ME Association regular research roundup

ME/CFS and Long Covid Research: 26 June – 03 July 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 nine new ME/CFS studies and twenty 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 highlighted one of the ME/CFS studies in more detail below:

Paper six (6) is a preprint (i.e. it has not been peer-reviewed and the science verified) delving into finding a biomarker for ME/CFS and Long Covid, the study specifically focuses on the increased levels of circulating fibronectin, depleted IgM and heightened reactivation of EBV and HSV-1.

This study involved a lot of complex science and interactions, which builds on the previous work on herpesvirus (HHV) reactivation. The team strongly believe that herpesvirus reactivation is a key mechanism in ME/CFS and Long Covid development.

In summary, the basic findings of this research are:

  • Epstein-Barr virus (EBV) and HSV-1 reactivation causes the enzyme herpesvirus dUTPases to be produced in an antibody response.
  • Producing this also causes increased circulating fibronectin (FN1) levels in serum (a multifunctional, adhesive glycoprotein that plays an important role in tissue repair, regulating cell attachment and motility).
  • In addition this enzyme causes a depletion of natural IgM against fibronectin ((n)IgM-FN1) (the initial antibody produced by the adaptive immune system in response to a foreign pathogen).
  • These finding correlate with the severity of disease and are present in Long Covid and ME/CFS.
  • Herpesvirus duTPase proteins are also shown to cause cellular damage.
  • Long Covid and ME/CFS are shown to be molecularly similar but also can be distinguished between.

This study is from Bhupesh Prustry’s research group, which there has been a lot of driven hype about. The research involved a large international collaboration of 35 scientists, with several different small studies being reported on. It may, therefore, have been better to just report on one area (focusing on a well-designed strong study), instead of the large mix in this very long paper). A lot of caution needs to be taken in the results, firstly and foremost the results have not been verified and to fully establish a biomarker significantly more replication and research is needed.

Another concern over the research is the lack of consistency used when drawing comparisons between groups, with different statistical methods being used, therefore some of the methodological approaches could be questioned in whether they are manipulating the data to find results. Furthermore, when looking at the results in greater detail it’s only those with severe ME that can be identified from healthy controls, therefore the biomarker is not universal in its application. The study is written in a way that findings are immediately ready for dissemination, but this is not the case. Hopefully, some of these problems will be ironed out in the peer-review process.

(N.B. We have previously covered some of the brief points of this research in a conference report.)

ME/CFS Research References and Abstracts (13 – 19 June)

1. Comparing Frequency and Severity Ratings for ME/CFS versus Controls

Jason LA, Benner S, Hansel N.

Psych. 2023; 5(3):662-669.


Most questionnaires for somatic symptoms focus on occurrence, frequency, or severity, and in doing so, they might not be able to comprehensively assess the burden that symptoms present to patients. For example, a symptom might occur at a high frequency but only a minimal severity, so that it is less likely to be a burden on a patient; whereas a symptom that has both a high frequency and severity is more likely to be negatively impacting a patient.

Study 1 examined frequency and severity scores for classic Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) symptoms among patients with ME/CFS versus a control group.

Findings in Study 1 indicate there were more frequency/severity discrepancies for individuals with ME/CFS versus the control group. Study 1 concluded that collecting data on both measures of symptom burden provides unique indicators that can better assess the burden of the symptoms on patients.

In a separate data set, Study 2 reported reliability data on slight differences in the time period and the way the severity was assessed.

Study 2 findings indicated high levels of reliability for these changes in the time period and the way questions were asked. These studies provide important psychometric properties that could lead to more reliable and valid assessments of patients with post-viral illnesses.

2. Sleeping and Dietary Factors Associated with Chronic Fatigue Syndrome in Taiwanese Preschoolers

Huang S-F, Duan H-Y.

Children. 2023; 10(7):1149.


The purpose of this research was to investigate the sleeping and dietary factors associated with the prevalence of chronic fatigue syndrome among Taiwanese preschoolers.

Five-year-old preschoolers were randomly selected using a stratified multistage random cluster sampling method. The parents of the preschoolers completed a questionnaire containing items related to symptoms of fatigue and sleeping and dietary habits among the preschoolers. A total of 1536 valid questionnaires were returned.

After obtaining the data, the researchers analyzed them using descriptive statistics and a chi-square test. The following results were obtained:

(1) chronic fatigue syndrome was typically indicated by yawning during the day, feeling tired, and appearing sleepy;

(2) the preschoolers with high sleep quality, adequate sleeping time, and a regular sleep schedule exhibited a lower degree of fatigue;

(3) half of the preschoolers who ate three nutritionally balanced meals a day at a regular time exhibited a lower degree of fatigue.

Among the three dimensions studied, fatigue was most strongly associated with the “sleepy and inactive/blunted responses/lacking in energy” dimension, followed by the “difficulty concentrating” dimension, and, finally, the “localized pain” dimension.

In this study, the association between sleeping habits and symptoms of fatigue in preschool children was verified. The associations of dietary factors with symptoms of fatigue were not confirmed. It is suggested that parents establish a good sleep schedule for preschool children based on the study findings.

3. Eye Movement Desensitization and Reprocessing Therapy in Chronic Fatigue Syndrome: A Single-Case Experiment Testing the Effect on Persistent Negative Evaluation of Fatigue

Bouman, Sacha; Müller, Fabiola; Onghena, Patrick; Knoop, Hans.

Journal of EMDR Practice and Research, Jun 2023.


Background: While cognitive behavioral therapy (CBT) for chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) can lead to the normalization of fatigue levels and resumption of activities, a subgroup of patients still evaluates fatigue negatively.

Objective: The objective was to investigate whether eye movement desensitization and reprocessing (EMDR) therapy leads to a less negative evaluation of fatigue.

Method: This was a randomized single-case experimental study. Five CFS/ME patients (all female, mean age of 35 years), who had completed CBT but still evaluated fatigue negatively, received EMDR therapy. The primary outcome, that is, negative evaluation of fatigue, was assessed daily (three items, e.g., “My fatigue is frustrating”). During EMDR therapy sessions, distress in response to a selected image was measured. Clinical assessments were performed before, directly after, and 1 month after EMDR therapy.

Results: During EMDR therapy sessions, all patients reported high distress related to memories of having CFS/ME. EMDR therapy led to a reduction in this distress. Daily measured negative evaluations of fatigue declined in three patients, albeit not significantly. Three of five patients showed clinically relevant improvement in evaluations of fatigue on clinical pre-/post measures.

Conclusion: EMDR therapy can reduce emotional distress associated with fatigue, but it is unclear whether it can change its negative evaluation.

4. Dose-effect of long-snake-like moxibustion for chronic fatigue syndrome: a randomized controlled trial

Luo H, Gong R, Zheng R, Tan J, Chen R, Wu J, Ma T.

J Transl Med. 2023 Jul 3;21(1):430.


Background: The dose-effect relationship of Long-snake-like moxibustion for chronic fatigue syndrome (CFS) remains poorly understood. In order to address this gap, we designed this trial to assess the association between different treatment duration of Long-snake-like moxibustion and its effects on CFS based on the combination measurements of the subjective patient-reported scales with objective medical infrared imaging technology─Thermal Texture Maps (TTM).

Methods: From December 2020 to January 2022, 60 female CFS patients were recruited and equally allocated to two groups: Group A, receiving 60-min Long-snake-like moxibustion per treatment, and Group B, receiving 30-min Long-snake-like moxibustion per treatment. The treatment was administered 3 times per week for a total of 4 weeks.

The primary outcome was defined as the improvement of symptoms measured by the Fatigue scale-14 (FS-14), and secondary outcomes were designated as the improvement in Symptoms Scale of Spleen-Kidney Yang Deficiency, Self-rating depression scale, and Self-rating anxiety scale. TTM scanning was employed twice for CFS patients (before and after 4-week treatment) and once for Healthy control subjects (HCs).

Results: At week 4, the scores of FS-14 and Symptoms Scale of Spleen-Kidney Yang Deficiency in Group A were significantly lower than those in Group B (physical fatigue: 5.00 vs. 6.00, with 95%CI – 2.00 to 0.00, p = 0.003; FS-14 total score: 8.00 vs. 9.00, with 95%CI – 3.00 to 0.00, p = 0.012; total score of Symptoms Scale of Spleen-Kidney Yang Deficiency: 9.80 vs. 13.07, with 95%CI – 5.78 to – 0.76, P = 0.012). All thermal radiation values of the two groups increased, and statistical differences in ΔTs between Group A and HCs were not obtained.

More significant correlations between symptoms improvements and ΔT changes were observed in Group A, and its ΔT changes in Upper Jiao, Shenque (CV8), Zhongwan (CV12), Danzhong (CV17), Zhiyang (GV9), Dazhui (GV14), upper arm, thoracic segments, lumbar segments, renal region, popliteal fossa strongly correlated with the improvement of Spleen-Kidney Yang Deficiency symptoms.

Conclusions: In the same course of treatment, the positive dose-effect relationship was found between the treatment duration of Long-snake-like moxibustion and CFS effect assessment. 60-min Long-snake-like moxibustion per treatment were associated with optimal clinical response and TTM improvement.

5. The Role of Hypothalamic Phospholipid Liposomes in the Supportive Therapy of Some Manifestations of Long Covid: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Brain Fog

 Menichetti, F. 2023, 2023070005.


Long Covid is a heterogeneous clinical condition in which Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and brain fog stand out among the different clinical symptoms and syndromes. The cerebral metabolic alterations and neuroendocrine disorders seem to constitute an important part of Long Covid.

Given the substantial lack of drugs and effective therapeutic strategies, hypothalamic phospholipid liposomes which have been on the market for several years as adjuvant therapy of cerebral metabolic alterations resulting from neuroendocrine disorders, can be taken into consideration in an overall therapeutic strategy that aims to control the Long Covid associated symptoms and syndromes. Their pharmacological mechanisms and clinical effects strongly support their usefulness in Long Covid.

Our initial clinical experience corroborates this rationale. Further research is imperative in order to obtain robust clinical evidence.

6. Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID

Zheng Liu, Claudia Hollmann, Sharada Kalanidhi, Arnhild Grothey, Sam Keating, Irene Mena-Palomo,  Stephanie Lamer, Andreas Schlosser, Agnes Kaiping, Carsten Scheller, Franzeska Sotzny, Anna Horn, Carolin Nürnberger, Vladimir Cejka, Boshra Afshar, Thomas Bahmer, Stefan Schreiber, Jörg Janne Vehreschild, Olga Miljukov, Christian Schäfer, Luzie Kretzler, Thomas Keil, Jens-Peter Reese, Felizitas A Eichner, Lena Schmidbauer, Peter U Heuschmann, Stefan Störk, Caroline Morbach, Gabriela Riemekasten, Niklas Beyersdorf, Carmen Scheibenbogen, Robert K Naviaux, Marshall Williams, Maria E Ariza, Bhupesh K Prusty.

medRxiv [Preprint]


Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions.

Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID.

We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS.

Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients.

Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

7. Comprehensive profiling of the human intestinal DNA virome and prediction of disease-associated bacterial hosts in severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Shen-Yuan Hsieh, George M. Savva, Andrea Telatin, Sumeet K. Tiwari, Mohammad A. Tariq, Fiona Newberry, Katharine A. Seton, Catherine Booth, Amolak S. Bansal, Thomas Wileman, Evelien M. Adriaenssens, Simon R. Carding.

medRxiv [Preprint]


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disorder of unknown etiology with severely affected patients being house- and/or bedbound.

A historical association with chronic virus infection and subsequent recent reports correlating intestinal microbial dysbiosis with disease pathology prompted us to analyze the intestinal virome in a small cohort of severely-affected ME/CFS patients and same household healthy controls (SHHC).

Datasets from whole metagenomic sequencing (WMS) and sequencing of virus-like particles (VLP)-enriched metagenomes from the same fecal sample yielded diverse, high-quality vOTUs with high read coverage and high genome completeness.

The core intestinal virome was largely composed of tailed phages in the class Caudoviricetes with no significant differences in alpha diversity between ME/CFS and SHHC groups. However, the WMS dataset had a higher Shannon measure than the VLP dataset (p < 0.0001), with VLP- and WMS-derived sequences indicating differential abundances within several viral families and different viral compositions in beta diversity.

This confirms that combining different isolation methodologies identifies a greater diversity of viruses including extracellular phages and integrated prophages. DNA viromes and bacteriomes from ME/CFS and SHHC groups were comparable with no differences in any alpha or beta diversity measures.

One vOTU derived from the VLP-derived dataset was assigned to ssDNA human virus smacovirus 1. Using an in-silico approach to predict cohort-based bacterial hosts, we identified members of the Anaerotruncus genus interacting with unique viruses present in ME/CFS microbiomes; this may contribute to the GI microbial dysbiosis described in ME/CFS patients.

8. Coaching to Strengthen Critical Success Factors in Integrative Care for Chronic Fatigue Patients: The Patient Needs-Resources Model

Diana Araja, Angelika Krumina, Zaiga Nora-Krukle, Uldis Berkis and Modra Murovska.

Frontier in Neuroscience- Volume 17 – 2023.


Theoretical and empirical studies discover that an integrative approach is particularly important in chronic disorders and multiple long-term conditions, such as chronic fatigue.

Chronic fatigue syndrome (CFS) is a classic example of a potentially severe, multisystemic illness with a wide diversity of symptoms and the corresponding diagnostic complexity. The prevalence of CFS-like syndromes expanded in the context of the COVID-19 pandemic, increasing the disorder and treatment burden. Thus, this article aimed to draw attention to the possibilities to strengthen the integrative approach to diagnosing and treating chronic disorders and multiple long-term conditions.

The main critical success factors identified for integrative approaches were: a holistic approach, that provides a more comprehensive diagnostic and personalised treatment strategy, a multidisciplinary team, and patient engagement.

The strengths and weaknesses of these factors were explored and coaching was identified as a potential unifying and reinforcing element.

Coaching has a wide spectrum of manifestations clearly representing a holistic approach, that has been successfully used in multidisciplinary team building. Moreover, coaching exposes support addressing the patient engagement issues identified by the Patient Needs-Resources Model (PN-R Model) such as low levels of self-efficacy, optimism, and subjective well-being. Coaching may assist patients to identify and prioritize their goals, becoming aware of their personal resources, developing strategies for managing symptoms, and building skills to increase their self-efficacy and active engagement in the treatment process.

Therefore, the authors emphasize coaching as a perspective element of optimization of patient care, that requires additional theoretical and long-term empirical research.

9. MTHFR and LC, CFS, POTS, MCAS, SIBO, EDS: Methylating the Alphabet

Chambers P.

Qeios; 2023. [Preprint]


Long Covid (LC), Chronic Fatigue Syndrome (CFS), Postural Orthostatic Tachycardia Syndrome (POTS), Mast Cell Activation Syndrome (MCAS), Small Intestine Bacterial Overgrowth (SIBO), and Ehlers-Danlos Syndrome (EDS) are all loosely connected, some poorly defined, some with overlapping symptoms.

The female preponderance, the prominence of fatigue and chronic inflammation, and methylenetetrahydrofolate reductase (MTHFR) abnormalities may connect them all. Indeed differential methylation may lie at the root. Two – EDS and MTHFR – are genetic. But epigenetic factors may ultimately determine their phenotypic expression.

Oxidative stress, overloaded mitochondria, an antioxidant and nutrient shortfall, and suboptimal gut microbiome appear to be the primary determinants. A deep dive into the folate and methionine cycles is undertaken in an attempt to connect these syndromes.

The active forms of vitamin D and vitamins B2,3,6,9,12 are shown to be biochemically integral to optimal methylation and control of the epigenome. Their status largely determines the symptoms of abnormal MTHFR in all its phenotypes. The wider implications for aging, cancer, cardiovascular disease, neurodegenerative disease, and autoimmune disease are briefly explored.

Long-COVID Research References

  1. Physiological underpinnings of long COVID: what have we learned?
  2. The potential role of Rhodiola rosea L. extract WS® 1375 for patients with post-COVID-19 fatigue
  3. Clinical and Biomarker Profile Responses to Rehabilitation Treatment in Patients with Long COVID Characterized by Chronic Fatigue
  4. Polysomnographic parameters in long-COVID chronic insomnia patients
  5. Trajectory of Post-COVID Self-Reported Fatigue and Dyspnoea in Individuals Who Had Been Hospitalized by COVID-19: The LONG-COVID-EXP Multicenter Study
  6. Precision Medicine for More Oxygen (P4O2)—Study Design and First Results of the Long COVID-19 Extension
  7. Advancing the Management of Long COVID by Integrating into Health Informatics Domain: Current and Future Perspectives
  8. A Pilot Study of Short-Course Oral Vitamin A and Aerosolised Diffuser Olfactory Training for the Treatment of Smell Loss in Long COVID
  9. Long COVID in Young Patients: Impact on Lung Volume Evaluated Using Multidetector CT
  10. Long COVID: Complications, Underlying Mechanisms, and Treatment Strategies
  11. Youth Mental Health Outcomes up to Two Years After SARS-CoV-2 Infection Long-COVID or Long-Pandemic Syndrome: A Retrospective Cohort Study
  12. Thromboembolism in the Complications of Long COVID-19
  13. Immunological dysfunction and mast cell activation syndrome in long COVID
  14. Unlocking the Mysteries of Long COVID in Children and Young People: Insights from a Policy Review and Social Media Analysis in the UK
  15. Internal tremors and vibrations in long COVID: a cross-sectional study
  16. Long COVID and its cardiovascular consequences: What is known?
  17. A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms
  18. The Use of Bedside Echocardiography to Diagnose Post-COVID Cardiomyopathy and Left Ventricular Thrombus in the Emergency Department
  19. Detrimental effects of COVID-19 in the brain and therapeutic options for long COVID: The role of Epstein–Barr virus and the gut–brain axis
  20. The opportunity for massage therapy development for relieving long COVID symptoms: a literature review

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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