MEA Research Roundup

ME/CFS and Long Covid Research: 18 – 24 October 2022 

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.

ME/CFS Research Published 18 – 24 October 2022 

It’s been an incredibly busy week for research. There have been nine new ME/CFS studies and thirteen studies on Long Covid. 

Paper eight (8) and nine (9) included in this review are not peer-reviewed published studies but have been included out of interest to show other fields of study. Paper eight (8) is a conference paper on the use of assistive robots in ME/CFS and Long Covid, while paper nine (9) is a PhD thesis which uses statistical methods to identify which patients will benefit from the use of CBT. 

We have highlighted two studies below: 

Paper one (1) is a novel piece of research on the reactivation of viruses after a mild or asymptomatic Covid-19 infection in ME/CFS. This study analysed a range of viruses in the blood and saliva of 95 non-vaccinated ME/CFS patients and 110 healthy controls (referred to as healthy donors by the authors). 

The results showed that following a Covid-19 infection, both groups had significant latent virus reactivation, with herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K) being detected in the saliva. However, in the ME/CFS patients this response was significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG. Results show that even mild or asymptomatic Covid-19 infection can cause the potential trigger for latent viruses, such as herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), meaning that ME/CFS patients are more susceptible and have stronger reactions to a Covid-19 infection. This provides further evidence for altered immune responses in ME/CFS. 

Results from this study are interesting and the study has strength in its reasonable scale. Findings could explain why, when infected by other viruses ME/CFS patients tend to become more unwell and for longer than healthy controls, due to the role of dormant viruses being activated. It is also interesting that results were only significant in the saliva and not the blood, which could have implications in future studies, and lead to more significant results. The authors suggested this could be due to herpesviruses being common in the oral cavity making them easy traceable in saliva. Furthermore, it should also be noted that previous studies have shown that when studying antibodies for Covid-19, the saliva should be used.  

I do hope these results are followed up, as these findings have the potential for the development of new treatments looking at boosting the antiviral immune response as well as a role in immunological tests for diagnosis.  

Paper two (2) is a preprint (meaning it has not been peer-viewed and the science verified) on cerebrospinal fluid proteomes in ME/CFS and the overlapping conditions Fibromyalgia (FM). This study looked at answering the question of whether these two illnesses are distinct entities or not, using 15 ME/CFS patients with FM and 15 ME/CFS patients without FM. The study concluded that “ME/CFS and fibromyalgia as currently defined are not distinct entities”. 

There are several problems with this study, including its small sample size which makes it extremely hard to find statistically significantly difference, such as there being no healthy control group and no FM only group. Therefore, it makes it difficult to support the researchers concluding statement as the proteome profile might be the same in healthy controls. I would be interested in seeing how these group compare if the study was repeated, and also what comments are made when it goes through the peer-review process. 

We have seen several studies on Fibromyalgia in the past two weeks, Paper six (6) reviews the cardiorespiratory fitmess and neuromuscular function in ME/CFS and FM, unsurprisingly finding that these are lower than healthy controls. 

You may also be interested in reading Paper six (6) in the Long Covid Reference Section which is from the well-known researchers van Campen and Visser, who shown in this research that the patients with longer duration of Long Covid have reduced prevalence of POTS but continue to have abnormal cerebral blood flow. We also reported on a paper from this research group last week, showing that the prevalence of POTS and orthostatic intolerance is no different in the ME/CFS population to the Long Covid. 

ME/CFS Research References and Abstracts  

1. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome 

Apostolou E, Rizwan M, Moustardas P, Sjögren P, Bertilson BC, Bragée, Polo O and Rosén A. 

Front. Immunol. 13:949787 

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts. 

Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva. 

Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs. 

Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma. 

2. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and fibromyalgia are indistinguishable by their cerebrospinal fluid proteomes 

Steven E. Schutzer, Tao Liu, Chia-Feng Tsai, Vladislav A. Petyuk, Athena A. Schepmoes, Yi-Ting Wang, Karl K. Weitz, Jonas Bergquist, Richard D. Smith, Benjamin H Natelson 

bioRxiv [Preprint] 


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other.  

To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other.  

We examined two separate groups of ME/CFS, one with (n=15) and one without (n=15) fibromyalgia.  

We quantified a total of 2,083 proteins using immunoaffinity depletion, tandem mass tag isobaric labeling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1,789 that were quantified in all the CSF samples.  

ANOVA analysis did not yield any proteins with an adjusted p-value < 0.05. This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities. 

3. Subjective and objective cognitive function in adolescent with chronic fatigue following Epstein-Barr virus infection 

Merete GlenneØie, Astrid Sofie BuerRødø, Maria SlettenBølgen, MariaPedersen, Tarjei TørreAsprusten, Vegard Bruun BratholmWyller 

Journal of Psychosomatic Research, 111063 [In Press, Journal Pre-proof] 


  • Adolescents with CFS report cognitive difficulties. 
  • Adolescents with CFS report more cognitive difficulties than those with CF. 
  • There were no impairments in objective measures of cognitive function. 


Objective: Cognitive difficulties are among the most disruptive and disabling problems reported by chronic fatigue syndrome (CFS) sufferers. Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and CFS. The aim of this study was to investigate subjectively reported and objectively measured cognitive functioning in fatigued and non-fatigued adolescents six months after EBV infection. 

Methods: A total of 195 adolescents (12–19 years) with acute EBV infection were followed prospectively for six months, after which they were grouped as chronically fatigued (CF+) and non-fatigued (CF−) cases based on questionnaire score; the CF+-group was further subgrouped according to CFS diagnosis. A group of 70 healthy controls was also included. Groups were cross-sectionally compared on objective measures of processing speed, executive functions and memory, and subjective cognitive functioning. 

Results: There were no group differences regarding objective cognitive measures, but the CF+-group reported significantly (p < 0.001) more cognitive problems (cognitive symptoms sum score = 9.5) compared to the CF−-group (cognitive symptoms sum score = 5.3) and the healthy control group (cognitive symptoms sum score = 6.4). The CFS subgroup rated symptoms scores even higher but did not differ on cognitive performance tests. 

Conclusion: Subjective experiences of cognitive difficulties characterize adolescents with CF and CFS six months after acute EBV infection, whereas objective measures of cognitive impairment are inconspicuous. 

4. Factors Influencing the Prognosis of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Ghali A, Lacout C, Fortrat J-O, Depres K, Ghali M, Lavigne C. 

Diagnostics. 2022; 12(10):2540. 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term debilitating multisystem condition with poor prognosis. Studies that examined predictors of ME/CFS outcomes yielded contradictory results.  

We aimed to explore epidemiological and clinical prognostic factors of ME/CFS using operationalized criteria for recovery/improvement.  

Adult ME/CFS patients who attended the Internal Medicine Department of Angers University Hospital, Angers, France between October 2011 and December 2019, and were followed up until December 2020, were included retrospectively. Their medical records were reviewed for data collection.  

Patients were classified into two groups according to the presence or absence of recovery/improvement (R/I) and compared for epidemiological characteristics, fatigue features, post-exertional malaise severity, clinical manifestations, and comorbidities.  

The subgroups of recovered and significantly improved patients were then compared. 168 patients were included.  

Recovery and improvement rates were 8.3% and 4.8%, respectively. Older age at disease onset was associated with R/I (OR 1.06 [95% CI 1.007–1.110] (p = 0.028)), while diagnostic delay was inversely associated with R/I (OR 0.98 [95% CI 0.964–0.996] (p = 0.036)).  

The study findings confirmed the poor prognosis of ME/CFS and the deleterious effect of diagnostic delay on disease progression. Interestingly, being older at disease onset was associated with better outcomes, which offers hope to patients for recovery/improvement even at an advanced age. 

5. Global prevalence of chronic fatigue syndrome among long COVID-19 patients: A systematic review and meta-analysis 

Salari, N., Khodayari, Y., Hosseinian-Far, A. et al.  

BioPsychoSocial Med 16, 21 (2022).  


Background: Chronic fatigue syndrome is a persistent and debilitating disorder. According to several studies, chronic fatigue syndrome has been identified among recovered COVID-19 patients as the most common symptom of long COVID. The aim of this systematic review and meta-analysis study was to obtain the prevalence of chronic fatigue syndrome in long COVID cases. 

Methods: In this systematic review and meta-analysis, we analysed reported results of studies that assessed the occurrence of chronic fatigue syndrome among COVID-19 patients four weeks after the onset of symptoms. The study selection was commenced by searching PubMed, Web of Science, Science Direct, Scopus, Embase, and Google scholar using the keywords of Chronic fatigue syndrome, COVID-19, and post-COVID-19 syndrome. The searches were without a lower time limit and until April 2022. Heterogeneity of studies was assessed using the I2 index, and a random effects model was used for analysis. Data analysis was performed within the Comprehensive Meta-Analysis software (version 2). 

Results: The pooled prevalence of chronic fatigue syndrome four weeks after the onset of COVID-19 symptoms, in 52 studies with a sample size of 127,117, was 45.2% (95% CI: 34.1-56.9%). Meta-regression analysis in examining the effects of the two factors of sample size, and year of study on the changes in the overall prevalence, showed that with increasing sample size, and year of study, the prevalence of chronic fatigue syndrome among long COVID patients (p < 0.05). 

Conclusion: Our results show that the overall prevalence of chronic fatigue syndrome as a long COVID symptom is 45.2%. Chronic fatigue after infection with COVID-19 can negatively affect personal and social lives. Given such significant negative consequences caused by the syndrome, it is recommended that health policymakers allocate funds to reduce the adverse effects of this syndrome, by creating programs to support long COVID patients. 

6. Fibromyalgia and Chronic Fatigue Syndromes: A systematic review and meta-analysis of cardiorespiratory fitness and neuromuscular function compared with healthy individuals 

Zambolin F, Duro-Ocana P, Faisal A, Bagley L, Gregory WJ, Jones AW, McPhee JS.  

PLoS One. 2022 Oct 20;17(10):e0276009. 


Objective: To determine cardiorespiratory fitness and neuromuscular function of people with CFS and FMS compared to healthy individuals. 

Design: Systematic review and meta-analysis. 

Data sources: PubMed, Medline, CINAHL, AMED, Cochrane Central Register of Controlled Trials (CENTRAL), and PEDro from inception to June 2022. 

Eligible criteria for selecting studies: Studies were included if presenting baseline data on cardiorespiratory fitness and/or neuromuscular function from observational or interventional studies of patients diagnosed with FMS or CFS. Participants were aged 18 years or older, with results also provided for healthy controls. Risk of bias assessment was conducted using the Quality Assessment Tool for Quantitative Studies (EPHPP). 

Results: 99 studies including 9853 participants (5808 patients; 4405 healthy controls) met our eligibility criteria. Random effects meta-analysis showed lower cardiorespiratory fitness (VO2max, anaerobic threshold, peak lactate) and neuromuscular function (MVC, fatigability, voluntary activation, muscle volume, muscle mass, rate of perceived exertion) in CFS and FMS compared to controls: all with moderate to high effect sizes. 

Discussion: Our results demonstrate lower cardiorespiratory fitness and muscle function in those living with FMS or CFS when compared to controls. There were indications of dysregulated neuro-muscular interactions including heightened perceptions of effort, reduced ability to activate the available musculature during exercise and reduced tolerance of exercise. 

7. Key Features of a Multi-Disciplinary Hospital-Based Rehabilitation Program for Children and Adolescents with Moderate to Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS 

Hiremath S, Doukrou M, Flannery H, Carey C, Gregorowski A, Ward J, Hargreaves D, Segal TY.  

International Journal of Environmental Research and Public Health. 2022; 19(20):13608 


Purpose of the study: There is limited published data on treatment or outcomes of children and young people (CYP) with moderate or severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).  

Here, we describe outcomes of moderate and severe ME/CFS in CYP treated in a tertiary adolescent service. This information is useful when planning services for CYP and families affected by moderate/severe ME/CFS and to guide future management trials and commissioning decisions.  

Study Design: A retrospective review was conducted of medical records of the 27 CYP who received ward-based treatment in 2015. Notes were retrospectively reviewed to assess progress in four markers of wellbeing over the period of treatment: (i) mobility, (ii) education, (iii) sleep and (iv) involvement in social/recreational activities.  

Results: A total of 23/27 (85%) showed improvement in one or more domains over their period of ward-based therapy. 19/27 (70%) of patients showed improvement in physical ability. In 15/23 patients (65%), there was an improvement in ability to access education, in 12/24 (50%) sleep improved, and 16/27 (59%) demonstrated an improvement in socialising/ability perform recreational activities.  

Conclusion/Implications: A multidisciplinary hospital-based rehabilitation programme for moderate and severe ME/CFS was associated with improvement in at least one area of wellbeing in 85% of the CYP we reviewed. These data may be used as a baseline to evaluate the impact of other models of delivering care for this patient group. It may be useful when considering other groups such as those affected by Post-COVID Syndrome. 

8. Assistive Robots for Long COVID and ME/CFS Support: Challenges and Opportunities 

Signe Redfield, Mae Seto, Nicholas D’Amore 

2022 IEEE Canadian Conference on Electrical and Computer Engineering (CCECE) – 18-20 September 2022 


Many people infected with COVID-19 have found that they still experience health effects months and even years afterward, with the pandemic representing one of the largest mass-disabling events in modern history, affecting people from all demographics.  

It is proposed here that modern robotics methods have the potential to substantially improve the quality of life for long COVID patients and to help them recover more quickly.  

This paper describes what long COVID is and what its symptoms are, presents requirements for robotic capabilities to assist patients, and considers patient feedback on the possible challenges associated with developing and implementing such a solution. 

9. Applying latent class cluster analysis and data mining methods to identify classes of chronic fatigue syndrome patients that are predictive of treatment success 

Clapperton, Ben 

PhD thesis [King's College London] 


Chronic fatigue syndrome (CFS) is a condition characterised by chronic disabling fatigue and other symptoms that currently cannot be explained by any underlying medical condition. It is estimated that 250,000 of the UK population suffer from CFS.  

Although clinical trials support the effectiveness of cognitive behaviour therapy in terms of fatigue and physical functioning, the success rate for individual patients is modest. Patients vary in their response and little is known about which factors predict or moderate their treatment outcomes.  

Identifying moderators of treatment effect is typically done in a regression-based approach by assessing interactions between clinical and other baseline variables and treatment groups. Moderators typically are of small effect size and prediction models often show poor accuracy in predicting outcomes.  

My project took a different approach to identify classes of patients with similar baseline characteristics. I compared a model-based cluster analysis method of Latent Class Analysis against an automatic distribution-free machine learning algorithm, Self-Organising Maps.  

The classes identified were tested for predictive usefulness of treatment effects. Characteristics of the classes can be used to inform clinicians about the types of individuals who benefit from specific treatments.  

The suitability of the clustering methods was compared using data on CFS patients in two datasets, a large clinical cohort study and a randomised clinical trial.  

Using the trial data, I also compared the performance of the clustering techniques against a computer-intensive statistical learning penalised regression method which provides predictions without clustering.  

The LASSO regression model was also developed to identify moderators of treatment success. These comparisons allow the assessment of the potential advantages of clustering approaches and their capability 

Long-COVID Research References  

  1. SARS-CoV-2-on-Chip for Long COVID Management 
  1. An Exercise Prescription as a Novel Management Strategy for Treatment of Long COVID 
  1. Post-COVID-19 syndrome symptoms after mild and moderate SARS-CoV-2 infection 
  1. Blood group O is associated with post-COVID-19 syndrome in outpatients with a low comorbidity index 
  1. Serological biomarkers of COVID-19 severity at hospital admission are not related to long-term post-COVID pain symptoms in hospitalized COVID-19 survivors 
  1. Long-Haul COVID Patients: Prevalence of POTS Are Reduced but Cerebral Blood Flow Abnormalities Remain Abnormal with Longer Disease Duration 
  1. Psychiatric and neurological complications of long COVID 
  1. Rehabilitation of Neuropsychiatric Symptoms in Patients with Long-COVID: Position Statement 
  1. Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study 
  1. Long COVID: An inevitable sequela of SARS-CoV-2 infection 
  1. Invasive assessment of coronary microvascular dysfunction in patients with long COVID – outcomes of a pilot study 
  1. Gut Microbiota Dynamics in Relation to Long-COVID-19 Syndrome: Role of Probiotics to Combat Psychiatric Complications 
  1. Headache in Post-COVID-19 Patients: Its Characteristics and Relationship with the Quality of Life 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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