MEA Research Roundup

ME/CFS and Long Covid Research: 28 March – 03 April 2023 

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 28 March – 3 April 2023 

It’s been a quieter week for ME/CFS research ahead of Easter with two new ME/CFS studies but twenty new Long Covid studies. 

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

Paper one (1) looks at sex differences and function following exercise in 22 females and 15 males with ME/CFS and 14 healthy controls. What differs with this research is that a more tolerable level of exercise was used, which was a six-minute exercise test followed by 30 seconds of squats on two consecutive days. Patients in this study were assessed for fatigue, function, and heart rate over 15 days, with the exercise taking place on days 8 and 9. 

Unfortunately, results from this study were disappointing: 

  • The ME/CFS group showed high self-reported fatigue and impaired physical function, whereas healthy controls did not show fatigue or function abnormalities.  
  • No significant post-exercise changes were found for heart rate variability (HRV) in ME/CFS. 
  • Female patients showed increased fatigue after the initial walk test, but this effect was short-term. 
  • Male patients showed a decrease in self-reported work limitation in the days after exercise.  
  • ME/CFS patients had returned to baseline fatigue levels at day-15 of the research, with decreasing fatigue levels on day 9 to 15. 
  • The healthy control group evidenced a decrease in HRV after the walk tests from Day 9–14. 
  • The researchers expected to show that females compared to males would show slower exercise recovery on autonomic or self-report (e.g. fatigue) measures but results did not support this. 

We frequently see intensive cardiopulmonary exercise testing (CPET) used in studies to induce PEM, which is extremely difficult ethically to employ in a ME/CFS population and will only have the milder severities participating. Previous research has shown that on average it takes two-weeks to recover from CPET (Moore et al., 2023).  

It is refreshing to see an exercise study that is more tolerable to pwME and could be conducted at home, which allows expansion of participants included, however, there is a lack of detail given on the severity and function of those included in this research. Furthermore, this level of exercise will be far above the capabilities of many with ME, especially the severely affected so will still not capture the whole range of severities.  

As shown in this research, it is extremely difficult to achieve the right balance between a lower burden exercise protocol and being able to detect small biological changes. It is a shame that no biological measures or chemical changes were measured in the blood or urine, as we have seen some promising research in this field of late (e.g. Glass et al., 2023, previous research comment here). Unfortunately, findings from this research led to the conclusion that more rigorous exercise testing is needed. Hopefully, advances in this field will allow the right balance to be achieved so we can establish the level of exertion that is needed to trigger PEM and find biological changes. 

Some of the highlights in the Long Covid research this week, include: 

  • Paper one (1) looks at interleukin-6 (IL-6) to determine whether levels pre-Covid-19 determines fatigue experienced in Long Covid. IL-6 has been investigated in a number of Long Covid studies, and is a multifunctional cytokine that plays a central role in host defence due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response, furthermore it plays a key role in persistent fatigue. Unfortunately, the study did not find a specific link between Covid-19 infection, increased IL-6 levels (pre-infection) and resulting fatigue. 
  • Papers two (2) and three (3) which are not strictly on Long Covid, but review evidence to date on brain structure changes from Covid-19 infection to up to one year after. The research shows that Covid-19 causes brain shrinkage and prolonged neurological symptoms related to the areas of the brain effected. 
  • Paper four (4) looks at changes in monocytes (a type of white blood cell involved in fighting infections) from hospitalisation with Covid-19, to 9 months afterwards compared to respiratory syncytial virus (RSV) or influenza A (flu). The study found that unique monocyte signatures develop in Long Covid which were not present in RSV or flu. The results show that monocyte migration plays a key role in Long Covid pathophysiology. 

ME/CFS Research References and Abstracts  

1. Sex differences in post-exercise fatigue and function in myalgic encephalomyelitis/chronic fatigue syndrome 

Friedberg F, Adamowicz JL, Bruckenthal P, Milazzo M, Ramjan S, Zhang X, Yang J.  

Sci Rep. 2023 Apr 3;13(1):5442. 


To assess biobehavioral sex differences in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) utilizing a low burden exercise protocol, 22 females and 15 males with ME/CFS and 14 healthy controls underwent two six-min walk tests.  

Fifteen daily assessments were scheduled for fatigue and function ratings and heart monitoring. Six-min walk tests were conducted on days 8 and 9.  

The ME/CFS group showed high self-report fatigue and impaired physical function, whereas healthy controls did not show fatigue or function abnormalities.  

In patients, no significant post-exercise changes were found for heart rate variability (HRV); however, heart rate decreased in ME/CFS males from Day 14 to Day 15 (p = 0.046).  

Female patients showed increased fatigue (p = 0.006) after the initial walk test, but a downward slope (p = 0.008) in fatigue following the second walk test.  

Male patients showed a decrease in self-report work limitation in the days after exercise (p = 0.046).  

The healthy control group evidenced a decrease in HRV after the walk tests from Day 9-14 (p = 0.038).  

This pilot study did not confirm hypotheses that females as compared to males would show slower exercise recovery on autonomic or self-report (e.g. fatigue) measures. A more exertion-sensitive test may be required to document prolonged post-exertional abnormalities in ME/CFS. 

2. Natural killer cytotoxicity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a multi-site clinical assessment of ME/CFS (MCAM) sub-study 

Querec, T.D., Lin, JM.S., Chen, Y. et al.  

J Transl Med 21, 242 (2023).  


Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by substantial reduction in function accompanied by profound unexplained fatigue not significantly relieved by rest, post-exertional malaise, and other symptoms.  

Reduced natural killer (NK) cell count and cytotoxicity has been investigated as a biomarker for ME/CFS, but few clinical laboratories offer the test and multi-site verification studies have not been conducted. 

Methods: We determined NK cell counts and cytotoxicity in 174 (65%) ME/CFS, 86 (32%) healthy control (HC) and 10 (3.7%) participants with other fatigue associated conditions (ill control [IC]) from the Multi-Site Clinical Assessment of ME/CFS (MCAM) study using an assay validated for samples shipped overnight instead of testing on day of venipuncture. 

Results: We found a large variation in percent cytotoxicity [mean and (IQR) for ME/CFS and HC respectively, 34.1% (IQR 22.4–44.3%) and 33.6% (IQR 22.9–43.7%)] and no statistically significant differences between patients with ME/CFS and HC (p-value = 0.79).  

Analysis stratified on illness domain measured with standardized questionnaires did not identify an association of NK cytotoxicity with domain scores. Among all participants, NK cytotoxicity was not associated with survey results of physical and mental well-being, or health factors such as history of infection, obesity, smoking, and co-morbid conditions. 

Conclusion: These results indicate this assay is not ready for clinical implementation and studies are needed to further explore immune parameters that may be involved in the pathophysiology of ME/CFS. 

Long-COVID Research References  

  1. Long-COVID fatigue is not predicted by pre-pandemic plasma IL-6 levels in mild COVID-19 infection 
  1. Brain Disorders: Impact of Mild SARS-CoV-2 May Shrink Several Parts of the Brain 
  1. Direct and indirect impact of SARS-CoV-2 on the brain 
  1. Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID 
  1. COVID-19 Vaccination for the Prevention and Treatment of Long COVID: A Systematic Review and Meta-analysis 
  1. Miscellaneous neuromuscular symptoms and signs in long Covid 
  1. Neurologic manifestations of long COVID differ based on acute COVID-19 severity 
  1. Co-production of a feasibility trial of pacing interventions for Long COVID 
  1. Potential Prion Involvement in Long COVID-19 Neuropathology, Including Behavior 
  1. Metabolic and endocrine complications of long COVID-19: A review 
  1. Long COVID as a chronic illness: giving credibility to support students 
  1. Occupational differences in the prevalence and severity of long-COVID: Analysis of the ONS Coronavirus (COVID-19) Infection Survey 
  1. Long Covid, a contemporary sequalae: considerations for advanced clinical practice 
  1. Rapid flow cytometric analysis of fibrin amyloid microclots in Long COVID 
  1. Long COVID in autoimmune rheumatic diseases 
  1. Thrombophilia and Immune-Related Genetic Markers in Long COVID 
  1. Coronavirus (COVID-19) Pandemic – A Comprehensive Review of Demographics, Comorbidities, Vaccines, Therapeutic Development, Blood Type, and Long Covid 
  1. Vaccine perceptions among Black adults with long COVID 
  1. Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults 
  1. Long COVID and the cardiovascular system-elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: a joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial and Pericardial Diseases 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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