Research Roundup

ME/CFS and Long Covid Research: 26 September – 02 October 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 eight new ME/CFS studies and twenty-four new Long Covid studies this week.

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

Paper one (1) is a preprint [meaning that it has not been peer-reviewed and the science verified] on immune cell proteomes in Long Covid and ME/CFS. This study uses proteomics which is a large-scale study of proteins, looking at their interactions, function, composition, structure and cellular activities. These types of studies provide a large data output and a wealth of information.

This study included 9 people with ME/CFS, 6 with Long Covid and 5 healthy controls. The ME/CFS dataset used had previously been collected and the proteins had been analysed using the same methodology (previous study using this data can be found here: Sweetman et al., 2020). This study aimed to investigate how closely related Long Covid and ME/CFS are.

The study found that immune cell proteomes in Long Covid and ME/CFS have similar functional changes. Other findings include:

  • The immune system activity on Long Covid patients (one year after illness) is dramatically different from healthy controls.
  • Statistical techniques (in this case the use of principle component analysis (PCA)) allowed all Long Covid patients to be separated from healthy controls.
  • The study looked into 3131 proteins, 162 were differentially regulated (79 down-regulated and 83 up-regulated) in which 37 were related to immune functions and 21 to mitochondrial functions in Long Covid patients.
  • The previously collected ME/CFS dataset, showed 346 differentially regulated proteins compared to controls.
  • Long Covid and ME/CFS patients were found to have overlapping proteins, with enriched molecular pathways which related to immune functions and mitochondrial functions which suggest that immune pathophysiology and energy production is involved in both conditions.

This study provides some exciting data, but is extremely limited by the sample size, which makes some of the conclusions drawn questionable. A few things to note about this study:

  • There is a lack of information on the healthy control cohort, such as we don’t know if they had a previous Covid-19 infection or not.
  • The ME/CFS cohort had an average illness duration of 16 years, whereas for Long Covid patients this was 1 year. This means that the two conditions will likely be at different stages, and any differences found in this study maybe a reflection of this. However, this also gives the opportunity of following the disease course over time in Long Covid patients.
  • The disease cohorts are also not age and gender matched, with an average age of 39 in the Long Covid cohort and 49 for the ME/CFS cohort.
  • Some details in this study are lacking, as they are covered in the previous research, such as the diagnostic technique for the ME/CFS cohort.
  • Using previous cohorts is often found to limit studies where data collection is not robust, meaning differing methods could influence results. However, this was carried out by the same group, (although members differed).

We often find that multi-omic studies (in this case proteomics, but we often see metabolomic studies) are cable of providing us a wealth of information about the mechanisms behind illnesses, producing meaningful and statistical results. More large-scale studies like this one are needed as it is likely that they would be able to tell us much more about ME/CFS and Long Covid.

ME/CFS Research References

1. Immune cell proteomes of Long COVID patients have functional changes similar to those in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Katie Peppercorn, Christina D. Edgar, Torsten Kleffmann, Warren. P Tate.

ResearchSquare [preprint]


Of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ~ 10% develop the chronic post-viral debilitating condition, Long COVID (LC). Although LC is a heterogeneous condition, about half of cases have a typical post-viral fatigue condition with onset and symptoms that are very similar to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

A key question is whether these conditions are closely related. ME/CFS is a post-stressor fatigue condition that arises from multiple triggers.

To investigate the pathophysiology of LC, a pilot study of patients and healthy controls has used quantitative proteomics to discover changes in peripheral blood mononuclear cell (PBMC) proteins. A principal component analysis separated all Long COVID patients from healthy controls.

Analysis of 3131 proteins identified 162 proteins differentially regulated, of which 37 were related to immune functions, and 21 to mitochondrial functions.

Markov cluster analysis identified clusters involved in immune system processes, and two aspects of gene expression-spliceosome and transcription.

These results were compared with an earlier dataset of 346 differentially regulated proteins in PBMC’s from ME/CFS patients analysed by the same methodology.

There were overlapping protein clusters and enriched molecular pathways particularly in immune functions, suggesting the two conditions have similar immune pathophysiology as a prominent feature, and mitochondrial functions involved in energy production were affected in both conditions.

2. Investigating the Effect of COVID-19 Infection on Professional Athletes’ Post-infection With a Focus on Fatigue and Chronic Fatigue Syndrome

Reza Sarwary, Minna Tareen, Mevhibe Hocaoglu.



Introduction and objectives: COVID-19 has been reported to cause long-term sequela including persistent fatigue and Chronic Fatigue Syndrome (CFS) in the general population. However, it remains to be seen if similar effects are observed in an athlete population. The aetiology and pathophysiology are poorly understood but is thought to be multi-factorial. Patient reported outcome measures are commonly used to improve patient-centred outcomes (PROMs). They are essential to assess patient quality of life post-COVID infection. This paper aims to assess the effect of COVID-19 on athletes’ long-term fatigue and CFS and identify the PROMs used to characterise this.

Methodology: Articles were selected for extraction based on the eligibility criteria and PRISMA guidelines. The inclusion criteria required papers to assess competitive athletes over eighteen years of age who were clinically diagnosed with COVID-19. Articles were extracted to assess different variables including type of sport, type of athlete and ethnicity. Key terms were obtained using MeSH trees and utilised with Web of Science and NCBI Pubmed. Papers were graded by quality using the Hawker quality assessment tool.

Results and discussion: Forty articles (N=40) were identified for full-text screening (N=8). Eight were selected for extraction based on the eligibility criteria. Data was obtained on athlete characteristics, sport characteristics, properties of PROM measurement techniques and fatigue presentation. Male athletes were found to be 10-50% more likely than female athletes to suffer from persistent fatigue symptoms (N=2). Persistent fatigue was present in 9-10% Athletes from mixed backgrounds and genders (N=2). Initial fatigue was documented to be between 47-56% (N=2). A heterogenous range of PROMs were utilised to assess symptoms including fatigue and excluded emotional or mental fatigue.

Conclusion: COVID-19 is associated with signs of persisting fatigue and potentially CFS in athlete populations. More work needs to be done to develop standardised and validated PROMs specific to CFS.

3. Is there a role for traditional and complementary medicines in managing chronic fatigue? A systematic review of randomized controlled trials

Yuxiao Li, Jingya Yang, Chi Ian Chau, Junnan Shi, Xianwen Chen, Hao Hu, Carolina Oi Lam Ung.

Frontiers in Pharmacology, Volume 14, 2023.


Introduction: Chronic fatigue syndrome (CFS) is an increasingly common condition that is challenging to treat due to unclear etiology and a lack of consensus on clinical diagnosis and treatment guidance. Many affected people resorted to using traditional and complementary medicines (T&CMs). However, the evidence for T&CMs for CF has been inconclusive and continues to evolve. The study aims to identify, summarize and assess the most recent evidence on the efficacy and safety of T&CMs for CFS.

Methods: Randomized controlled trials (RCTs) investigating T&CMs for CFS published in English of Chinese between 1 January 2013 and 31 December 2022 were searched from 7 databases. RCTs comparing T&CMs with no treatment, placebo, or pharmacological medicine were included, irrespective of language or blinding.

The Consolidated Standards of Reporting Trials Statement extensions for Chinese herbal medicine Formulas (CONSORT-CHM) and the Cochrane Collaboration’s Risk of Bias tool were used to evaluate the quality and risk of bias of included studies.

Results: A total of 62 RCTs investigating 43 types of T&CMs and involving 5,231 participants with CFS were included in this review. The primary outcome measures mainly included the scoring of fatigue symptoms using the validated tool Fatigue Scale-14 (FS-14) or the TCM syndrome score.

The main interventions showing overall efficacy were Chaihu Guizhi Decoction and Buzhong Yiqi combined with Xiao Chaihu Decoction, and 148 ingredients were identified, including Astragali Radix, Glycyrrhizae Radix et Rhizoma, Atractylodis Macrocephalae Rhizoma, and Bupleuri Radix.

The most significant effect was the improvement of fatigue, followed by TCM-diagnosed symptoms and other psychological conditions. No serious adverse effect had been reported. However, the quality of the RCTs included RCTs were found to be suboptimal, and the risk of bias remained uncertain.

Conclusions: Some evidence from RCTs supported the efficacy and safety of T&CM in CFS. However, given the methodological and quality heterogenicity of the included studies, the recommendations of T&CMs in treating CFS remain inconclusive. To develop better quality evidence about T&CMs for CFS, future studies should employ more objective diagnosis standards and outcome measurements, larger sample size, and better bias control, and ensure the compliance with the corresponding reporting guidelines.

4. Assessing Functional Capacity in ME/CFS: A Patient Informed Questionnaire

 Sommerfelt, K.; Schei, T.; Seton, K.A.; Carding, S.R.

Preprints 2023, 2023092091


Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is an acquired disease with significant morbidity that affects both children and adults. Effective tools to assess functional capacity (FC) are severely lacking which has significant consequences for timely diagnosis, assessments for patient disability benefits and assessing the impact and effectiveness of interventions.

In interventional research the inability to assess FC can result in an incomplete assessment of the potential effect of the intervention. Specifically of concern is that if an intervention is effective in reducing symptom load, patients may increase their activity level to reach a pre-intervention symptom load. Thus, if FC is not accurately assessed, beneficial treatment outcomes may be missed.

To address this issue, using extensive, repeated patient feedback we have developed a new questionnaire, FUNCAP, to achieve optimal FC assessment in ME/CFS patients.

The questionnaire covers eight domains and activity types: A. Personal hygiene / basic functions, B. Walking / movement, C. Being upright, D. Activities in the home, E. Communication, F. Activities outside the home, G. Reactions to light and sound, and H. Concentration.

Through five rounds of anonymous web-based surveys and a further test – retest validation round, two versions of the questionnaire were developed; a longer version comprising 55 questions (FUNCAP55) to improve diagnostic and disability benefit/ insurance FC assessments and a shorter version (FUNCAP27) for interventional research and less extensive FC assessments. FUNCAP may also be useful in other conditions where fatigue and PEM is present, such as Long Covid.

5. Re-visiting professional ethics in psychotherapy: Reflections on the use of talking therapies as a supportive adjunct for myalgic encephalomyelitis / chronic fatigue syndrome and ‘medically unexplained symptoms’

Joanne Hunt, Charlotte Blease.

OSF preprints


Following years of debate over the effectiveness of cognitive behavioural therapy for myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), public health bodies in the UK and beyond have determined that no psychotherapy is clinically proven for this patient group.

In the field of ME/CFS and the wider arena of ‘medically unexplained symptoms’ (MUS), patient survey data and qualitative research capturing patient experiences and psychotherapist attitudes suggest that therapeutic practice may sometimes fall short of required ethical standards. This raises questions about how psychotherapists can safely support, as opposed to treat, people with these debilitating conditions.

We consider four ethical principles that feature throughout psychotherapists’ codes of practice, those of respect, competence, responsibility, and integrity, and discuss examples of good and poor practice in this arena as evinced by recent empirical literature.

Following this, we offer a variety of suggestions to help strengthen ethical psychotherapy practice among patients with ME/CFS and other MUS. In terms of practitioner education, we recommend greater emphasis on humility and reflexive practice, exploration of personal as well professional ethics, and integration of patient expertise-by-experience, accompanied with latest evidence, into foundational and on-going training.

In terms of practice, we suggest consideration of formalized patient-focused feedback systems and greater transparency visà-vis patient access to clinical notes. Finally, we underline the importance of elevating patients from mere subjects to co-producers of psychotherapy research.

6. Chronic fatigue syndrome – challenge in diagnosis and management: a literature review

Nieciecka A, Tomys-Składowska J, Lamch M, Jabłońska M, Błasik N, Janiszewska M, Wójcik-Kula A.

Journal of Medical Science JMS [Online ahead of print]

Introduction. Chronic fatigue syndrome is a disease that includes a number of various symptoms, among which the most characteristic symptom is fatigue. Diagnostic criteria are not unambiguous and vary depending on the scientific society by which they were developed. The aim of this review is to discuss the phenomenon of chronic fatigue, including its diagnostic criteria, epidemiology, pathophysiology, symptoms, and pharmacological and non-pharmacological strategies.

Material and methods. 45 articles published were reviewed and placed in the PubMed and Google Scholar databases.

Results. Chronic fatigue syndrome is defined as a group of symptoms whose dominant symptom is fatigue that persists after rest for at least 6 months. The Oxford or CDC criteria are most commonly used to make the diagnosis. Statistics on prevalence are inconclusive. There are several theories of origin – infectious, immunological, neuroendocrine, bioenergetic, neurological, autonomic and genetic.

Other symptoms of chronic fatigue syndrome include sleep and memory disorders or muscle and joint pain. Current treatment focuses on symptomatic treatment, including education, diet, and physical activity, as well as pharmacotherapy for pain, sleep, and cognition.

Discussion. Diagnosis and treatment of chronic fatigue syndrome undoubtedly is a medical challenge, due to non-specific symptoms, multifactorial pathogenesis and difficult to estimate prevalence of this disease. Future scientific development should focus especially on exploring the pathomechanism of CFS, which would enable the implementation of causal treatment.

7. Aetiological Understanding of Fibromyalgia, Irritable Bowel Syndrome, Chronic Fatigue Syndrome and Classificatory Analogues: A Systematic Umbrella Review

Maria Kleinstäuber, Andreas Schröder, Sarah Daehler, Karen Johanne Pallesen, Charlotte U. Rask, Mathias Sanyer, Omer Van den Bergh, Marie Weinreich Petersen, Judith G. M. Rosmalen.

Clinical Psychology in Europe, 2023, Vol. 5(3), Article e11179.

Background: This umbrella review systematically assesses the variety and relative dominance of current aetiological views within the scientific literature for the three most investigated symptom defined functional somatic syndromes (FSS) and their classificatory analogues within psychiatry and psychology.

Method: An umbrella review of narrative and systematic reviews with and without meta-analyses based on a search of electronic databases (PubMed, Web of Science, Embase, PsychINFO) was conducted. Eligible reviews were published in English, focused on research of any kind of aetiological factors in adults diagnosed with fibromyalgia syndrome (FMS), irritable bowel syndrome (IBS), chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and somatic symptom disorder (SSD)/somatoform disorder (SFD).

Results: We included 452 reviews (132 systematic reviews including meta-analyses, 133 systematic reviews, 197 narrative reviews), of which 132 (29%) focused on two or more of the investigated health conditions simultaneously. Across diagnoses, biological factors were addressed in 90% (k = 405), psychological in 33% (k = 150), social in 12% (k = 54), and healthcare factors in 5% (k = 23) of the reviews.

The methodological quality of the included systematic reviews (k = 255) was low (low/ critically low: 41% [k = 104]; moderate: 49% [k = 126]; high quality: 10% [k = 25]). The high-quality systematic reviews suggest that deficient conditioned pain modulation, genetic factors, changes in the immune, endocrinological, gastrointestinal, cardiovascular, and nervous system, and psychosocial factors such as sexual abuse and pain catastrophizing increase the risk for FSS.

Conclusion: Only very few systematic reviews have used comprehensive, biopsychosocial disease models to guide the selection of aetiological factors in FSS research. Future research should strive for higher scientific standards and broaden its perspective on these health conditions.

8. Diagnosis and Management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Stephanie L. Grach, Jaime Seltzer, Tony Y. Chon, Ravindra Ganesh.

Mayo Clinic Proceedings, Volume 98, Issue 10, 2023, Pages 1544-1551.


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic neurologic disease often preceded by infection.

There has been increased interest in ME/CFS recently because of its significant overlap with the post-COVID syndrome (long COVID or post-acute sequelae of COVID), with several studies estimating that half of patients with post-COVID syndrome fulfill ME/CFS criteria.

Our concise review describes a generalist approach to ME/CFS, including diagnosis, evaluation, and management strategies.

Long-COVID Research References

  1. Cognitive dysfunction in post-COVID-19 condition: Mechanisms, management, and rehabilitation
  2. Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents
  3. Hyperbaric Oxygen Therapy Counters Oxidative Stress/Inflammation-Driven Symptoms in Long COVID-19 Patients: Preliminary Outcomes
  4. A brief overview of SARS-CoV-2 infection and its management strategies: a recent update
  5. Relationship between the structure, function and endothelial damage, and vascular ageing and the biopsychological situation in adults diagnosed with persistent COVID (BioICOPER study). A research protocol of a cross-sectional study
  6. Post-COVID-19 cholangiopathy: Systematic review
  7. Potential long-term neurological and gastrointestinal effects of COVID-19: A review of adult cohorts
  8. The Long Road of Long COVID: Specific Considerations for the Allergist and Immunologist
  9. Severe, Persistent, Disruptive Fatigue Post-SARSCoV-2 Disproportionately Affects Young Women
  10. Experiences of people with long COVID: Symptoms, support strategies and the Long COVID Optimal Health Programme (LC‐OHP)
  11. Pathophysiological mechanisms in Long Covid: A mixed method systematic review
  12. A Multidisciplinary Rehabilitation Approach to Chronic Pain Patients in the Post-COVID-19 Era
  13. Clinical Features and Follow-up of Referred Children and Young People With Long COVID
  14. Effect of monovalent COVID-19 vaccines on viral interference between SARS-CoV-2 and several DNA viruses in patients with long-COVID syndrome
  15. 15-month post-COVID syndrome in outpatients: Attributes, risk factors, outcomes, and vaccination status – longitudinal, observational, case-control study
  16. Integrating patient-reported physical, mental, and social impacts to classify long COVID experiences
  17. A Systematic Review of the Physical and Cardiorespiratory Impairments in People Who Experience Long COVID
  18. Functional performance recovery after individualized nutrition therapy combined with a patient-tailored physical rehabilitation program versus standard physiotherapy in patients with long COVID: a pilot study
  19. An Update of Cardiopulmonary Rehabilitative Measures in LongCOVID-19 Patients: A Systematic Review
  20. A thesis of clinical research and practice: Psychological Associations with Long Covid, Long Covid: Finding Resolution in a Dichotomised World and Summary of clinical practice and assessments
  21. The chronifcation of post‑COVID condition associated with neurocognitive symptoms, functional impairment and increased healthcare utilization
  22. Sleeping monsters: chronic infections in COVID-19 pathogenesis
  23. Cognitive-linguistic difficulties in adults with Long COVID: A follow-up study
  24. Is Pulmonary Involvement a Distinct Phenotype of Post-COVID-19?

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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