ME Association regular research roundup

ME/CFS and Long Covid Research: 15 – 21 August 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).

There have been seven new ME/CFS studies and eighteen new Long Covid studies this week.


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

We have also listed the ME/CFS references which have been missed in the last two weeks (due to sickness), with seven new references in the first week of August and six new references last week.

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

Paper three (3) looks at the long-term symptom severity and clinical biomarkers in those with post-covid syndrome (PCS, i.e. Long Covid) comparing these to the subset of patients who also met the diagnostic criteria for ME/CFS (referred to as PCS-ME/CFS), i.e. this study looked at PCS vs PCS-ME/CFS.

The study included 106 patients who have moderate to severe fatigue and exertion intolerance at three time points following Covid-19 infection (3–8 (baseline), 9–16, and 17–20 months). The researchers evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters.

A range of findings were discovered which showed that the two groups differed, this included:

  • The PCS-ME/CFS were diagnosed based on the Canadian Consensus Criteria (CCC) which included 55 patients out of the 106 in the total study cohort.
  • PCS-ME/CFS patients reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Furthermore, higher levels of disability were found in PCS-ME/CFS group (shown using the bel disability scale).
  • Fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were more pronounced in the PCS-ME/CFS group.
  • Pain was seen to affect the PCS-ME/CFS more severely than the PCS group.
  • Neurological symptoms were seen to affect both groups, but hypersensitivities to noise, light and temperature were more pronounced in the PCS-ME/CFS especially at follow-up.
  • Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies.
  • Lower hand grip strength (HGS) at onset correlated with symptom persistence and burden, particularly in patients with PCS-ME/CFS.
  • Postural orthostatic tachycardia syndrome (POTS) was found almost exclusively in the PCS-ME/CFS group.

This is quite a simple study but it does reveal a range of interesting results which add to the field. Results clearly show that those who meet the CCC definitions for ME/CFS are unlikely to see significant improvement in the 20 months following infection.

The research group involved in this study, included a large group of investigators based out of Charité’s Fatigue Centre in Berlin, including Carmen Scheibenbogen, who we commonly see ME/CFS research from. It is therefore a great shame that we did not see these results compared to an ME/CFS group without a Covid-19 trigger, which the team would have easy access to and could allow further differentiation between groups.

There are not many other limitations to this research, however, as ever there was a disproportionate balance of males and females. Despite the fairly reasonably sized study, the researchers did also experience high group drop out levels, with 19 patients dropping out (12 with PCS and 7 with  PCS-ME/CFS), and another 46 did not complete the follow-ups. Overall, this study provides some useful results allowing separation of groups and also implications for managing PCS conditions.

You may also be interested in reading this week, Paper four (4) which is an ME Association Ramsay Research Funded project on home-based physiological testing conducted during everyday activity. The research revealed a huge range of potential abnormalities that varied between individuals that have previously not been reported. The protocol was found to be feasible and acceptable for people with mild to severe ME. You can read a summary of the findings of this study on our website. In the previous weeks of research, there has been a lot of interest in research showing that a particular protein which disrupts a cells energy structure may be a culprit in ME/CFS (& Long Covid). The full paper can be read here and an easily digestible summary can be found on our website

ME/CFS Research References (15 – 21 August 2023)

1. The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome

Hanson, MR.

PLoS Pathog. 2023 Aug 17; 19(8): e1011523.


No Abstract Available

2. eLearning improves allied health professionals' knowledge and confidence to manage medically unexplained chronic fatigue states: A randomized controlled trial

Matthew D. Jones, Sally M. Casson, Benjamin K. Barry, Sophie H. Li, Trinidad Valenzuela, Joanne Cassar, Camillo Lamanna, Andrew R. Lloyd, Carolina X. Sandler.

Journal of Psychosomatic Research, 2023: 111462.


  • eLearning is acceptable to clinicians.
  • eLearning improves clinicians' knowledge of chronic fatigue states.
  • eLearning improves clinicians' confidence to manage chronic fatigue states.
  • eLearning has little impact on clinicians' practice behaviours.


Objectives: To evaluate the impact of eLearning by allied health professionals on improving the knowledge and confidence to manage people with medically unexplained chronic fatigue states (FS).

Methods: Using a parallel randomized controlled trial design, participants were randomized 1:1 to a 4-week eLearning or wait-list control group. Knowledge and self-reported confidence in clinical skills to implement a therapeutic intervention for patients with FS were assessed at baseline, post-intervention and follow-up. Secondary outcomes (adherence and satisfaction with online education, knowledge retention) were also assessed. Data was analyzed using intention-to-treat.

Results: There were 239 participants were randomized (eLearning n = 119, control n = 120), of whom 101 (85%) eLearning and 107 (89%) control participants completed baseline assessments and were included in the analysis. Knowledge (out of 100) improved significantly more in the eLearning group compared to the control group [mean difference (95% CI) 8.6 (5.9 to 11.4), p < 0.001].

Knowledge was reduced in the eLearning group at follow-up but was still significantly higher than baseline [6.0 (3.7 to 8.3), p < 0.001]. Median change (out of 5) in confidence in clinical skills to implement the FS intervention was also significantly greater in the eLearning group compared to the control group [knowledge: eLearning (1.2), control (0); clinical skills: eLearning (1), control (0.1); both p < 0.001)]. Average time spent on the eLearning program was 8.8 h. Most participants (80%) rated the lesson difficulty as at the “right level”, and 91% would recommend it to others.

Conclusions: eLearning increased knowledge and confidence to manage FS amongst allied health professionals and was well-accepted.

3. Long-term symptom severity and clinical biomarkers in post-COVID-19/chronic fatigue syndrome: results from a prospective observational cohort

Franziska Legler, Lil Meyer-Arndt, Lukas Mödl, Claudia Kedor, Helma Freitag, Elisa Stein, Uta Hoppmann, Rebekka Rust, Kirsten Wittke, Nadja Siebert, Janina Behrens, Andreas Thiel, Frank Konietschke, Friedemann Paul, Carmen Scheibenbogen, Judith Bellmann-Strobl.

eClinicalMedicine,Volume 63, 2023.


Background: Post-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the long-term health consequences for patients with PCS with disabling fatigue remain unclear.

Methods: In this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3–8, 9–16, and 17–20 months). The study was conducted at the Charité’s Fatigue Centre and the Charité’s outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC).

The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers.

Findings: Patients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS.

Interpretation: Our findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity.

4. Home-based testing protocol to measure physiological responses to everyday activities in ME: a feasibility study

Nicola Clague-Baker, Sarah Tyson, Karen Leslie, Helen Dawes, Michelle Bull & Natalie Hilliard.

 Fatigue: Biomedicine, Health & Behavior.


Background and objectives: Individuals with Myalgic Encephalomyelitis (ME) have shown altered physiological responses during maximum cardiopulmonary exercise testing. However, maximal testing is not representative of the everyday activities reported to cause or increase symptoms in ME, and is not accessible for those with severe or very severe illness. The aim of this study was to assess the feasibility and acceptability of a home-based testing protocol to measure physiological responses in ME to everyday activity.

Methods: Researchers attended participants’ homes to collect data and provide equipment for independent testing. Adults with ME who met the International Consensus Criteria wore a portable metabolic assessment system and a physiological stress monitor. Blood pressure, heart rate, oxygen saturation and lactic acid were assessed during a range of everyday positions and activities in their own homes.

Results: Online recruitment yielded 70 volunteers in 24 h. 17 eligible individuals reflecting a range of illness severities were enrolled. All participants found the procedures acceptable with 12 (70%) subjects completing every listed activity. Apparent physiological abnormalities were identified in all participants.

Conclusion: Physiological measurement during everyday activities was feasible for our participants who represented a range of ME severities. Activities must be adapted for different levels of severity to avoid significant symptom exacerbation. Further research is needed to develop home-based assessment protocols to advance the biobehavioral understanding of ME.

5. Long COVID, POTS, CFS and MTHFR: Linked by Biochemistry and Nutrition

Patrick W Chambers.

Journal of Orthomolecular Medicine. 38.


The recent pandemic has energized research spotlighting chronic fatigue disorders. The similarities between Long COVID (LC) and Chronic Fatigue Syndrome (CFS), often accompanied by postural orthostatic tachycardia syndrome (POTS) are striking.

Furthermore, the majority afflicted with LC and CFS may be those with methylenetetrahydrofolate reductase (MTHFR) polymorphisms, present in the majority of Americans and characterized by hypomethylation. Elevated homocysteine (Hcy) and depressed B9 and B12 may be links. Speculation about an association between these laboratory analytes and MTHFR abnormalities has been previously reported (Regland et al., 2015).

The absence of a blood-brain barrier (BBB) in CNS circumventricular organs (CVOs) that control autonomic and neuroendocrine functions, problematic in LC, CFS, POTS, and MTHFR, is provocative. Diffusion of CNS Hcy is associated with brain fog, cognitive impairment, and dementia. This provides a distinct link between MTHFR variants and the fog of LC, CFS, and POTS.

Small intestine bacterial overgrowth (SIBO), present in about 17% of Americans, is linked to POTS, mast cell activation syndrome (MCAS), and Ehlers Danlos syndrome (EDS). All exhibit histamine intolerance and female predominance. This may be due to hypomethylation and/or intestinal diamine oxidase (DAO) deficiency.

Metabolism of monoamines and histamine requires methylation. Specific CNS nuclei in CVOs may also provide insight to the POTS paradox. The similar gut microbiomes of LC/CFS (and vitamin D deficiency) may via CVOs trigger an imbalance in glutamate/GABA neurotransmission that translates to neuroendocrine and baroreflex dysfunction. Homozygosity for the MTHFR 677T allele can facilitate hypermethylation via an alternative “rescue” riboflavin pathway triggered by significant Hcy increase.

Hypermethylation predominates in Long Covid. The primary problem in these syndromes is compromised mitochondrial function due to oxidative stress induced by an antioxidant shortfall.

Victims are also frequently deficient in 25(OH)D3 (the storage form of vitamin D), magnesium, and B vitamins, consumed by the persistent chronic inflammatory state. Estrogen increases histamine, norepinephrine, and bradykinin (BKN), which may in part explain the brain fog and its predilection for females.

6. The demographic features of fatigue in the general population worldwide: a systematic review and meta-analysis

Yoon J-H, Park N-H, Kang Y-E, Ahn Y-C, Lee E-J and Son C-G.

Front. Public Health 11:1192121


Background: Fatigue is one of the most common subjective symptoms that impairs daily life and predict health-related events. This study aimed to estimate the prevalence of fatigue in the global population.

Methods: PubMed and the Cochrane Library were used to search for relevant articles from inception to December 31, 2021. Studies with prevalence data of fatigue in the general population were selected and reviewed by three authors independently and cross-checked. Regarding subgroups, adults (≥18 years), minors (<18 years), and specific occupation population (participants in each study being limited to a specific occupational group), and fatigue types and severity, meta-analysis was conducted to produce point estimates and 95% confidence intervals (95% CI).

Results: From the initial 3,432 studies, 91 studies accounting for 115 prevalence data points (623,624 participants) were finally selected. The prevalence of general fatigue (fatigue lasting < 6 months, or fatigue of unspecified duration) was 20.4% (95% CI, 16.7–25.0) in adults, 11.7% (95% CI, 5.2–26.6) in minors, and 42.3% (95% CI, 33.0–54.2) in specific occupations. Chronic fatigue (fatigue lasting more than 6 months) affected 10.1% (95% CI, 8.2–12.5) of adults, 1.5% (95% CI, 0.5–4.7) of minors, and 5.5% (95% CI, 1.4–21.6) of subjects in specific occupations. There was an overall female-predominant prevalence for all subgroup analyses, with a total odds ratio of 1.4 (95% CI, 1.3–1.6).

Regarding the severity and presence of medical causes, the total prevalence of moderate fatigue [14.6% (95% CI, 9.8–21.8)] was 2.4-fold that of severe fatigue [6.1% (95% CI, 3.4–11.0)], while unexplained fatigue (fatigue experienced by individuals without any underlying medical condition that can explain the fatigue) was ~2.7-fold that of explained fatigue (fatigue experienced by individuals with a medical condition that can explain the fatigue); as proportion of 40.0% of physical, 8.6% of mental, and 28.4% of mixed cause.

Conclusions: This study has produced the first comprehensive picture of global fatigue prevalence in the general population, which will provide vital reference data contributing to fatigue-related research, including the prevention of diseases.

7. In severe first episode major depressive disorder, psychosomatic, chronic fatigue syndrome, and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity

Michael Maes, Abbas F Almulla, Bo Zhou, Ali Abbas Abo Algon, Pimpayao Sodsai.

ResearchGate [Preprint]


Background: Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors.

Aims: To delineate the impact of ACE+NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles.

Methods: ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls.

Results: Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated).

Partial Least Squares analysis shows that ACE+NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor.

Conclusions: The physiosomatic and FF symptoms of FE-MDMD are partly caused by immuneassociated neurotoxicity due to Th-1 polarization, T helper-1, and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.

ME/CFS Research References (1 – 7 August 2023)

1. DNA methylation signatures of functional somatic syndromes: Systematic review

2. Hypothalamus volumes in adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): impact of self-reported fatigue and illness duration

3. A population-based investigation into the prevalence of chronic fatigue syndrome in United States military Veterans with chronic pain

4. Consequences of sarcolemma fatigue on maximal muscle strength production in patients with myalgic encephalomyelitis/chronic fatigue syndrome

5. Chronic inflammation, neuroglial dysfunction, and plasmalogen deficiency as a new pathobiological hypothesis addressing the overlap between post-COVID-19 symptoms and myalgic encephalomyelitis/chronic fatigue syndrome

6. Evaluation of a Webinar to Increase Health Professionals’ Knowledge about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

7. Assessing health state utilities for people with myalgic encephalomyelitis/chronic fatigue syndrome in Australia using the EQ-5D-5L, AQoL-8D and EQ-5D-5L-psychosocial instruments

ME/CFS Research References (8 – 14 August 2023)

1. Characterizing Sjögren-Associated Fatigue: A Distinct Phenotype from ME/CFS

2. Contesting oppressive regimes of truth: A critical feminist re-examination of (bio)psychosocial hegemony in the field of myalgic encephalomyelitis / chronic fatigue syndrome

3. WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

4. The importance of estimating prevalence of ME/CFS in future epidemiological studies of long COVID

5. A Scoping Review of Pacing for Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Lessons Learned for the Long COVID Pandemic

6. Longterm course of neuropsychological symptoms and ME/CFS after SARS-CoV-2-infection: a prospective registry study

Long-COVID Research References (15 – 21 August 2023)

  1. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? 
  2. Evaluation of Post–COVID-19 Cognitive Dysfunction: Recommendations for Researchers
  3. Post-COVID-19 syndrome management: Utilizing the potential of dietary polysaccharides
  4. Cocreation of Assistive Technologies for Patients With Long COVID: Qualitative Analysis of a Literature Review on the Challenges of Patient Involvement in Health and Nursing Sciences
  5. Long Covid requires a global response centred on equity and dialogue
  6. Effect of Physical Exercise-Based Rehabilitation on Long COVID: A Systematic Review and Meta-analysis
  7. Post-COVID-19 Symptoms in Adults with Asthma—Systematic Review
  8. The Long Covid-19 Syndrome the Spike Protein and Stem Cells, the Underrated Role of Retrotransposons, a Working Hypothesis
  9. Predictors of Post-COVID-19 Functional Status Scale in hospitalized patients recovering from SARS-CoV-2 infection
  10. Compounding for the Treatment of COVID-19 and Long COVID, Part 4: The Legacy of Chronic COVID
  11. The microbiome in post-acute infection syndrome (PAIS)
  12. The effect of long-haul COVID-19 toward domains of the health-related quality of life among recovered hospitalized patients
  13. Forming a consensus opinion to inform long COVID support mechanisms and interventions: a modified Delphi approach
  14. Long-term health consequences among individuals with SARS-CoV-2 infection compared to individuals without infection: results of the population-based cohort study CoMoLo Follow-up
  15. Pathophysiology, diagnosis, and management of neuroinflammation in covid-19
  16. Postacute sequelae of COVID-19 at 2 years
  17. Prevalence, pathogenesis and spectrum of neurological symptoms in COVID-19 and post-COVID-19 syndrome: a narrative review
  18. L-Arginine in Restoring ‘Immune Dysregulation’ in Long COVID: It’s the Therapeutic Role Beyond the Routine Dietary Supplement!

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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