Research Roundup

ME/CFS and Long Covid Research: 31 October – 6 November 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

There have been five new ME/CFS studies and twenty-two new Long Covid studies this week.

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

Paper five (5) is a study from Norway looking into the acknowledgement by specialist healthcare providers of post-exertional malaise (PEM) and how this affects patient outcomes and quality of care.

Post-exertional malaise (PEM) occurs after even small amounts of activity which leads to the worsening of symptoms and reduction in function ability:

  • is often delayed in onset by hours or days,
  • is often disproportionate to the activity,
  • has a prolonged recovery time that may last hours, days, weeks or longer,
  • it is a hallmark symptom of ME/CFS.

The study used online surveys covering specialist healthcare services for ME/CFS at rehabilitation centres in Norway as well as two regional hospitals. This resulted in the evaluation of 788 rehabilitation stays, 86 hospital consultations and 89 hospital interventions.

The main finding was unsurprisingly that PEM is frequently not acknowledged by specialist healthcare and not addressing PEM substantially increased the likelihood of decline in health and functioning. This was also strongly associated with reduced perceived care quality, satisfaction and benefit. Other findings included:

  • PEM was addressed in 48% of the rehabilitation stays, 43% of the consultations and 65% of the hospital interventions.
  • Failure to address PEM roughly doubled the risk of health deterioration following rehabilitation and hospital intervention.
  • PEM-focus during the clinical contact was associated with significantly higher scores on patients' rated care satisfaction and benefit of both consultation and intervention.
  • Addressing PEM resulted in positive views about healthcare providers' level of knowledge of ME/CFS, their acknowledgment of symptoms, obtained knowledge, and the perceived suitability of intervention.
  • These findings also have relevance in the field to the treatment of Long Covid.

At the moment only the abstract is available for this research, with the publication in progress, therefore, there is a limited amount of analysis we can do on this piece of research.

However, the results are not surprising with the acknowledgement of PEM resulting in better patient outcomes. This research was solely focused on Norway, therefore, we do not know the proportion of specialist healthcare centres acknowledging ME/CFS in the UK, which would of course be interesting to know. Furthermore, the acknowledgement rate seems unexpectedly high for what we would expect from Norway, especially seeing that previous research has reported a substantial lack of knowledge among healthcare providers and inadequate support for the severely ill (Sommerfelt et al., 2023).

You may also be interested in reading this week:

  • Paper one (1) which is on the use of Qigong as a treatment for ME/CFS, we have seen a range of other studies published on this topic, which can be found here.
  • Paper two (2) which is on the genetic risks for severe and fatigue dominant Long Covid and commonalities with ME/CFS. We have previously shared news articles from the company PrecisionLife who conducted this research which is now published in the Journal of Translational Medicine. The group have also previously published a paper on the genetic risk factors of ME/CFS, with news article here.
  • Paper three (3) promotes CBT as a treatment for ME/CFS, against the current NICE guideline, you can read Dr Shepherd’s comments on this here.

ME/CFS Research References

1. Effect of Prolong-life-with-nine-turn-method (Yan Nian Jiu Zhuan) Qigong on fatigue and gastrointestinal function in patients with chronic fatigue syndrome: Study protocol for a randomized controlled trial

Gu, You, Guo, Xie, Guan, Xie, Cheng, Ji, Yao.

PLoS One (IF: 3.7) 18(11) e0287287 


Introduction: Chronic fatigue syndrome (CFS) is a physical and mental disorder in which long-term fatigue is the main symptom. CFS patients are often accompanied by functional gastrointestinal diseases (FGIDs), which lead to decreased quality of life and increased fatigue.

Prolong-life-with-nine-turn-method (PLWNT) is a kind of physical and mental exercise. Its operation includes adjusting the mind, breathing and cooperating with eight self-rubbing methods and one upper body rocking method. PLWNT was used to improve the digestive function in ancient China and to treat FGIDs such as functional dyspepsia and irritable bowel syndrome in modern times.

Previous studies have shown that PLWNT can reduce fatigue in patients with CFS. But it is unclear whether the effect of PLWNT on CFS fatigue is related to gastrointestinal function. The aim of this study was to explore the relationship between PLWNT and fatigue and gastrointestinal function in patients with CFS.

Methods: This study is a non-inferiority randomized controlled trial (RCT). The whole study period is 38 weeks, including 2 weeks of baseline evaluation, 12 weeks of intervention and 6 months of follow-up. Ninety-six CFS patients will be stratified random assigned to the intervention group (PLWNT) and the control group (cognitive behavior treatment) in the ratio of 1:1 through the random number table generated by SPSS.

In the evaluation of results, Multidimensional Fatigue Inventory-20 (MFI-20), Gastrointestinal Symptom Rating Scale (GSRS), Bristol Stool Form Scale (BSFS), and Short Form 36 item health survey (SF-36) will be evaluated at week 0 (baseline), week 6 (midterm), week 12 (endpoint) and month 9 (follow up). The intestinal flora will be evaluated at week 0 (baseline) and week 12 (endpoint). The data results will be processed by statistical experts.

The data analysis will be based on the intention to treat principle and per-protocol analysis. In the efficacy evaluation, repeated measurement analysis of variance will be used for data conforming to normal distribution or approximate normal distribution. The data which do not conform to the analysis of repeated measurement variance will be analyzed by the generalized estimation equation Linear discriminant analysis will be used to clarify the difference species of intestinal flora. The significance level sets as 5%. The safety of interventions will be evaluated after each treatment session.

Discussion: This trial will provide evidence to PLWNT exerting positive effects on fatigue and gastrointestinal function of CFS. It will further explore whether the improvement of PLWNT on CFS fatigue is related to gastrointestinal function.

2. Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis

Taylor K, Pearson M, Das S, Sardell J, Chocian K, Gardner S.

J Transl Med. 2023 Nov 1;21(1):775. 


Background: Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It is characterized by a diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems.

Studies have so far largely failed to identify genetic associations, the mechanisms behind the disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that present with similar symptoms.

Methods: We used a combinatorial analysis approach to identify combinations of genetic variants significantly associated with the development of long COVID and to examine the biological mechanisms underpinning its various symptoms.

We compared two subpopulations of long COVID patients from Sano Genetics' Long COVID GOLD study cohort, focusing on patients with severe or fatigue dominant phenotypes. We evaluated the genetic signatures previously identified in an ME/CFS population against this long COVID population to understand similarities with other fatigue disorders that may be triggered by a prior viral infection.

Finally, we also compared the output of this long COVID analysis against known genetic associations in other chronic diseases, including a range of metabolic and neurological disorders, to understand the overlap of pathophysiological mechanisms.

Results: Combinatorial analysis identified 73 genes that were highly associated with at least one of the long COVID populations included in this analysis. Of these, 9 genes have prior associations with acute COVID-19, and 14 were differentially expressed in a transcriptomic analysis of long COVID patients.

A pathway enrichment analysis revealed that the biological pathways most significantly associated with the 73 long COVID genes were mainly aligned with neurological and cardiometabolic diseases. Expanded genotype analysis suggests that specific SNX9 genotypes are a significant contributor to the risk of or protection against severe long COVID infection, but that the gene-disease relationship is context dependent and mediated by interactions with KLF15 and RYR3.

Comparison of the genes uniquely associated with the Severe and Fatigue Dominant long COVID patients revealed significant differences between the pathways enriched in each subgroup. The genes unique to Severe long COVID patients were associated with immune pathways such as myeloid differentiation and macrophage foam cells. Genes unique to the Fatigue Dominant subgroup were enriched in metabolic pathways such as MAPK/JNK signaling.

We also identified overlap in the genes associated with Fatigue Dominant long COVID and ME/CFS, including several involved in circadian rhythm regulation and insulin regulation. Overall, 39 SNPs associated in this study with long COVID can be linked to 9 genes identified in a recent combinatorial analysis of ME/CFS patient from UK Biobank.

Among the 73 genes associated with long COVID, 42 are potentially tractable for novel drug discovery approaches, with 13 of these already targeted by drugs in clinical development pipelines. From this analysis for example, we identified TLR4 antagonists as repurposing candidates with potential to protect against long term cognitive impairment pathology caused by SARS-CoV-2. We are currently evaluating the repurposing potential of these drug targets for use in treating long COVID and/or ME/CFS.

Conclusion: This study demonstrates the power of combinatorial analytics for stratifying heterogeneous populations in complex diseases that do not have simple monogenic etiologies. These results build upon the genetic findings from combinatorial analyses of severe acute COVID-19 patients and an ME/CFS population and we expect that access to additional independent, larger patient datasets will further improve the disease insights and validate potential treatment options in long COVID.

3. Does the effect of cognitive behavior therapy for chronic fatigue syndrome (ME/CFS) vary by patient characteristics? A systematic review and individual patient data meta-analysis

Kuut TA, Buffart LM, Braamse AMJ, Csorba I, Bleijenberg G, Nieuwkerk P, Moss-Morris R, Müller F, Knoop H.

Psychol Med. 2023 Nov 6:1-10.


Debate is ongoing on the efficacy of cognitive behavior therapy (CBT) for myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). With an individual patient data (IPD) meta-analysis we investigated whether the effect of CBT varied by patient characteristics. These included post-exertional malaise (PEM), a central feature of ME/CFS according to many.

We searched for randomized controlled trials similar with respect to comparison condition, outcomes and treatment-protocol. Moderation on fatigue severity (Checklist Individual Strength, subscale fatigue severity), functional impairment (Sickness Impact Profile-8) and physical functioning (Short Form-36, subscale physical functioning) was investigated using linear mixed model analyses and interaction tests. PROSPERO (CRD42022358245). Data from eight trials (n = 1298 patients) were pooled.

CBT showed beneficial effects on fatigue severity (β = -11.46, 95% CI -15.13 to -7.79); p < 0.001, functional impairment (β = -448.40, 95% CI -625.58 to -271.23); p < 0.001; and physical functioning (β = 9.64, 95% CI 3.30 to 15.98); p < 0.001.

The effect of CBT on fatigue severity varied by age (pinteraction = 0.003), functional impairment (pinteraction = 0.045) and physical activity pattern (pinteraction = 0.027). Patients who were younger, reported less functional impairments and had a fluctuating activity pattern benefitted more. The effect on physical functioning varied by self-efficacy (pinteraction = 0.025), with patients with higher self-efficacy benefitting most. No other moderators were found.

It can be concluded from this study that CBT for ME/CFS can lead to significant reductions of fatigue, functional impairment, and physical limitations. There is no indication patients meeting different case definitions or reporting additional symptoms benefit less from CBT. Our findings do not support recent guidelines in which evidence from studies not mandating PEM was downgraded.

4. Patient perspectives of recovery from myalgic encephalomyelitis/chronic fatigue syndrome: An interpretive description study

Hasan Z, Kuyvenhoven C, Chowdhury M, Amoudi L, Zeraatkar D, Busse JW, Sadik M, Vanstone M.

J Eval Clin Pract. 2023 Nov 6. [Epub ahead of print.]


Aims and objectives: Myalgic encephalomyelitis (ME), also called chronic fatigue syndrome (CFS), is characterised by persistent fatigue, postexertional malaise, and cognitive dysfunction. It is a complex, long-term, and debilitating illness without widely effective treatments. This study describes the treatment choices and experiences of ME/CFS patients who have experienced variable levels of recovery.

Method: Interpretive description study consisting of semi-structured qualitative interviews with 33 people who met the US Centers for Disease Control (2015) diagnostic criteria for ME/CFS and report recovery or symptom improvement.

Results: Twenty-six participants endorsed partial recovery, and seven reported full recovery from ME/CFS. Participants reported expending significant time and energy to identify, implement, and adapt therapeutic interventions, often without the guidance of a medical practitioner. They formulated individualised treatment plans reflecting their understanding of their illness and personal resources. Most fully recovered participants attributed their success to mind-body approaches.

Conclusion: Patients with ME/CFS describe independently constructing and managing treatment plans, due to a lack of health system support. Stigmatised and dismissive responses from clinicians precipitated disengagement from the medical system and prompted use of other forms of treatment.

5. Focus on Post-Exertional Malaise when approaching ME/CFS in specialist healthcare improves satisfaction and reduces deteriorations

Marjon E. Wormgoor, Sanne C. Rodenburg.

Frontiers in Neurology 14- 2023.


Background: Post-Exertional Malaise (PEM) is considered a hallmark characteristic of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). This may also apply to subgroups of patients with long COVID induced ME/CFS. However, it is uncertain to what extent PEM is acknowledged in routine specialist healthcare for ME/CFS patients, and how this affects patient outcomes.

Objective: This study aims to evaluate to what extent ME/CFS patients experienced focus on PEM in specialist healthcare practice and its significance for outcome and care quality.

Methods: Data from two online cross-sectional surveys covering specialist healthcare services for ME/CFS patients at rehabilitation institutes in Norway and at two regional hospitals respectively, were analyzed. Evaluations of 788 rehabilitation stays, 86 hospital consultations and 89 hospital interventions were included.

Logistic regression models and Mann-Whitney U tests were used to quantify the impact of addressing PEM on health and functioning, care satisfaction or benefit. Spearman's rank correlation and Cronbach's alpha of focus on PEM with the respondents' perception of healthcare providers' knowledge, symptom acknowledgement and suitability of intervention were assessed as measures for care quality and their internal consistency, respectively.

Results: PEM was addressed in 48% of the rehabilitation stays, 43% of the consultations and 65% of the hospital interventions. Failure to address PEM roughly doubled the risk of health deterioration following rehabilitation (OR=0.39, 95%CI 0.29-0.52; 40.1% vs 63.2% P= <.001) and hospital intervention (OR=0.34, 95%CI 0.13-0.89; 22.4% vs. 45.2%, P=.026).

PEM-focus during the clinical contact was associated with significantly higher scores on patients' rated care satisfaction and benefit of both consultation and intervention. Furthermore, addressing PEM was (inter)related to positive views about healthcare providers' level of knowledge of ME/CFS, their acknowledgment of symptoms, obtained knowledge, and the perceived suitability of intervention (Cronbach's alpha ≥ 0.80).

Conclusion: PEM is still frequently not acknowledged in specialist healthcare practice for ME/CFS patients in Norway. Not addressing PEM substantially increased the probability of a decline in health and functioning following intervention and was strongly associated with reduced perceived care quality, satisfaction and benefit. These findings may be related to the applied explanatory models for ME/CFS and are most likely of relevance to long COVID.

Long-COVID Research References

  1. Long-term cognitive dysfunction after the COVID-19 pandemic: a narrative review
  2. Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis
  3. Children and Young People with Long COVID—Comparing Those Seen in Post-COVID Services with a Non-Hospitalised National Cohort: A Descriptive Study
  4. A Review Article on Exercise Intolerance in Long COVID: Unmasking the Causes and Optimizing Treatment Strategies
  5. Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients' complaints, and clinical predictors
  6. Treatment of 95 post-Covid patients with SSRIs
  7. Unified Protocol for the transdiagnostic treatment of emotional disorders in people with post COVID-19 condition: study protocol for a multiple baseline n-of-1 trial
  8. Psychological risk factors for Long COVID and their modification: study protocol of a three-arm, randomised controlled trial (SOMA.COV)
  9. The long-term health outcomes, pathophysiological mechanisms and multidisciplinary management of long COVID
  10. From COVID-19 to long COVID; the forms of the neurological manifestations
  11. Experiences and care needs of children with long Covid: a qualitative study
  12. Strategies to Manage the Thinking and Emotional Difficulties of Long COVID: A Guide for Patients and Families
  13. Post-acute sequelae of COVID-19 in solid organ transplant recipients
  14. Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors
  15. Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19
  16. Hyperbaric Oxygen Treatment for Long COVID: From Molecular Mechanism to Clinical Practice
  17. Core outcome measurement instruments for use in clinical and research settings for adults with post-COVID-19 condition: an international Delphi consensus study
  18. Long COVID: a new word for naming fibromyalgia?
  19. Examining the relationship between inflammatory biomarkers during COVID‐19 hospitalization and subsequent long‐COVID symptoms: A longitudinal and retrospective study
  20. A Multi-label Classification Study for the Prediction of Long-COVID Syndrome
  21. Predictive models of long COVID
  22. Allergic diseases as risk factors for Long-COVID symptoms: Systematic review of prospective cohort studies

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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