MEA Research Roundup

ME/CFS and Long Covid Research: 20 – 26 September 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.

Audio commentary by Dr Katrina Pears

ME/CFS Research Published 20 – 26 September 2022 

After a couple of very quiet weeks with only a handful of new ME/CFS studies being published, we have suddenly seen a flurry of research. There have been nine new ME/CFS studies and fourteen studies on Long Covid. 

We have highlighted two studies below: 

Paper one (1) investigates the adaptive immune response and microbiota in severe ME/CFS. This study used a high throughput method where they profiled the response of severe ME/CFS patients and healthy controls against microbiota and viral antigens represented in a pre-existing library of 244,000 antigens. 

Results showed that those with  severe ME/CFS exhibited distinct serum antibody responses against the bacteria Lachnospiraceae, specifically its flagellin which is a structural protein inside the flagellum, which helps bacterial motility. The research team also applied computer models which further showed distinct immune responses against gut microbiota, these results show involvement of microbiota and the immune system in ME/CFS. The results also have the potential for providing diagnostic tests and biomarkers for ME/CFS. 

One of the strengths of this study is the use of 40 patients with severe ME/CFS and 40 healthy controls, where samples were collected from the UK ME/CFS Biobank which the ME Association’s Ramsay Research Fund supports the running costs of (see more information here). Using the UK ME/CFS Biobank helped to ensure the accurate diagnosis of patients and also remove any biases related to geography or sample handling. Furthermore, it is also nice to see a study using severe ME/CFS patients as these are definitely lacking, although differences may not be so pronounced in other severities.  

Nevertheless, this study has its limitations, such as its small scale, using only one time point, and it is impossible to profile all antigen responses against a known library as it is impossible to capture all viral and bacterial antigens. Furthermore, like most studies on gut microbiota it is impossible to know if results are the cause of the disease or as a result, for example many people with ME/CFS change their diet, for example as a result of increasing food intolerances or the change in ability to cook decreasing food diversity.  

Professor Eleanor Riley, who is a Professor Emerita, Immunology and Infectious Disease, University of Edinburgh and a former  member of the research team at the ME Biobank, has provided her expert comment on this piece of research, which can be read here

Paper two (2) is a preprint study, meaning the science has not been peer-reviewed and verified, this study tried to tie several different aspects of ME/CFS together: circadian rhythms (including circadian skin temperature rhythm), orthostatic intolerance (dysautonomia), and endothelium dysfunction (layer of cells lining blood vessels, see our previous research summary here). This study used 67 female ME/CFS and 48 healthy controls, who underwent orthostatic tests, alongside a range of other measurements. 

Unsurprisingly, the researchers found alterations in circadian rhythms and hemodynamic measures that are associated with endothelial dysfunction in ME/CFS, supporting previous evidence of dysautonomia. The results can be further broken down, with a range of significant results for ME/CFS patients (compared to controls) as follows: 

  • higher blood pressure and heart rate values at rest,  
  • higher amplitude of the circadian activity rhythm, 
  • higher circulating levels of endothelin-1 (ET-1) (a endothelial biomaker), 
  • higher vascular cell adhesion molecule-1 (VCAM-1) (a endothelial biomaker), 
  • Furthermore, in ME/CFS, ET-1 levels were associated with the stability and amplitude of the temperature rhythm, i.e. ET-1 levels were linked to the severity of autonomic symptoms and wrist temperature. 

This study is strong in its reasonable sample size (for ME/CFS research) and the researchers also removed further variation in the results by only using a female cohort (although this is also a limitation). However, the results do not allow causation to be explored and only mild-moderate severities of ME/CFS were investigated. 

At first glance I thought this study was trying to link together too many different factors. However, the study found a good range of significant results and important associations, using fairly simple measurements and tests. This study also adds to the building evidence for endothelium dysfunction in ME/CFS (see our previous research summary here) but importantly it is the first study to link this to autonomic nervous system (ANS) dysfunction. I hope these findings will be verified by another group, which then could lead to therapeutic interventions being targeted.  

There are quite a few studies this week which cover the overlapping conditions of ME/CFS and Long Covid. Papers four (4), six (6) and seven (7) further strengthen the similarities between ME/CFS and Long Covid. While paper nine (9) shows that lowered oxygen saturation and increased body temperature in the initial phases of a COVID-19 infection largely predicts later development of chronic fatigue syndrome in Long Covid. Unfortunately, this study is behind a paywall so we cannot fully evaluate the study. 

ME/CFS Research References and Abstracts(6 – 13 September) 

1. Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients 

Thomas Vogl, Iris N. Kalka, Shelley Klompus, Sigal Leviatan, Adina Weinberger, Eran Segal 

Sci. Adv. 8, eabq2422 (2022) 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with an unclear etiology and pathogenesis. Both an involvement of the immune system and gut microbiota dysbiosis have been implicated in its pathophysiology.  

However, potential interactions between adaptive immune responses and the microbiota in ME/CFS have been incompletely characterized.  

Here, we profiled antibody responses of patients with severe ME/CFS and healthy controls against microbiota and viral antigens represented as a phage-displayed 244,000 variant library.  

Patients with severe ME/CFS exhibited distinct serum antibody epitope repertoires against flagellins of Lachnospiraceae bacteria.  

Training machine learning algorithms on this antibody-binding data demonstrated that immune responses against gut microbiota represent a unique layer of information beyond standard blood tests, providing improved molecular diagnostics for ME/CFS.  

Together, our results point toward an involvement of the microbiota-immune axis in ME/CFS and lay the foundation for comparative studies with inflammatory bowel diseases and illnesses characterized by long-term fatigue symptoms, including post–COVID-19 syndrome. 

2. Circadian skin temperature rhythm and dysautonomia in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the role of endothelin-1 in the vascular dysregulation 

Trinitat Cambras, Maria Fernanda Zerón-Rugerio, Antoni Díez-Noguera et al. 

ResearchSquare [Preprint] 


Purpose: There is accumulating evidence of autonomic dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, little is known about its association with circadian rhythms and endothelial dysfunction. This study aimed to explore the relationship between autonomic responses using an orthostatic test, skin temperature circadian variations, and circulating endothelial biomarkers in ME/CFS.  

Methods: Sixty-seven adult female ME/CFS patients and 48 matched healthy controls were enrolled. Demographic and clinical characteristics suggestive of autonomic disturbances were assessed using validated self-reported outcome measures. Postural changes in blood pressure [BP], heart rate [HR], and wrist temperature (WT) were recorded during the orthostatic test. Actigraphy during one week was used to determine the 24-hour profile of peripheral temperature and motor activity. Circulating endothelial biomarkers were also measured as indicators of endothelial functioning.  

Results: ME/CFS patients showed higher BP and HR values than healthy controls at rest (p < 0.05 for both), and also higher amplitude of the circadian activity rhythm (p < 0.01). Circulating levels of endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in ME/CFS (p < 0.05). In ME/CFS, ET-1 levels were associated with the stability and amplitude of the temperature rhythm, (p < 0.01), and also with the self-reported questionnaires (p < 0.001).  

Conclusions: ME/CFS patients exhibited alterations in circadian rhythms and hemodynamic measures that are associated with endothelial dysfunction, supporting previous evidence of dysautonomia in ME/CFS. Future investigation in this area is needed to assess vascular tone abnormalities and dysautonomia which may provide therapeutic targets for ME/CFS. 

3. Polyphenols as possible alternative agents in chronic fatigue: a review 

Ullah, H., Khan, A., Riccioni, C. et al.  

Phytochem Rev (2022) 


Chronic fatigue syndrome (CFS) is a pathological state of extreme tiredness that lasts more than six months and may possess an impact on the social, emotional, or occupational functioning of an individual. CFS is characterized by profound disabling fatigue associated with infectious, rheumatological, and neurological symptoms.  

The current pharmacological treatment for CFS does not offer a complete cure for the disease, and none of the available treatments show promising results.  

The exact mechanism of the pathogenesis of the disease is still unknown, with current suggestions indicating the overlapping roles of the immune system, central nervous system, and neuroendocrine system.  

However, the pathological mechanism revolves around inflammatory and oxidative stress markers.  

Polyphenols are the most abundant secondary metabolites of plant origin, with potent antioxidant and anti-inflammatory effects, and can exert protective activity against a whole range of disorders.  

The current review is aimed at highlighting the emerging role of polyphenols in CFS from both preclinical and clinical studies. Numerous agents of this class have shown promising results in different in vitro and in vivo models of chronic fatigue/CFS, predominantly by counteracting oxidative stress and the inflammatory cascade.  

The clinical data in this regard is still very limited and needs expanding through randomized, placebo-controlled studies to draw final conclusions on whether polyphenols may be a class of clinically effective nutraceuticals in patients with CFS. 

4. Long-term neuromuscular consequences of SARS-Cov-2 and their similarities with myalgic encephalomyelitis/chronic fatigue syndrome: results of the retrospective CoLGEM study 

Retornaz F, Rebaudet S, Stavris C, Jammes Y.  

J Transl Med. 2022 Sep 24;20(1):429 


Background: Patients with long-COVID often complain of continuous fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise. No data are available on EMG recording of evoked myopotentials (M-waves) or exercise-induced alterations in long-COVID patients, providing evidence of muscle membrane fatigue.  

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) develops in more than half of patients after an infectious disease, particularly viral diseases. A large proportion (around 70%) of these patients have neuromuscular disorders with M-wave alterations during and after exercise.  

Our hypothesis was that M-wave alterations would be also found in long-COVID patients, in association with neuromuscular symptoms, similar to ME/CFS. 

Methods: This retrospective observational ColGEM (Covid LonG Encéphalomyelite Myalgique) study compared 59 patients with long-COVID and 55 ME/CFS patients with a history of severe infection who presented before the COVID pandemic.  

All of these patients underwent the same protocol consisting of a questionnaire focusing on neural and neuromuscular disorders and M-wave recording in the rectus femoris muscle before, during, and 10 min after a progressive cycling exercise. Maximal handgrip strength (MHGS) and maximal exercise power were also measured. The frequency of symptoms and magnitude of M-wave changes in the two groups were compared using non-parametric and parametric tests. 

Results: The frequency of fatigue, myalgia, sleep problems, cognitive dysfunction, and post-exertional malaise as well as the magnitude of exercise-induced M-wave alterations were the same in the two groups. By contrast, digestive problems were less present in long-COVID. M-wave alterations were greater in ME/CFS patients as in those with long-COVID when the highest muscle strength and highest exercise performance were measured. 

Conclusions: These high clinical and biological similarities between long-COVID and ME/CFS support the hypothesis that SARS-Cov-2 infection can cause ME/CFS symptoms. Trial registration Registered retrospectively. 

5. Exosome-Associated Mitochondrial DNA from Patients with ME/CFS Stimulates Human Cultured Microglia to Release IL-1β 

Tsilioni I, Natelson B, Theoharides TC.  

Eur J Neurosci. 2022 Sep 24. [Epub ahead of print.] 


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease that presents with fatigue, sleep disturbances, malaise, and cognitive problems.  

The pathogenesis of ME/CFS is presently unknown and serum levels of potential biomarkers have been inconsistent.  

Here we show that mitochondrial DNA (mtDNA) associated with serum exosomes, is increased in ME/CFS patients only after exercise.  

Moreover, exosomes isolated from patients with ME/CFS stimulate significant release of IL-1β from cultured human microglia.  

These results provide evidence that activation of microglia by serum-derived exosomes may serve as a potential novel pathogenetic factor and target for treatment of ME/CFS.  

6. The Fatigue-Related Symptoms Post-Acute SARS-CoV-2: A Preliminary Comparative Study 

Thomas M.  

Int J Environ Res Public Health. 2022 Sep 16;19(18):11662.  


A sizeable sub-group of individuals continue to experience persistent debilitating symptoms post-acute SARS-CoV-2. Although these can vary from person to person, fatigue appears to be the most common symptom.  

Post-viral fatigue has been documented in conditions such as influenza, infectious mononucleosis and more recently chronic fatigue syndrome (CFS).  

The current study uses measures that successfully describe the fatigue-related symptoms associated with CFS to investigate the fatigue experienced post-acute SARS-CoV-2. Twenty-six volunteers were recruited from Long COVID support groups active on social media.  

Data were collected anonymously using an online survey platform. These data were compared to pre-pandemic data from non-fatigued and CFS groups.  

The post-acute SARS-CoV-2 volunteers reported significantly higher levels of fatigue and cognitive difficulties than the non-fatigued controls. They also report more individual symptoms (such as lack of concentration) and problems with sleep quality.  

There was a similarity between the post-acute SARS-CoV-2 volunteers and the CFS group in terms of levels of depression, perceived stress, emotional distress and cognitive difficulties.  

Although this was a small-scale study, it demonstrates the range of symptoms experienced post-acute SARS-CoV-2. In addition, the similarities between this group and CFS suggests the need for further research into the mechanisms at play here, the need to identify those at risk of long-term symptoms and the development of possible interventions. 

7. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground? 

Ryabkova, V.A.; Gavrilova, N.Y.; Fedotkina, T.V.; Churilov, L.P.; Shoenfeld, Y. 

Preprints 2022, 2022090289 


A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation.  

We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders.  

Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition.  

Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals.  

Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, “dysfunction of the autonomic nervous system”, “neurological sensory / motor disorders” and “pain syndromes”.  

Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing.  

The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02).  

There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group.  

Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls.  

The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences. 

8. Post-COVID myalgic encephalomyelitis in chronic heart disease patient: A case series 

Holder, K. G.; Vemulapalli, V.; Daines, B.; Kankam, A.; Galvan, B.; Nambiar, R. 

Journal of Investigative Medicine; 70(2):475, 2022. 


Purpose of Study: Myalgic encephalomyelitis (ME), also called chronic fatigue syndrome, is a condition characterized by severe fatigue that impairs a patient's ability to perform common daily activities.  

Criteria for ME include 6 months of fatigue-limited daily activities, unrefreshing sleep, and symptom exacerbation following physical or mental strain, and orthostatic intolerance.  

New reports indicate that ME incidence may be higher in specific patient populations. This study was designed to investigate the association between ME and Cardiovascular disease in patients recovering from COVID-19 infection.  

Methods: Used The patient population used for this study includes 19 patients that were referred to the Amarillo Heart Group in Amarillo, TX who also tested positive for Covid-19 at least 6 months prior to September 1, 2021.  

The patients that fit this timeline were asked a series of standardized questions and rate the severity of their symptoms on a scale of 0 to 5, with 0 being the absence of symptoms and 5 being the most severe. Two sets of questions were created and named Life Spheres Criteria (4 questions) and Symptoms Criteria (3 questions) based on the 2015 IOM Diagnostic Criteria for CFS. Rating more than 1 Life Spheres question as a 3 or higher or rating all 3 Symptoms Criteria questions as a 3 or higher indicated Chronic Fatigue Syndrome. Information from the survey, including time since infection, demographics, and question scores, were analyzed.  

Summary of Results: Our study included 10 women and 10 men, with the average amount of time since Covid-19 infection being 328.17 ± 41.36 days. Worsening of symptoms with mild exertion was the most commonly endorsed criteria (3.58 ± 1.64) and the least common criterion was fatigue reducing activity in school (2.00 ± 1.94).  

Women scored higher in every category except reduced activity in school when compared to men. However, there was no significant difference in symptom scores between the two groups with the Combined Fatigue Score being 2.89 ± 1.47 for women and 2.67 ± 1.59 for men.  

Nearly all symptom scores significantly positively correlated with one another, meaning if one category was high it was likely for other categories to be high as well.  

Ultimately, when looking at the Cumulative Pearson Correlation Scores, reduced social life, difficulty concentrating, and symptoms worsening with mild exertion were found to be most predictive of a high Combined Fatigue Score.  

Conclusions: In this case series, over 80% of patients met the criteria for Post-COVID Myalgic Encephalomyelitis. While the link between ME and both COVID-19 and cardiovascular disease has been established, little is known about the severity of ME in patients who have a history of both cardiovascular disease and COVID-19 infection.  

To our knowledge, this is the first study to examine ME in patients with both of these predisposing conditions. A high degree of clinical suspicion for ME should be used when screening and treating cardiac patients who have been infected with COVID-19. 

9. Lowered oxygen saturation and increased body temperature in acute COVID-19 largely predict chronic fatigue syndrome and affective symptoms due to Long COVID: A precision nomothetic approach 

Al-Hadrawi DS, Al-Rubaye HT, Almulla AF, Al-Hakeim HK, Maes M.  

Acta Neuropsychiatr. 2022 Sep 22:1-12. [Epub ahead of print.] 


Background: Long coronavirus disease 2019 (LC) is a chronic sequel of acute COVID-19. The exact pathophysiology of the affective, chronic fatigue and physiosomatic symptoms (labelled as “physio-affective phenome”) of LC has remained elusive. 

Objective: The current study aims to delineate the effects of oxygen saturation (SpO2) and body temperature during the acute phase on the physio-affective phenome of LC. 

Method: We recruited 120 LC patients and 36 controls. For all participants, we assessed the lowest SpO2 and peak body temperature during acute COVID-19, and the Hamilton Depression and Anxiety Rating Scale (HAMD/HAMA) and Fibro Fatigue (FF) scales 3-4 months later. 

Results: Lowered SpO2 and increased body temperature during the acute phase and female sex predict 60.7% of the variance in the physio-affective phenome of LC. Using unsupervised learning techniques, we were able to delineate a new endophenotype class, which comprises around 26.7% of the LC patients and is characterised by very low SpO2 and very high body temperature, and depression, anxiety, chronic fatigue, and autonomic and gastro-intestinal symptoms scores. Single latent vectors could be extracted from both biomarkers, depression, anxiety and FF symptoms or from both biomarkers, insomnia, chronic fatigue, gastro-intestinal and autonomic symptoms. 

Conclusion: The newly constructed endophenotype class and pathway phenotypes indicate that the physio-affective phenome of LC is at least in part the consequence of the pathophysiology of acute COVID-19, namely the combined effects of lowered SpO2, increased body temperature and the associated immune-inflammatory processes and lung lesions. 

Long-COVID Research References  

  1. Lactoferrin as Possible Treatment for Chronic Gastrointestinal Symptoms in Children with Long COVID: Case Series and Literature Review 
  1. Long COVID symptoms in exposed and infected children, adolescents and their parents one year after SARS-CoV-2 infection: A prospective observational cohort study 
  1. Long-term neurologic outcomes of COVID-19 
  1. Creative Long Covid: A qualitative exploration of the experience of Long Covid through the medium of creative narratives 
  1. Neurological post-acute sequelae of SARS-CoV-2 infection (PASC) 
  1. Differential diagnosis and pathogenesis of the neurological signs and symptoms in COVID-19 and long-COVID syndrome 
  1. Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long-COVID symptoms 
  1. Molecular Mimicry between SARS-CoV-2 and Human Endocrinocytes: A Prerequisite of Post-COVID-19 Endocrine Autoimmunity? 
  1. Investigating Topic Modeling Techniques to Extract Meaningful Insights in Italian Long COVID Narration 
  1. Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system 
  1. Long COVID symptoms in a population-based sample of persons discharged home from hospital 
  1. Post-COVID-19 Syndrome: A Novel Diagnosis 
  1. An international study of post-COVID sleep health 
  1. Rehabilitation in long COVID-19: A mini-review 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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