MEA Research Roundup

ME/CFS and Long Covid Research: 01 – 07 November 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).


The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

Audio Commentary by Dr Katrina Pears 

ME/CFS Research Published 1 – 7 November 2022

There’s been a variety in research this week from reviews to biological studies. However, there have only been three new ME/CFS studies but seventeen studies on Long Covid. 

We have highlighted two of the studies below:  

Paper one (1) is a review article on autoimmune autonomic nervous system imbalances, and includes the conditions: Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome.  

The authors review the current evidence on autoantibodies against G protein-coupled receptors (GPCR) (anti-GPCR) in all of the conditions listed. GPCR may be known under several different names, including seven-(pass)-transmembrane domain receptors, 7TM receptors (as they pass through the membrane seven times) and serpentine receptors. GPCR are expressed by almost all cells, and are involved in a number of different activities, including but not exclusive too: activating intracellular signalling pathways which regulate cell trafficking and migration, secretion of inflammatory cytokines, and neurotransmission. Due to their role in cell recognition and signalling processes, they are often a target for drugs. Research has shown that in some conditions, the imbalance of anti-GPCR (either increased or decreased compared to controls) plays a role in development of autoimmune conditions. For example, in Long Covid, higher levels of the anti-GPCR Anti-DSG 2 antibodies have been found, which has been implicated in the cardiac pathology (Lee et al., 2022). 

(Un)fortunately we cannot read the full review as it is behind a paywall, so we cannot see the sections which are specific to ME/CFS. However, for me, this review is looking into too many different conditions and trying to cover too many bases, while the chance of something insightful being gained from this is very small. We saw another review like this published by one of the same authors back in the summer (Mahroum and Shoenfeld, 2022), so it is unusual that another review has been published containing the same mix of conditions. 

The image above is taken from the review article, and is the authors hypothesis of the development of autoimmune autonomic nervous system imbalance in different conditions. 

Paper two (2) looked at using functional MRI (fMRI) scans to look at different networks in the brain, called the brain salience (SA) and default mode (DMN) networks, and how this differs between healthy controls and those with ME/CFS.  

Interestingly, and what really stands out about this study is that they used participants with ME/CFS who were diagnosed with different criteria: International Consensus Criteria (ICC) (18 participants) and the Fukuda criteria (24 participants) to see how these compare. This is the first study I have come across of this nature which is coupled with a biological study, which is reassuring as the Fukuda criteria is heavily criticised in its use to diagnosis ME/CFS, especially when used in research. For example, problems with the Fukuda criteria include: post-exertional malaise (PEM) is not compulsory which leads to misdiagnosis, and it is not easy to use on a clinical level (a review on the contrasting case definitions has been written by Brown et al., 2013). 

Unfortunately, we cannot read the full study as it is behind a paywall, but the abstract provides enough detail to show us that there is different neuropathology involved in ME/CFS patients who are diagnosed with the ICC criteria to those diagnosed with the Fukuda criteria, as different brain connectively was found during fMRI tasks and these differed from the healthy controls. Furthermore, the different regulatory connections were consistent with the impaired cognitive performance and sleep-wake cycle of ME/CFS, providing further supporting evidence of neurological problems in ME/CFS. 

You may also be interested in reading several of the other studies in this week’s roundup: 

Paper three (3) in the ME/CFS reference section is a review article which further reinforces the benefit of active pacing in managing symptoms

In the Long Covid Reference section these studies might also be of interest: 

Paper one (1) is on the protocol which will be used to test the effectiveness of the use of hyperbaric oxygen therapy for treatment of Long Covid, therefore there are no results in this study. Interestingly, in the abstract of this protocol, the authors claim that hyperbaric oxygen treatments have been shown to be effective in ME/CFS (and fibromyalgia) although there is only one study showing this in each condition (Akarsu et al., 2013; Efrati et al.,2015). We have covered the use of hyperbaric oxygen therapy in more detail in one of our previous research roundups

Paper two (2) is a case report on Long Covid and pregnancy, and provides some guidance for care providers. With the rapid pace of research into Long Covid, it is surprising that we have not seen any studies into pregnancy, which is also an area lacking within ME/CFS research. With the increase in recognition of the similarity between these two conditions, research is needed in this area, hopefully the ME Association funded project due to start next Summer will provide some answers surrounding pregnancy.  

Paper three (3) is a review article on the possible use of melatonin in Long Covid, and it has been suggested that melatonin may also be useful in reducing other symptoms such as poor cognitive function/ brain fog and pain as well as sleep disturbances. Although currently no proper clinical trials have been conducted, Dr Charles Shephard has also provided a comment on this review. 

ME/CFS Research References and Abstracts  

1. Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants 

Malkova AM and Shoenfeld 

Autoimmunity Reviews 2022: 103230 [In Press, Pre-proof] 


Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are frequently accompanied by clinical symptoms characteristic for dysautonomia: severe fatigue, dizziness, fogginess, memory loss, dry mouth and eyes, hearing dysfunction, tachycardia etc.  

The recent discovery of an imbalance of autoantibodies against G protein-coupled receptors (GPCR) in some autoimmune diseases, post-COVID syndrome, SBIs allowed researchers to assume the novel mechanism in these conditions – autoimmune autonomic nervous system imbalance. 

In this review, all data published on an imbalance of autoantibodies against GPCR, clinical symptoms and pathogenic mechanisms in CFS, Fibromyalgia, SBIs, COVID and PCS, SBS, POTS, and some autoimmune diseases were analyzed. Possible criteria to diagnose the autoimmune autonomic nervous system imbalance were created. 

2. Connectivity between Salience and Default Mode Networks and subcortical nodes distinguishes between two classes of ME/CFS 

Su J, Thapaliya K, Eaton-Fitch N, Marshall-Gradisnik SM, Barnden LR.  

Brain Connect. 2022 Nov 9. [Epub ahead of print.] 


Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease with unknown pathophysiology. Functional MRI (fMRI) studies in ME/CFS have reported disparate connectivities for the brain salience (SA) and default mode (DMN) networks.  

In this study, we acquired resting state and task fMRI with an advanced scanner for improved subject numbers: 24 healthy controls (HC) and 42 ME/CFS patients, 18 meeting International Consensus Criteria (ICC) and 24 meeting Fukuda criteria.  

We evaluated mean FC between SA and DMN network hub, and subcortical regions known to be involved in ME/CFS. We tested the hypothesis that ME/CFS connectivity differed from HC and the ICC and Fukuda classes are distinguished by different connectivities with HC for different pairs of SA, DMN or subcortical hubs.  

During resting state fMRI only two connections differed from HC, both for Fukuda ME/CFS and both with an SA hub. During task fMRI 10 ME/CFS connections differed from HC, 5 for ICC and 5 for Fukuda. None were common to both classes.  

Eight of the 10 different connections involved an SA hub, six of 10 were weaker in ME/CFS, 4 stronger. SA connections to the hippocampus and brainstem reticular activation system (RAS) differed from and were stronger than HC. The SA mediates the relative activity of the DMN and executive networks and imbalance will have functional consequences. The RAS and hippocampus modulate cortical activation.  

Different regulatory connections are consistent with the impaired cognitive performance and sleep-wake cycle of ME/CFS. Different neuropathology is involved in ICC and Fukuda classes. 

3. The effectiveness of activity pacing interventions for people with chronic fatigue syndrome: a systematic review and meta-analysis 

Casson S, Jones MD, Cassar J, Kwai N, Lloyd AR, Barry BK, Sandler CX.  

Disabil Rehabil. 2022 Nov 8:1-15. [Epub ahead of print.] 


Purpose: To investigate whether activity pacing interventions (alone or in conjunction with other evidence-based interventions) improve fatigue, physical function, psychological distress, depression, and anxiety in people with chronic fatigue syndrome (CFS). 

Materials and methods: Seven databases were searched until 13 August 2022 for randomised controlled trials that included activity pacing interventions for CFS and a validated measure of fatigue. Secondary outcomes were physical function, psychological distress, depression, and anxiety. Two reviewers independently screened studies by title, abstract and full text. Methodological quality was evaluated using the PEDro scale. Random-effects meta-analyses were performed in R. 

Results: 6390 articles were screened, with 14 included. Good overall study quality was supported by PEDro scale ratings. Activity pacing interventions were effective (Hedges' g (95% CI)) at reducing fatigue (-0.52 (-0.73 to -0.32)), psychological distress (-0.37 (-0.51 to -0.24)) and depression (-0.29 (-0.49 to -0.09)) and improving physical function (mean difference 7.18 (3.17-11.18)) when compared to no treatment/usual care. The extent of improvement was greater for interventions that encouraged graded escalation of physical activities and cognitive activities. 

Conclusion: Activity pacing interventions are effective in reducing fatigue and psychological distress and improving physical function in CFS, particularly when people are encouraged to gradually increase activities. 

Long-COVID Research References  

  1. Hyperbaric oxygen for treatment of long COVID-19 syndrome (HOT-LoCO): protocol for a randomised, placebo-controlled, double-blind, phase II clinical trial 
  1. Post-COVID-19 condition and pregnancy 
  1. Possible Application of Melatonin in Long COVID 
  1. Brain 18F-FDG PET imaging in outpatients with post-COVID-19 conditions: findings and associations with clinical characteristics 
  1. Physiological factors affecting the mechanical performance of peripheral muscles: A perspective for long COVID patients through a systematic literature review 
  1. Cardiac Manifestations of Post-Acute COVID-19 Infection 
  1. Newonset neuropsychiatric sequelae and ‘longCOVID’ syndrome (Review) 
  1. Extended coagulation profile of children with Long Covid: a prospective study 
  1. Traditional Chinese medicine combined with Moxibustion in the treatment of “long-COVID” A protocol for systematic review and meta-analysis 
  1. Complexity and Challenges of the Clinical Diagnosis and Management of Long COVID 
  1. Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID 
  1. Health-related quality of life in persons post-COVID-19 infection in comparison to normative controls and chronic pain patients 
  1. Postural orthostatic tachycardia syndrome and post-acute COVID-19 
  1. Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology 
  1. Low perforin expression in CD8+ T lymphocytes during the acute phase of severe SARS-CoV-2 infection predicts long COVID 
  1. Long COVID and the Neuroendocrinology of Microbial Translocation Outside the GI Tract: Some Treatment Strategies 
  1. Pediatric Long-COVID: A Review of the Definition, Epidemiology, Presentation, and Pathophysiology 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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