MEA Research Roundup

ME/CFS and Long Covid Research: 13 – 19 December 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 13 – 19 December 2022 

The break for the Christmas period has kicked in this week, with a lull in research, which has particularly affected the number of Long Covid studies we have seen. 

There have been four new ME/CFS studies and six new Long Covid studies. 

There are two slightly different studies which are included in this roundup. Paper two (2) is an abstract from a conference, so not a full study to read but a lot of detail is given, which is on the role of leptin and inflammatory related biomarkers in ME/CFS. Paper three (3) is not directly on ME/CFS but on the use of cognitive behavioural therapy (CBT) in long term conditions, particularly focusing on fatigue outcomes. 

We have highlighted one of the ME/CFS studies in detail below: 

Paper one (1) is a preprint study (meaning it has not been peer-viewed and the science verified) on autoantibodies (AAb). This study looked into the changes in blood content of 33 naturally occurring autoantibodies to a range of different tissues in both ME/CFS and Fibromyalgia patients (FM). 

There has been quite a lot of interest of late into autoantibodies, particularly in against G protein-coupled receptors (GPCR) (anti-GPCR), however this study looks more in depth into the naturally occurring autoantibodies. To give some background: 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). However, this study differed from all previous studies we have seen on autoantibodies as it looked at those naturally occurring and not GPCR. 

The researchers in this study found that ME/CFS patients with and without FM (+/-) were characterised with more frequent and larger deviations in their immunoreactivity to GABA- receptors than controls (a type of receptor that responds to a neurotransmitter, they help to inhibit or reduce nerve impulses). Although no other significant differences were found in the other naturally occurring autoantibodies, however, the levels were correlated to symptoms, such as fatigue, pain and depression. Interestingly, the strength of the correlation differed between the groups studied (ME/CFS +/- FM and controls). 

A number of studies have debated whether ME/CFS is an autoimmune disease, results from this study suggest that it is not but is a condition of dysregulated natural autoimmunity. A few things that can be noted from this study: 

  • This was a pilot study so the sample size was reasonably small, with three different groups: 11 participants with ME/CFS and FM, 11 participants with ME/CFS and no FM, and 11 healthy controls. However, a good size (double) compared to many pilot studies we see. 
  • It is a shame there was not an only FM group for comparison, which would help to define the biological differences between ME/CFS and FM. 
  • Patients in this study were included when they met all three of the most commonly used criteria for diagnosis (Fukuda, Canadian Consensus and IOM), meaning the inclusion criteria for ME/CFS was more rigorous than other studies. However, there is no mention of the different severities, which are likely to vary when looking at autoantibodies.  
  • Results provide one snapshot in time, so we do not know how results vary with the duration of illness (duration varied from 1-35 years, average of 6 years for the ME/CFS+FM group).  
  • Furthermore, only having one time point is particularly relevant for the questionnaires which looked at symptoms as symptoms vary hugely with time, such as post-exertional malaise, so this in turn will affect the correlations seen in autoantibodies and symptoms. 
  • The correlation of symptoms with autoantibodies is also in line with those results reported previously by Freitag et al., 2021

The science in this paper is fairly complicated and the way the data is presented makes it difficult to know if these results are of significant interest, with a lack of figures/graphs comparing information for all three groups (these are all displayed separately making comparison hard). However, there does seem to be a lack of statistically significant results. Only further study will show whether autoantibodies have a significant role in ME/CFS.  

You may also be interested in reading paper four (4) in the ME/CFS reference section which further supports the evidence for the high prevalence of ME/CFS in those who have persistent Covid-19 symptoms. The first author of this paper is Dr Leonard Jason from De Paul University who we have seen numerous ME/CFS studies from this year. 

ME/CFS Research References and Abstracts  

1. Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity 

Ryabkova, V.A.; Gavrilova, N.Y.; Poletaeva, A.A.; Pukhalenko, A.I.; Koshkina, I.A.; Churilov, L.P.; Shoenfeld, Y.  

Preprints 2022, 2022120224  


(1) Background: Recent studies provide some evidence for the contribution of antibody-mediated autoimmune mechanisms to the nature of fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Much attention was paid to the autoantibodies (AAb) targeting G protein-coupled receptors as natural components of the immune system. However, natural AAb network is much more extensive, and has not been previously investigated in these disorders;  

(2) Methods: The enzyme immunoassays ELI-Viscero-Test and ELI-Neuro-Test were used to determine changes in serum content of a 33 natural AAb to neural, organ-specific and non-tissue-specific autoantigens a) in 11 FM patients with comorbid ME/CFS; b) in 11 ME/CFS patients without FM; c) in 11 healthy controls. Individual autoantibody profiles and their correlation with some clinical symptoms were analyzed.  

(3) Results: both patients with ME/CFS and ME/CFS+FM were characterized by more frequent and pronounced deviations in the immunoreactivity to GABA-receptors than healthy controls. Although the level of other natural AAb did not differ between study groups, AAb correlation signatures were changing in patients compared to healthy controls. Both in patients and healthy controls the level of natural AAb to various neural and tissue-specific antigens correlated with the severity of fatigue, bodily pain, depression, anxiety, physical and mental-health related quality of life. Notably, that widely different correlation patterns were observed between study groups.  

(4) Conclusions: Findings from this pilot study provide some evidence that the homeostasis of autoimmune relationships, which are possibly a physiological part of our immune system, may break down in FM and ME/CFS. The correlation of disease-induced perturbations in individual AAb profiles with some clinical symptoms may arise from the immune system's ability to reflect qualitative and quantitative changes in antigenic composition of the body. 

2. The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Rahaf Al Assil and Jarred W Younger 

Report from the Scientific Poster Session at the 16th Annual Cardiometabolic Health Congress in National Harbor, USA, 14–17 October 2021 

Purpose: Leptin is a member of the cytokine family; its receptor (LEPR-b) is the longest form receptor expressed in cells of the immune system; wherein LEPR-b deficiency causes a decrease in CD4+ cells. LEPR-b is located in hypothalamic and brain stem nuclei, and it primarily regulates energy status. As well, leptin indirectly regulates widespread pain and exercise tolerance by decreasing circulating cortisol.  

Hyperinsulinemia increases leptin production in adipocytes on a diurnal rhythm; however, the precise relationship between insulin, leptin and pro-inflammatory markers remains uncertain. In clinical settings, high-sensitivity C-reactive protein (hsCRP) has been widely used, as an inflammatory predictor for leptin-related cardiometabolic outcomes and chronic inflammatory symptoms. 

Leptin-related metabolic and inflammation dysregulations have been clinically reported in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but not fully elucidated. We examined the association of plasma insulin, leptin, and hsCRP levels with ME/CFS self-reported symptom severity. 

Methods: Prospective analyses were conducted on ME/CFS patients who met Fukuda/CDC criteria at Birmingham hospital, Alabama, U.S.A. The independent variables were hyperinsulinemia (>174 μIU/mL), hyperleptinemia/hypoleptinemia (>18.3/<3.3 ng/mL), residual inflammation risk (hsCRP ≥2 and ≠26.2 mg/L) and within-individual-variability (WIV) for each biomarker.  

WIV was defined for each individual as standard deviation/sample residuals adjusting for time and calculated from once-daily random plasma samples over 10–12 weeks.  

The primary outcomes were:  

(1) ME/CFS symptom score trends [generalized pain, persistent fatigue, sleep disturbance, impairment of concentration and memory (brain fog), and post-exertional malaise (PEM)] calculated from the MFI-20 questionnaire with anchors from 0 to 100 and recorded once daily over a matching 12–14 weeks, and  

(2) dichotomized symptom severity, with severe symptoms defined as scores > 60/100. After adjusting for age and time, we reported: (1) standard errors (SEM) and p-values for symptom trends using multivariable mixed-effect linear regression models, and (2) odds ratios for severe symptoms using multivariable alternating logistic regression models. 

Results: We included 29 ME/CFS patients. All were females and >18 years old. Hyperinsulinemia, hyperleptinemia/hypoleptinemia, and residual inflammation risk were 7%, 80%/7%, and 74%, respectively.  

The medians of insulin-WIV, leptin-WIV and hsCRP-WIV were [(0.24; IQR 0.15–0.38), (0.25; IQR 0.15–0.40), (0.33; IQR 0.18–0.51)] respectively. On average, hyperleptinemic patients had the highest leptin-WIV and 50% of them had residual inflammation risk.  

Severe (fatigue, pain, brain fog, sleep disturbance, and PEM) were reported in 50%, 29%, 41%, 30%, and 57% of patients, respectively. In the adjusted analysis, worse fatigue scores (7.49; SEM, 2.23; p = 0.002) were associated with higher insulin-WIV.  

Hyperleptinemia (OR 1.54; 95% CI 1.13–2.09) compared to hypoleptinemia, and residual inflammation risk (OR 1.65; 95% CI 1.21–2.25) were associated with higher odds of severe fatigue. Worse pain scores (7.17; SEM, 2.30; p = 0.005) were associated with higher leptin-WIV, and (8.45; SEM, 2.25; p = 0.0009) higher hsCRP-WIV, and residual inflammation risk (OR 1.75; 95% CI 1.34–2.29) was associated with higher odds of severe pain.  

Severe brain fog scores (9.20; SEM, 2.44; p = 0.0008) were associated with higher insulin-WIV, higher leptin-WIV (4.73; SEM, 2.12; p = 0.03). Residual inflammation risk (OR 1.40; 95% CI 1.16–1.77) was associated with higher odds of severe brain fog.  

Hyperleptinemia (OR 0.60; 95% CI 0.43–1.19) was associated with lower odds of severe PEM compared to hypoleptinemia, and better sleep quality was associated (6.07; SEM, 1.70; p = 0.001) with higher insulin-WIV, and (3.37; SEM, 1.47; p = 0.03) higher leptin-WIV. 

Conclusions: In patients with ME/CFS, symptoms severity was associated with hyperleptinemia, inflammation and within-individual-variability of these biomarkers. Leptin and hsCRP may be clinically useful in predicting symptom severity.  

Larger clinical trials are needed to further examine the prediction and causality of these biomarkers in the development of ME/CFS diagnosis. The efficacy and safety of anti-inflammatory therapies may be evaluated in sub-clusters of ME/CFS with metabolic responses and inflammation dysregulations to improve patient-reported symptoms. 

3. The relation between cognitive-behavioural responses to symptoms in patients with long term medical conditions and the outcome of cognitive behavioural therapy for fatigue – A secondary analysis of four RCTs 

M. de Gier, F. Picariello, M. Slot, A. Janse, S. Keijmel, J. Menting, M. Worm-Smeitink, H. Beckerman, V. de Groot, R. Moss-Morris, H. Knoop 

Behaviour Research and Therapy 2022: 104243 


  • Similar beliefs and behaviour moderate effect of CBT on fatigue across conditions. 
  • The mediators of the effect of CBT on fatigue are also similar across conditions. 
  • The findings support a transdiagnostic approach in the treatment of fatigue. 


Background: Cognitive behavioural therapy (CBT) is effective in reducing fatigue across long-term conditions (LTCs). This study evaluated whether cognitive and behavioural responses to symptoms: 1) differ between LTCs and 2) moderate and/or mediate the effect of CBT on fatigue. 

Method: Data were used from four Randomized Controlled Trials testing the efficacy of CBT for fatigue in Chronic Fatigue Syndrome/ME (N = 240), Multiple Sclerosis (N = 90), Type 1 Diabetes Mellitus (N = 120) and Q-fever fatigue syndrome (N = 155). Fatigue severity, assessed with the Checklist Individual Strength, was the primary outcome. Differences in fatigue perpetuating factors, assessed with the Cognitive Behavioural Responses to Symptoms Questionnaire (CBRQ), between diagnostic groups were tested using ANCOVAs. Linear regression and mediation analyses were used to investigate moderation and mediation by CBRQ scores of the treatment effect. 

Results: There were small to moderate differences in CBRQ scores between LTCs. Patients with higher scores on the subscales damage beliefs and avoidance/resting behaviour at baseline showed less improvement following CBT, irrespective of diagnosis. Reduction in fear avoidance, catastrophising and avoidance/resting behaviour mediated the positive effect of CBT on fatigue across diagnostic groups. 

Discussion: The same cognitive-behavioural responses to fatigue moderate and mediate treatment outcome across conditions, supporting a transdiagnostic approach to fatigue. 

4. ME/CFS and Post-Exertional Malaise among Patients with Long COVID 

Jason, L.A.; Dorri, J.A.  

Neurol. Int. 2022, 15, 1–11. 


This study sought to ascertain the prevalence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) among a sample of 465 patients with Long COVID.  

The participants completed three questionnaires: (1) a new questionnaire measuring both the frequency and severity of 38 common symptoms of COVID and Long COVID, (2) a validated short form questionnaire assessing ME/CFS, and (3) a validated questionnaire measuring post-exertional malaise.  

The population was predominantly white, female, and living in North America. The mean duration since the onset of COVID-19 symptoms was 70.5 weeks.  

Among the 465 participants, 58% met a ME/CFS case definition. Of respondents who reported that they had ME/CFS only 70.57% met criteria for ME/CFS and of those who did not report they had ME/CFS, 29.43% nevertheless did meet criteria for the disease: both over-diagnosis and under-diagnosis were evident on self-report.  

This study supports prior findings that ME/CFS occurs with high prevalence among those who have persistent COVID-19 symptoms. 

Long-COVID Research References  

  1. Factors Associated with Long Covid Symptoms in an Online Cohort Study 
  1. T cell responses to SARS-CoV-2 in people with and without neurologic symptoms of long COVID 
  1. Physical and mental health disability associated with long-COVID: Baseline results from a US nationwide cohort 
  1. Post-Viral Fatigue Following SARS-CoV-2 Infection during Pregnancy: A Longitudinal Comparative Study 
  1. Risk factors, health outcomes, healthcare services utilization, and direct medical costs of long COVID patient 
  1. Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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