ME Association regular research roundup

ME/CFS and Long Covid Research: 16 – 22 May 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

We have had a mixed bag of research this week. There have been seven new ME/CFS studies and twenty-three new Long Covid studies this week.

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

Paper two (2) is on uplifts and hassles relating to worsening of CFS. An uplift is a minor pleasant event, i.e. something that you enjoy doing and can make you feel good. Whereas, hassles are irritants, things that bother or annoy you. You can read a good summary of the hassles and uplifts scale here.

The study recruited 128 participants, and used an interview-based global impression of change rating to determine outcomes as improved, unchanged, or worsened at six- month follow-up. The combined Hassles and Uplifts scale (CHUS) was used weekly in online diaries over six months.

The study found:

  • No significant differences were found between the three global outcome groups (improved, unchanged, or worsened) when separated by age, sex or illness duration.
  • Working status was lower in the non-improved group.
  • Non-social hassles intensity showed an increasing trend for the worsened group.
  • Non-social hassles intensity showed a decreasing trend for the improved group.
  • For the worsened group, a downward trend was found for frequency of non-social uplifts.
  • Individuals with worsening as compared to improving illness showed significantly different six-month trajectories for weekly hassles and a deficit in uplifts.

There are quite a few concerns from this piece of work, for example:

  • The Fukuda criteria was used for diagnosis, which is heavily criticised in its use to diagnose ME/CFS, especially when used in research. For example, problems with the Fukuda criteria include: post-exertional malaise (PEM) is not compulsory which leads to misdiagnosis, and it is not easy to use on a clinical level (a review on the contrasting case definitions has been written by Brown et al., 2013). 
  • Throughout the research, there is no mention of ME (myalgic encephalomyelitis) and only chronic fatigue syndrome or CFS is used.
  • Behaviour intervention is suggested to improve the outcomes of those with ME/CFS, and the need for a clinician to identify the patient’s low-effort pleasurable activities. With further suggestions that Behavioural Activation and Acceptance and Commitment Therapy is also needed, so that patients can identify their own values and activities they enjoy.
  • Behavioural improvement and scheduling more frequent non-social uplifts is suggested as an alternative to graded exercise therapy (GET).
  • There is suggestion in this study that positive daily activities will decrease inflammation in CFS, the research says: “this may have relevance to CFS pathophysiology given that a large biobehavioural study in healthy adults suggested that the absence of positivity in daily life may be particularly consequential for inflammation”.
  • Activities which are suggested, include: listening to an inspirational speaker, going to a concert, watching ducks on a pond, or sharing a special moment with a spouse or friend.
  • There is no control group, so we do not know how the general population would respond over time to uplifts and hassles. This is also not a randomised study.
  • This is also the second study on the same theme (see previous study here).
  • It is also concerning that the first author of this research is Fred Friedberg who is a Professor in Applied Behavioural Medicine and is the President of the International Association for CFS/ME (IACFS), who also have their own scientific journal and organise yearly conferences. 

This is clearly not a strong piece of research, and there is definitely a need for the researcher to further understand ME/CFS and the fact that it cannot be cured by doing “nice” activities.

On a more positive note, you may also be interested in reading this week Paper three (3) which is a review on biomarkers for ME/CFS, Dr Charles Shepherd has written a comment on this research. Furthermore, Paper two (2) in the Long Covid Reference section also looks into biomarkers.

ME/CFS Research References and Abstracts 

1. Investigating the factors associated with meaningful improvement on the SF-36-PFS and exploring the appropriateness of this measure for young people with ME/CFS accessing an NHS specialist service: a prospective cohort study

Daisy M Gaunt*, Amberly L C Brigden, Chris Metcalfe, Maria Loades, Esther M Crawley.

BMJ Open [Accepted/ In Press].


Objectives: Paediatric myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is relatively common and disabling, but little is known about the factors associated with outcome. We aimed to describe the number and characteristics of young people reaching the 10-point minimal clinically important difference (MCID) of SF-36-Physical Function Subscale (SF-36-PFS), and to investigate factors associated with reaching the MCID.

Design: Prospective observational cohort.

Setting: A specialist UK National Health Service (NHS) ME/CFS service, Southwest England. Recruitment between March 2014 and August 2015.

Participants: 193 eligible patients with ME/CFS aged 8 to 17 years reported baseline data. 124 (65%) and 121 (63%) with outcome data at six- and 12-months, respectively.

Outcome measures: SF-36-PFS (primary outcome). Chalder Fatigue Questionnaire, school attendance, visual analogue pain scale, Hospital Anxiety and Depression Scale, Spence Young people Anxiety Scale, Clinical Global Impression scale, and EQ-5D-Y (secondary).

Results: At six-months 48/120 (40%) had reached the MCID for SF-36-PFS. This had increased to 63/117 (54%) at 12-months. On the CGI, 77% and 79% reported feeling either a little better, much better, or very much better. Those with worse SF-36-PFS at baseline assessment were more likely to achieve the MCID for SF-36-PFS at six-months (OR 0.97, 95% CI 0.96 to 0.99, p-value 0.003), but there was no evidence of effect at 12-months (OR 0.98, 95% CI 0.97 to 1.00, p-value 0.038). No other factors at baseline were associated with the odds of reaching the MCID at six-months. However, at 12-months there was strong evidence of an effect of pain on MCID (OR 0.97, 95% CI 0.95 to 0.99, p-value 0.001), and SF-36-PFS on MCID (OR 0.96, 95% CI 0.94 to 0.98, p-value 0.001).

Conclusions: 40% and 54% of young people reached the MCID at 6 and 12 months respectively. No factors at assessment (other than SF-36-PFS at six-months, and pain and SF-36-PFS at 12-months) are associated with MCID of SF-36-PFS at either six-, or 12- months. Further work is needed to explore the most appropriate outcome measure for capturing clinical meaningful improvement for young people with ME/CFS.

2. Uplifts and hassles are related to worsening in chronic fatigue syndrome A prospective study

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

Research Square [Preprint]. 2023 May 


Background: Limited published data suggests that absence of uplifts (minor pleasant events) is associated with clinical worsening in patients with chronic fatigue syndrome (CFS).

The current study aimed to assess the relation of illness worsening to the trajectories of social and non-social uplifts and hassles in a six-month prospective study in CFS. 

Methods: Participants were primarily in their 40s, female, white, and ill for over a decade. All participants (N=128) met criteria for CFS. The interview-based global impression of change rating was used to classify individual outcomes as improved, unchanged, or worsened at six- month follow-up. Uplifts and hassles, both social and non-social, were assessed with the Combined Hassles and Uplifts Scale (CHUS). The CHUS was administered weekly in online diaries over six months. Linear mixed effect models were utilized to examine linear trends for hassles and uplifts. 

Results: No significant differences were found between the three global outcome groups for age, sex, or illness duration; however, work status was significantly lower for the non-improved groups ( p <.001). Non-social hassles intensity showed an increasing slope for the worsened group ( p =.03) and a decreasing slope ( p =0.05) for the improved group. For the worsened group, a downward trend was found for frequency of non-social ( p =0.01) uplifts. 

Conclusion: Individuals with worsening as compared to improving illness in CFS show significantly different six-month trajectories for weekly hassles and a deficit in uplifts. This may have clinical implications for behavioral intervention.

3. Biomarkers for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review

Maksoud, R., Magawa, C., Eaton-Fitch, N. et al. 

BMC Med 21, 189 (2023).


Background:Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted condition that affects most body systems. There is currently no known diagnostic biomarker; instead, diagnosis is dependent on application of symptom-based case criteria following exclusion of any other potential medical conditions. While there are some studies that report potential biomarkers for ME/CFS, their efficacy has not been validated.

The aim of this systematic review is to collate and appraise literature pertaining to a potential biomarker(s) which may effectively differentiate ME/CFS patients from healthy controls.

Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane review guidelines. PubMed, Embase and Scopus were systematically searched for articles containing “biomarker” and “ME/CFS” keywords in the abstract or title and if they included the following criteria: (1) were observational studies published between December 1994 and April 2022; (2) involved adult human participants; (3) full text is available in English (4) original research; (5) diagnosis of ME/CFS patients made according to the Fukuda criteria (1994), Canadian Consensus Criteria (2003), International Consensus Criteria (2011) or Institute of Medicine Criteria (2015); (6) study investigated potential biomarkers of ME/CFS compared to healthy controls. Quality and Bias were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies.

Results: A total of 101 publications were included in this systematic review. Potential biomarkers ranged from genetic/epigenetic (19.8%), immunological (29.7%), metabolomics/mitochondrial/microbiome (14.85%), endovascular/circulatory (17.82%), neurological (7.92%), ion channel (8.91%) and physical dysfunction biomarkers (8.91%). Most of the potential biomarkers reported were blood-based (79.2%). Use of lymphocytes as a model to investigate ME/CFS pathology was prominent among immune-based biomarkers. Most biomarkers had secondary (43.56%) or tertiary (54.47%) selectivity, which is the ability for the biomarker to identify a disease-causing agent, and a moderate (59.40%) to complex (39.60%) ease-of-detection, including the requirement of specialised equipment.

Conclusions: All potential ME/CFS biomarkers differed in efficiency, quality, and translatability as a diagnostic marker. Reproducibility of findings between the included publications were limited, however, several studies validated the involvement of immune dysfunction in the pathology of ME/CFS and the use of lymphocytes as a model to investigate the pathomechanism of illness. The heterogeneity shown across many of the included studies highlights the need for multidisciplinary research and uniform protocols in ME/CFS biomarker research.

4. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

Wirth KJ, Löhn M.

Medicina. 2023; 59(5):978.


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood.

We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence.

Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.

5. Influence of Chronic Fatigue Syndrome Codiagnosis on the Relationship between Perceived and Objective Psychoneuro-Immunoendocrine Disorders in Women with Fibromyalgia

Otero E, Gálvez I, Ortega E, Hinchado MD. 

Biomedicines. 2023; 11(5):1488.


Although the predominant symptom in fibromyalgia (FM) is muscle pain, and fatigue in chronic fatigue syndrome (CFS), differential diagnosis is very difficult. This research investigates the psychoneuroimmunoendocrine disorders of FM patients and ascertains whether a previous CFS diagnosis affected them.

Through accelerometry objective parameters, physical activity/sedentarism levels in relation to fatigue are studied, as well as whether perceived levels of stress, anxiety, and pain correspond to objective biomarkers, all of these with respect to a reference group (RG) of women without FM.

FM patients have a worse psychological state and perceived quality of life than those with RG. These perceived outcomes are consistent with impaired objective levels of a sedentary lifestyle, higher systemic levels of cortisol and noradrenaline, and lower levels of serotonin.

However, FM patients with a previous CFS diagnosis had lower systemic levels of IL-8, cortisol, oxytocin, and higher levels of adrenaline and serotonin than FM patients without diagnosed CFS.

In conclusion, while perceived health parameters do not detect differences, when objective neuroimmunoendocrine parameters related to stress, inflammation, pain, and fatigue are used, people with CFS could be overdiagnosed with FM. This reinforces the need for objective biomarker assessment of these patients for better diagnostic discrimination between both syndromes.

6. Relationships Between Chronic Fatigue Syndrome, Experiential Avoidance, and Health-Related Quality of Life in Cervical Cancer Cases Mediated by Depression

Sakkaki S, Naderi F, Hafezi F.

Women. Health. Bull. 2023;10(2):2-9.


Background: The diagnosis of cervical cancer significantly affects the health-related quality of life (HRQOL) of women. This study aimed to investigate the relationships between chronic fatigue syndrome (CFS) and experiential avoidance (EA) with HRQOL, mediated by depression in women with cervical cancer.

Methods: This descriptive-correlational study selected 261 cervical cancer cases in Mashhad, Iran in 2021, using purposive sampling from October 10, 2021 to December 24, 2021. The research tools include the SF-36 Questionnaire, the Chalder Fatigue Scale, the Brief Experiential Avoidance Questionnaire, and Beck Depression Inventory. Data analysis was done using Pearson correlation coefficient and structural equation modeling in SPSS version 27 and AMOS version 24.

Results: The results indicated that all direct paths, with the exception of CFS, significantly correlated with HRQOL (P<0.001). Depression mediated the significant indirect paths of CFS to HRQOL and the significant relationship between EA and HRQOL (P<0.001).

Conclusions: The findings of this study revealed that CFS and EA were negatively related to HRQOL in women with cervical cancer. Moreover, depression mediated the relationship of CFS and EA with HRQOL.

7. Exploring overcontrolled personality traits in individuals with fibromyalgia and chronic fatigue syndrome

Eleanor Horton

PhD Thesis [Royal Holloway, University of London]

Abstract (Lay Summary)

Fibromyalgia (FM) is a long-term health condition affecting around 2% of the UK population. Symptoms of FM include widespread muscular pain, tiredness, fatigue, increased pain sensitivity, sleep problems, poor memory, and headaches. Research has also shown that individuals with FM may also be likely to experience mental health difficulties such as anxiety, depression, and personality disorders. As a result, psychological interventions or therapies have been recommended as a treatment option for individuals with FM.

One psychological therapy that has been shown to have a positive impact on pain and other FM symptoms is cognitive behavioural therapy (CBT). However, some individuals with FM do not appear to benefit from CBT and other individuals may find that their symptoms only improve in the short-term.

There is an increasing emphasis in the healthcare system to provide better support for individuals with long-term health conditions, particularly those who also experience mental health conditions. This has led to more research exploring how other psychological interventions may be effective in managing FM, therefore it is important to have an updated review of the literature.

This updated systematic review of the literature aimed to understand how effective a range of psychological interventions are for psychological outcomes such as anxiety, depression, and sleep quality in individuals with FM. The current review aimed to provide an update on previous reviews about psychological interventions for FM by including studies published from 2017 onwards.

Three electronic databases were searched for FM-based studies that used a randomised controlled (RCT) design to compare at least one psychological intervention to at least one comparative intervention, for example a waitlist control group. The studies included in the review had to include at least one psychological outcome such as a measure of depression or anxiety. Ten studies were included.

It was found that:

  • A range of psychological interventions were used; CBTs, personal construct therapy (PCT), internet-delivered exposure therapy (iExp), attachment-based compassion therapy (ABCT), mindfulness-based stress reduction (MBSR) and multicomponent interventions that include more than one approach combined.
  • All interventions showed improvements in at least one psychological outcome.
  • The number of different psychological outcomes and interventions that were measured across the studies made it challenging to make meaningful comparisons across the studies.
  • Overall, the findings were promising but further research is needed to understand if these improvements remain longer-term.

The empirical study hoped to build upon the systematic review as research has also found FM is linked to higher rates of personality characteristics such as perfectionism and alexithymia (a term used to describe a lack of emotional expression). These characteristics are part of an overcontrolled coping style, whereby a person’s biological temperament combined with environmental, cultural, or familial experiences, predisposes them to coping with challenges through rigid patterns of avoiding uncertainty or novelty, perfectionism, distancing from others and not expressing emotions (alexithymia).

Research suggests overcontrolled traits and coping are more prevalent in certain conditions that may be resistant to treatment, such as personality disorders which as stated, can co-occur frequently in FM. These overcontrolled traits are also found in chronic fatigue syndrome (CFS), another long-term health condition characterised by disabling fatigue and other symptoms that overlap with FM, such as sleep problems, muscle ache, depression, and personality disorders. As there are high rates of overlap and comorbidity between FM and CFS, both conditions were explored in the study.

The study aimed to explore whether overcontrolled traits and coping is higher in individuals with FM and CFS compared to individuals without these conditions. It was hoped that this may improve our understanding about personality and temperament and support the potential use of more personality-tailored treatment interventions for these client groups to improve the efficacy of current interventions.

The study used an online survey design with 129 individuals taking part. 40 reported diagnoses of FM and/or CFS, forming the clinical group. 89 individuals without these conditions formed the non-clinical control group. Participants were recruited online through advertising on social media and through Fibromyalgia Action UK. Participants completed a number or questionnaires about their health, broad overcontrol traits plus overcontrolled traits such as alexithymia, experiential avoidance, personal need for structure, sense of social safeness, and loneliness.

It was found that:

  • The two groups could not be considered significantly different from each other across the measures. This was due to mixed findings whereby the non-clinical group had higher levels of broad overcontrol than the clinical group, but the groups did not differ on personal need for structure, alexithymia, or emotional loneliness. The clinical group showed higher levels of experiential avoidance, social safeness, total and social loneliness.
  • Data from the two groups was therefore pooled together to run further analysis.
  • Overcontrolled traits were related to personal need for structure and loneliness but was not correlated with experiential avoidance or overall alexithymia.
  • Alexithymia, need for structure and social safeness significantly contributed to the model that predicted experiential avoidance, but overcontrol did not. Only social safeness significantly contributed to the model predicting loneliness.

The findings of the systematic review show that psychological interventions can be useful for FM and the empirical study showed that coping styles and individual personality characteristics may be important to understand further, potentially to tailor treatments to better meet the needs of individuals with conditions such as FM and CFS. However, this may need further exploration, and it is hoped that other clinicians or researchers may be encouraged to explore overcontrolled coping in other groups.

It is hoped that the systematic review and empirical study encourage further research into further understanding these conditions and highlights that there is still much we may need to understand further about how improvements are maintained or not and any factors that may impact this.

In the future, research would likely benefit from recruiting more participants from a range of different backgrounds, along with addressing the limitations discussed in this study. To maximise the reach of the study, findings will be shared with participants, organisations that assisted with advertising on social media. Findings will also be presented and potentially published in an academic journal.

Long-COVID Research References

  1. Musculoskeletal involvement: COVID-19 and post COVID 19
  2. Laboratory Findings and Biomarkers in Long COVID: What Do We Know So Far? Insights into Epidemiology, Pathogenesis, Therapeutic Perspectives and Challenges
  3. Prevalence of mental health problems among children with long COVID: A systematic review and meta-analysis
  4. Clinical characterization and factors associated with quality of life in Long COVID patients: Secondary data analysis from a randomized clinical trial
  5. Effectiveness of a telerehabilitation intervention using ReCOVery APP of long COVID patients: a randomized, 3-month follow-up clinical trial
  6. Exercise intolerance associated with impaired oxygen extraction in patients with long COVID
  7. Cardiopulmonary testing in long COVID-19 versus non–COVID-19 patients with undifferentiated Dyspnea on exertion
  8. Deficient GABABergic and glutamatergic excitability in the motor cortex of patients with long-COVID and cognitive impairment
  9. Biological mechanisms underpinning the development of Long COVID
  10. Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis
  11. Long- COVID and general health status in hospitalized COVID-19 survivors
  12. Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID
  13. First study results of the P4O2 long COVID cohort
  14. Long COVID: An Epidemic within the Pandemic
  15. The Renin-Angiotensin-System in COVID-19: Can Long COVID Be Predicted?
  16. De-black-boxing health AI: demonstrating reproducible machine learning computable phenotypes using the N3C-RECOVER Long COVID model in the All of Us data repository
  17. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation
  18. Ginkgo Biloba and Long COVID: In Vivo and In Vitro Models for the Evaluation of Nanotherapeutic Efficacy
  19. Multidisciplinary Center Care for Long COVID Syndrome – a Retrospective Cohort Study
  20. Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients
  21. Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms
  22. Experiences of improvement of everyday life following a rehabilitation programme for people with long-term cognitive effects of COVID-19: Qualitative study
  23. The association between the number of symptoms and the severity of Post-COVID-Fatigue after SARS-CoV-2 infection treated in an outpatient setting

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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