reduced medullary thymic epithelial cell numbers, thymic dendritic cell numbers, and thymic expression of AIRE and tissue-restricted antigens, in addition to increasing thymocyte apoptosis at the stage of negative selection.  

These findings strongly suggest that infection with a roseolovirus early in life results in disruption of central tolerance and development of autoimmune disease. 

4. Evaluating case diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): toward an empirical case definition 

Karl E. Conroy, Mohammed F. Islam & Leonard A. Jason  
Disability and Rehabilitation 

Abstract 

Purpose: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a variety of symptoms including post-exertional malaise, unrefreshing sleep, and cognitive impairment. A variety of case definitions (e.g., the Canadian Consensus Criteria (CCC), the Myalgic Encephalomyelitis International Consensus Criteria (ME-ICC), and the Institute of Medicine (IOM) criteria) have been used to diagnose patients. However, these case definitions are consensus-based rather than empirical. 

Materials and methods: The aim of the current study was to evaluate the validity of the aforementioned case definitions by factor analyzing a large, international sample (N = 2308) of ME/CFS symptom data. We performed primary and secondary exploratory factor analyses on the DePaul Symptom Questionnaire's 54-item symptom inventory. These results were compared to the CCC, the ME-ICC, and the IOM criteria. 

Results: We identified seven symptom domains, including post-exertional malaise, cognitive dysfunction, and sleep dysfunction. Contrary to many existing case criteria, our analyses did not identify pain as an independent factor. 

Conclusions: Although our results implicate a factor solution that best supports the CCC, revisions to the criteria are recommended. 

Implications for rehabilitation:  

  • ME/CFS is a chronic illness with no consensus regarding case diagnostic criteria, which creates difficulty for patients seeking assistance and disability benefits. 
  • The current study compared three commonly used case definitions for ME/CFS by factor analyzing symptomological data from an international sample of patients. 
  • Our results suggest three primary and four secondary symptom domains which differed from all three case definitions. 
  • These findings could help reduce barriers to care for those disabled with ME/CFS by guiding the development of an empirically-based case definition. 

5. Lasting Immunological Imprint of Primary Epstein-Barr Virus Infection With Associations to Chronic Low-Grade Inflammation and Fatigue 

Fevang B, Wyller VBB, Mollnes TE, Pedersen M, Asprusten TT, Michelsen A, Ueland T, Otterdal K.  
Front Immunol. 2021 Dec 20;12:715102. 

Abstract 

Background: Epstein-Barr virus (EBV) causes infectious mononucleosis (IM) that can lead to chronic fatigue syndrome. The CEBA-project (Chronic fatigue following acute EBV infection in Adolescents) has followed 200 patients with IM and here we present an immunological profiling of adolescents with IM related to clinical characteristics. 

Methods: Patients were sampled within 6 weeks of debut of symptoms and after 6 months. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated in vitro (n=68), and supernatants analyzed for cytokine release. Plasma was analyzed for inflammatory markers (n=200). The Chalder Fatigue Questionnaire diagnosed patients with and without chronic fatigue at 6 months (CF+ and CF- group, respectively) (n=32 and n=91, in vitro and plasma cohorts, respectively. 

Results: Broad activation of PBMC at baseline, with high levels of RANTES (Regulated on activation, normal T-cell expressed and secreted) in the CF+ group, and broad inflammatory response in plasma with high levels of T-cell markers was obeserved. At 6 months, there was an increased β-agonist response and RANTES was still elevated in cultures from the CF+ group. Plasma showed decrease of inflammatory markers except for CRP which was consistently elevated in the CF+ group. 

Conclusion: Patients developing chronic fatigue after IM have signs of T-cell activation and low-grade chronic inflammation at baseline and after 6 months. 

6. Appraisal of Long COVID: Lessons to be Learned from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 

Lewis Kazis, Mary Slavin, Hannah Bailey, Emily Hickey, Aileen Ledingham, Ananya Vasudevan, Ronald Tompkins, 
Archives of Physical Medicine and Rehabilitation, 103 (3): e3 

Abstract 

Objective(s): Little is known regarding after-effects of Long-COVID-19 (LC), while ME/CFS has been extensively researched. We performed a rigorous scoping review to inform a better definition of symptomatology of LC and cross-cutting similarities with ME/CFS. Our objective was to review the National Institutes of Health (NIH) ME/CFS Common Data Elements (CDEs), identify Patient Reported Outcome Measures (PROMs) and link items to the World Health Organization (WHO) International Classification of Functioning, Disability and Health (ICF) codes to inform efforts to define LC. 

Data Sources: NIH ME/CFS CDEs (Jan. 2020), Google Scholar, PubMed – search terms: Long COVID and ME/CFS. 

Study Selection: A review of 119 NIH ME/CFS CDEs applied the following inclusion criteria: 1) PROM based; 2) assess symptomatology; 3) specific to adults 18 years and over; 4) no visual or pictographic scales. 

Data Extraction: Of the 119 NIH ME/CFS CDEs, 38 met review criteria; items were entered into an Excel spreadsheet. Five researchers independently coded items using ICF linking rules and resolved discrepancies using a consensus-based process. 

Data Synthesis: Six articles specifically compared LC and ME/CFS for symptom overlap. Similarities between ME/CFS and Long COVID symptoms include: fatigue, post exertional malaise (PEM), cognitive symptoms, sleep dysfunction, pain, noise and light hypersensitivity, orthostatic intolerance, cardiac, gastrointestinal and immune pathologies. The 944 items from 38 PROM CDEs were coded based on common ME/CFS and LC symptoms. The percent of items linked to one or more ICF categories (1288 codes) was as follows: Body Function (b codes) 73%: Fatigability, N=252 (20%); Cognitive functions, N=234 (18%); Sleep functions, N=139, 11%; and Pain, N=119, (9%). Activity and Participation (d codes), N=332, (26%). Environment (e codes), N=11, 0.9%. 

Conclusions: The ICF provides a common language to assess ME/CFS and LC cross-cutting symptoms and their impact on body function, activity and participation. This review of ME/CFS CDE's can help identify common symptoms, such as PEM, and encourage appropriate symptom management to prevent cycles of overexertion and relapse for those with LC. 

7. Lessons from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome for Long COVID Part 4: Heart Rate Monitoring to Manage Postexertional Symptom Exacerbation 

Todd E. Davenport, Staci R. Stevens, Jared Stevens, Christopher R. Snell, J. Mark Van Ness 
JOSPT 

Abstract 

No abstract available. Full article available online 

Long-COVID Research References   

  1. Chronic cerebral aspects of long COVID, post-stroke syndromes and similar states share their pathogenesis and perispinal etanercept treatment logic 
  1. Endothelial dysfunction in acute and long standing COVID-19: A prospective cohort study 
  1. Long-term health-related quality of life in non-hospitalised COVID-19 cases with confirmed SARS-CoV-2 infection in England: Longitudinal analysis and cross-sectional comparison with controls 
  1. Sustained Impairment in Cardiopulmonary Exercise Capacity Testing in Patients after COVID-19: A Single Center Experience 
  1. Serial Changes of Long COVID Symptoms and Clinical Utility of Serum Antibody Titers for Evaluation of Long COVID 
  1. Long COVID-19 – a pathology of concern 
  1. Neurological outcomes one year after COVID-19 diagnosis: a prospective longitudinal cohort study 
  1. Lasting impact of infection extends to the brain 
  1. Gut dysbiosis and long COVID-19: Feeling gutted 
  1. Molecular Phenomic Approaches to Deconvolving the Systemic Effects of SARS-CoV-2 Infection and Post-acute COVID-19 Syndrome 
  1. Parosmia post COVID-19: an unpleasant manifestation of long COVID syndrome 
  1. Exploration of Human Serum Lipoprotein Supramolecular Phospholipids Using Statistical Heterospectroscopy in n-Dimensions (SHY- n): Identification of Potential Cardiovascular Risk Biomarkers Related to SARS-CoV-2 Infection 
  1. COVID-19 and the long-term cardio-respiratory and metabolic health complications 
  1. Nutritional Modulation of Gut Microbiota Alleviates Severe Gastrointestinal Symptoms in a Patient with Post-Acute COVID-19 Syndrome 
  1. Cognitive Impairment in Non-critical, Mild-to-Moderate COVID-19 Survivors 
  1. Post-COVID-19 syndrome. SARS-CoV-2 RNA detection in plasma, stool, and urine in patients with persistent symptoms after COVID-19 

Dr Katrina Pears
MEA Research Correspondent

  

  

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