ME/CFS and Long Covid Research: 15 – 21 March 2022

March 25, 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 from Katrina Pears

ME/CFS Research Published 15 – 21 March 2022 

It’s been a quieter week on the research front, but there has been a number of interesting studies to read, with five new ME/CFS studies and eight studies on Long Covid.  

We have highlighted two of the studies below:  

Paper 1 (one) is on cardiopulmonary exercise testing in ME/CFS, and investigates the extent to which exercise response is independent of ME/CFS or is caused by it. The scope of this study is that ME/CFS patients and healthy controls are matched for aerobic fitness (as well as comparing without being matched), in addition the study was large using 215 ME/CFS patients and 189 controls. 

The study found a number of significant findings when aerobic fitness was matched and unmatched, results showed ME/CFS was characterised by reduced oxygen uptake and heart rate (HR) performance, inefficient ventilation, and elevated perception of effort (RPE, measure of the ways a person feels during exercise).  

What is of particular interest is the findings when aerobic fitness was matched between ME/CFS patients and healthy controls, where many of the differences in cardiometabolic responses were removed. This showed that many of the differences usually seen in studies are explained by the differences in aerobic fitness, so not pathophysiologic characteristics. Differences which still remained are: 

  • breathing frequency,  
  • ventilatory equivalents for oxygen (VE/VO2, ratio of minute ventilation to oxygen production, which refers to number of liters of ventilation per liter of oxygen consumed),  
  • ventilatory equivalents for carbon dioxide (VE/VCO2, similar to Oxygen calculation but for carbon dioxide) 
  • ratings of perceived exertion (RPE, measure of the ways a person feels during exercise), 
  • higher tidal volumes for ME/CFS (amount of air that moves in and out of the lungs). 
  • In summary, these results show ME/CFS is characterised by inefficient exercise ventilation

The novel approach in this study will hopefully lead the way for improved exercise testing as it is critical to distinguishing fitness effects from those that are primary to the disease. There is a lot more which could be investigated from these findings, especially establishing the pathophysiological significance as well as changes over time. In practical terms, these results show that tolerable levels of activity can be carried out, although caution needs to be taken to avoid post-exertional malaise (PEM) which is not explored in this study as there is no second day of exercise testing. 

Paper three (3) looks at extracellular vesicles (EV) in severe and mild ME/CFS patients as a potential biomarker compared to healthy controls. EVs are small, membrane bound particles and have been shown to play a key role in intercellular signalling, as well as delivering proteins, metabolites, and nucleic acids to recipient cells. 

The study found that in severe patients there was a correlation between the EVs with B cell marker CD19 (a protein which is important in cancer diagnosis) and the platelet marker CD41a (a receptor for fibronectin). Although, due to the very small study, this finding was not consistently found between comparisons. The authors suggest that the findings from this study point to potential dysregulation of B cell and platelet activation, due to the higher levels found. 

It is a great shame that this study was so small, only using 10 patients in each cohort. The study could have been further limited by; the different disease stages, severities of illness as well as a range of male and female patients in a very small cohort. Therefore, further studies will need much more robust methodology to take these findings forward. 

You may also be interested in reading paper five (5) which is the largest genetic ME/CFS study to date. The study suggests possible implications of the TPPP genetic region (Tubulin polymerization promoting protein 1), which plays a key role in myelination of nerve cells and maintenance of the cytoskeleton. This genetic region has already been linked to MS, Parkinsons and Alzheimer’s disease.  There has been a lot of discussion about this paper in the Science for ME forum.  

ME/CFS Research References and Abstracts  

1. Cardiopulmonary, metabolic, and perceptual responses during exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Multi-site Clinical Assessment of ME/CFS (MCAM) sub-study 

Dane B. Cook, Stephanie VanRiper, Ryan J. Dougherty, Jacob B. Lindheimer, Michael J. Falvo, Yang Chen, Jin-Mann S. Lin, Elizabeth R. Unger, The MCAM Study Group  
PLoS ONE 17(3): e0265315. 


Background: Cardiopulmonary exercise testing has demonstrated clinical utility in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, to what extent exercise responses are independent of, or confounded by, aerobic fitness remains unclear. 

Purpose: To characterize and compare exercise responses in ME/CFS and controls with and without matching for aerobic fitness. 

Methods: As part of the Multi-site Clinical Assessment of ME/CFS (MCAM) study, 403 participants (n = 214 ME/CFS; n = 189 controls), across six ME/CFS clinics, completed ramped cycle ergometry to volitional exhaustion. Metabolic, heart rate (HR), and ratings of perceived exertion (RPE) were measured. Ventilatory equivalent (VE/VO2, VE/VCO2), metrics of ventilatory efficiency, and chronotropic incompetence (CI) were calculated. Exercise variables were compared using Hedges’ g effect size with 95% confidence intervals. Differences in cardiopulmonary and perceptual features during exercise were analyzed using linear mixed effects models with repeated measures for relative exercise intensity (20–100% peak VO2). Subgroup analyses were conducted for 198 participants (99 ME/CFS; 99 controls) matched for age (±5 years) and peak VO2 (~1 ml/kg/min-1). 

Results: Ninety percent of tests (n = 194 ME/CFS, n = 169 controls) met standard criteria for peak effort. ME/CFS responses during exercise (20–100% peak VO2) were significantly lower for ventilation, breathing frequency, HR, measures of efficiency, and CI and significantly higher for VE/VO2, VE/VCO2 and RPE (p<0.05adjusted). For the fitness-matched subgroup, differences remained for breathing frequency, VE/VO2, VE/VCO2, and RPE (p<0.05adjusted), and higher tidal volumes were identified for ME/CFS (p<0.05adjusted). Exercise responses at the gas exchange threshold, peak, and for measures of ventilatory efficiency (e.g., VE/VCO2nadir) were generally reflective of those seen throughout exercise (i.e., 20–100%). 

Conclusion: Compared to fitness-matched controls, cardiopulmonary responses to exercise in ME/CFS are characterized by inefficient exercise ventilation and augmented perception of effort. These data highlight the importance of distinguishing confounding fitness effects to identify responses that may be more specifically associated with ME/CFS. 

2. No difference in serum levels of B-cell activating receptor and antibodies against cytolethal distending toxin B and flagellin in post-infectious irritable bowel syndrome and chronic fatigue syndrome after Giardia infection 

Kurt Hanevik, Christina Saghaug, Maren Aaland, Kristine Morch, Nina Langeland 
JGH Open (2022):1-4 


Background and Aim: Functional gastrointestinal disorders (FGIDs) and chronic fatigue syndrome (CFS) frequently occur as comorbid conditions to each other. A shared etiology of these syndromes has been proposed because of their shared symptomatology and triggering by infections.  

Antibodies against the bacterial antigens cytolethal distending toxin B (CdtB) and flagellin have been proposed to be biomarkers of irritable bowel syndrome (IBS), especially diarrhea-predominant IBS (IBS-D). It is unknown if they may also be associated with comorbid conditions such as CFS. On the other hand, elevated level of B-cell activating factor (BAFF) has been associated with CFS and inflammatory bowel disease (IBD) and subjective food intolerance. 

Methods: We evaluated serum levels of anti-flagellin and anti-CdtB using an in-house enzyme-linked immunosorbent assay (ELISA) and BAFF with a commercially available ELISA kit in a cohort of patients who developed fatigue syndromes and/or FGIDs after Giardia infection, by comparing them with healthy controls without these conditions. 

Results: We did not find significant differences in circulating BAFF, anti-CdtB, or anti-flagellin antibody levels in these patient groups compared to healthy controls. Therefore, our results do not support a role for BAFF, anti-CdtB, or anti-flagellin antibodies as universal biomarkers for IBS or CFS. 

Conclusion: BAFF, anti-CdtB, or anti-flagellin antibodies cannot be considered as universal biomarkers for IBS or CFS. 

3. Fatigue-Related Cognitive-Behavioral Factors in Survivors of Childhood Cancer: Comparison with Chronic Fatigue Syndrome and Survivors of Adult-Onset Cancer 

van Deuren S, van Dulmen-den Broeder E, Boonstra A, Gielissen M, Blijlevens N, Loonen J, Knoop H.  
J Adolesc Young Adult Oncol. 2021 Feb;10(1):92-99.  


Purpose: Cancer-related fatigue is a burdensome late effect of cancer treatment. A pilot study showed the effectiveness of cognitive-behavioral therapy (CBT) in fatigued survivors of childhood cancer (CCS).  

The aim of this study is to investigate whether the six cognitive-behavioral factors that are addressed during CBT differ in CCS compared with patients with chronic fatigue syndrome (CFS) and survivors of adult-onset cancer (ACS). Levels of self-esteem, optimism, and depressive symptoms, variables that are also related to fatigue, were also compared between groups.  

Methods: Retrospective analyses were performed on 34 CCS (ages 11-42 years), 102 patients with CFS, and 95 ACS who were referred for evaluation of severe fatigue. Fatigue severity, possible cognitive-behavioral fatigue maintaining factors, depressive symptoms, self-esteem, and optimism were assessed using questionnaires and actigraphy.  

Results: No significant differences were found in the factors coping with the experience of having had cancer, fear of cancer recurrence, physical activity, and in levels of self-esteem and optimism. CCS attributed their fatigue significantly more often to psychosocial causes and reported fewer problems in sleep/rest compared with patients with CFS. Compared with ACS, CCS reported significantly more social support, more problems in sleep/rest, and more depressive symptoms.  

Conclusions: There is substantial overlap in cognitive-behavioral factors that can maintain fatigue between CCS and CFS patients or ACS. Also differences were found regarding attribution of fatigue, the sleep/rest pattern, social support, and depressive symptoms that might have clinical implications when CBT for fatigue is provided to CCS. 

4. Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Bonilla H, Hampton D, Marques de Menezes EG, Deng X, Montoya JG, Anderson J, Norris PJ.  
Front Immunol. 2022 Mar 4;13:841910.  


Myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS) is a serious disease whose cause has yet to be identified.  

Objective markers of the disease are also not well understood and would serve as important tools in diagnosis and management. One potential biomarker or transmitter of immune signals in ME/CFS is the extracellular vesicle (EV) compartment. These small, membrane bound particles have been shown to play a key role in intercellular signaling. Our laboratory has focused on methods of detection of EVS in clinical samples.  

In this study we explored whether the prevalence of EVs in the plasma of participants with mild or severe ME/CFS differed from the plasma of healthy control participants. By staining for multiple cell surface molecules, plasma EVs could be fingerprinted as to their cell of origin.  

Our study revealed a significant correlation between severe ME/CSF and levels of EVs bearing the B cell marker CD19 and the platelet marker CD41a, though these changes were not significant after correction for multiple comparisons.  

These findings point to potential dysregulation of B cell and platelet activation or homeostasis in ME/CFS, which warrants validation in a replication cohort and further exploration of potential mechanisms underlying the association. 

5. Genetic association study in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) identifies several potential risk loci 

Riad Hajdarevic, Asgeir Lande, Jesper Mehlsen, Anne Rydland, Daisy D. Sosa, Elin B. Strand, Olav Mella, Flemming Pociot, Øystein Fluge, Benedicte A. Lie, Marte K. Viken 
Brain, Behavior, and Immunity, Volume 102, 2022, Pages 362-369, 


  • Largest ME/CFS genetic study to date.  
  • Three different cohorts totaling >2500 patients. 
  • First Immunochip study in ME/CFS. 
  • Possible implication of TPPP genetic region. 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain.  

Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date.  

In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis.  

Even so, we did not find any ME/CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10−7), but we could not replicate the top SNP.  

However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004).  

Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance. 

Long-COVID Research References   

  1. Registered clinical trials investigating treatment of long COVID: a scoping review and recommendations for research 
  1. What Are the Long-term Pulmonary Sequelae of COVID-19 Infection? 
  1. Autoimmunity is a hallmark of post-COVID syndrome 
  1. A Call to Use the Multicomponent Exercise Tai Chi to Improve Recovery From COVID-19 and Long COVID 
  1. Acute COVID-19 severity and mental health morbidity trajectories in patient populations of six nations: an observational study 
  1. Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision? 
  1. Physical and mental health 3 months after SARS-CoV-2 infection (long COVID) among adolescents in England (CLoCk): a national matched cohort study 
  1. How Long is Your Covid? The Catch of ’22 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



Shopping Basket