ME/CFS and Long Covid Research: 29 March – 04 April 2022

April 8, 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 from Katrina Pears

ME/CFS Research Published 29 March – 4 April 2022 

It’s been a busy week for research with a lot of interesting research. There have been eight new ME/CFS studies and fourteen studies on Long Covid.  

We have highlighted two of the studies below:  

Paper one (1) is research funded by the MEA Ramsay Research Fund using samples from the ME Biobank, I was also involved in proof-reading the final draft before publishing. The purpose of this research is to work towards finding a diagnostic blood test or biomarker.  

The study employed a large range of statistical tests to help differentiate  between severe ME and healthy controls. The researchers looked at over 800 different components in the blood, reducing these to 32, with a particular focus on extracellular vesicles and microRNA. When investigating this the researchers found abnormalities in these plasma components in severe ME patients compared to healthy controls, which hopefully could be investigated further to find a diagnostic tool. 

There are a lot of complex terms in this paper, a brief summary of these is as follows: 

  • Extracellular vesicles are nanosized, membrane-bound particles which are naturally released from almost all types of cells. They can transport other molecules, such as DNA, RNA and proteins between cells as part of intracellular communication, particularly in immune system response. 
  • MircroRNAs (miRNA) are single-stranded non-coding RNA molecules which help regulate various biological processes including energy metabolism and immune system responses. 
  • Raman Spectroscopy is a laboratory analysis technique, and can for example provide information on chemical structure and molecular interactions. It is based upon the interaction of light with the chemical bonds within a material. 
  • Partial least squares discriminant analysis (PLS-DA) is a statistical method which is used to find the relationship between two variables. 

The findings of this study were limited by the small sample size, but the researchers hope to take these findings further, especially looking at the mechanisms involved in extracellular vesicles and microRNA. Furthermore, this is the second paper we have reported on recently looking at extracellular vesicles

We have also discussed this study on our Facebook page and hope that there will be a press release soon from Oxford University. 

Paper three (3) looks at changes in plasma metabolomics (study of the set of metabolites present within the blood) following exercise, showing disrupted response and recovery. The study used a two-day exercise event with four timepoints to explore the metabolic response.  

The most significant findings showed lipid and energy-related pathways and chemical structure clusters, which were differently affected by the first and second exercise sessions. Distinct to the ME/CFS cohort was that following the 24-hour recovery period, over one quarter of the pathways studied were shown to be statistically different, providing clues to metabolic disruption in post-exertional malaise (PEM). Many of these altered pathways are dependent on glutamate metabolism, which is crucial in organ homeostasis. 

This is a strong study with a lot of interesting findings and new insights into PEM, which is due to the methodology used allowing a range of different pathways to be studied. However, the study is limited by the sample size (60 ME/CFS, 45 controls), sex imbalanced (the authors expressed difficulty in recruiting male participants but took steps to minimise effect on results) but also pre-existing activity levels (controls were sedentary but that doesn’t mean activity is equal to ME/CFS patients). 

We have asked Nicola Baker to comment on this study as an expert in Cardiopulmonary Exercise Testing (CPET). 

You may also be interested in reading paper four (4) on predictors for developing severe ME/CFS following infectious mononucleosis. As well as paper six (6) which looks at the part of the brain known as the hippocampus and its role cognition and memory. 

ME/CFS Research References and Abstracts  

1. Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome With Partial Least Squares Discriminant Analysis: Relevance of Blood Extracellular Vesicles 

González-Cebrián A, Almenar-Pérez E, Xu J, Yu T, Huang WE, Giménez-Orenga K, Hutchinson S, Lodge T, Nathanson L, Morten KJ, Ferrer A and Oltra E  
Front. Med. 9:842991. 


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a chronic disease characterized by long-lasting persistent debilitating widespread fatigue and post-exertional malaise, remains diagnosed by clinical criteria.  

Our group and others have identified differentially expressed miRNA profiles in the blood of patients. However, their diagnostic power individually or in combinations seems limited.  

A Partial Least Squares-Discriminant Analysis (PLS-DA) model initially based on 817 variables: two demographic, 34 blood analytic, 136 PBMC miRNAs, 639 Extracellular Vesicle (EV) miRNAs, and six EV features, selected an optimal number of five components, and a subset of 32 regressors showing statistically significant discriminant power.  

The presence of four EV-features (size and z-values of EVs prepared with or without proteinase K treatment) among the 32 regressors, suggested that blood vesicles carry relevant disease information.  

To further explore the features of ME/CFS EVs, we subjected them to Raman micro-spectroscopic analysis, identifying carotenoid peaks as ME/CFS fingerprints, possibly due to erythrocyte deficiencies.  

Although PLS-DA analysis showed limited capacity of Raman fingerprints for diagnosis (AUC = 0.7067), Raman data served to refine the number of PBMC miRNAs from our previous model still ensuring a perfect classification of subjects (AUC=1).  

Further investigations to evaluate model performance in extended cohorts of patients, to identify the precise ME/CFS EV components detected by Raman and to reveal their functional significance in the disease are warranted. 

2. The Journey Towards Becoming Diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Patients’ Experiences 

Bo Christer Bertilson, Petra Christensson, Gabriella Bernhoff, Bo Christer Bertilson and Hanne Konradsen 
EC Neurology 14.2 (2022): 49-56. 

Background: Myalgic encephalomyelitis/chronic fatigue syndrome is a disease that negatively affects patients’ quality of life. Previous research has shown that these patients are commonly not taken seriously when seeking medical attention.  

Aim: The aim was to examine the experiences of patients with ME/CFS regarding their interaction with Swedish primary healthcare professionals. Method: The study used a qualitative and exploratory design, taking place in a specialist clinic in Sweden. Data consisted of interviews with 13 patients with ME/CFS, which were analysed using content analysis.  

Findings: For patients, it was Feeling truly connected during the period before they received a diagnosis. Time is an important factor, and in the phase from initial symptoms to diagnosis, Knowledge is power.  

Conclusion: Patients with ME/CFS were met with different levels of knowledge and interest from healthcare professionals. These challenges might be related to the relative unawareness and lack of knowledge of the disease and the underlying cultural scepticism still present. 


  • A continued relationship with a specific health care professional is important for patients who waits for a diagnosis. 
  • When a patient consultation is planned, it is important that the patient is given enough time to explain the situation from her/ his point of view. 
  • Patients value health care professionals who have specific knowledge of the impact of the disease they are treated for. 

3. Plasma metabolomics reveals disrupted response and recovery following maximal exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Germain A, Giloteaux L, Moore GE, Levine SM, Chia JK, Keller BA, Stevens J, Franconi CJ, Mao X, Shungu DC, Grimson A, Hanson MR.  
JCI Insight. 2022 Mar 31:e157621. [Epub ahead of print.] 


Post-exertional malaise (PEM) is a hallmark symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).  

We monitored the evolution of 1,157 plasma metabolites in 60 ME/CFS cases (45 females, 15 males) and in 45 matched healthy control subjects (30 females, 15 males) before and after two maximal Cardiopulmonary Exercise Test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients.  

Four timepoints allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of ME/CFS cases compared to the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds.  

Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid- as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions.  

The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component to the homeostasis of many organs in the body, including the brain. 

4. Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Following Infectious Mononucleosis 

Jason LA, Cotler J, Islam MF, Furst J, Katz BZ.  
J Rehabil Ther. 2022;4(1):1-5.  


Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM. 

Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM. Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM. We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of those who developed ME/CFS and severe ME/CFS following IM. 

Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM, were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM. 

Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS. 

5. A Causal-Pathway Phenotype of Chronic Fatigue Syndrome due to Hemodialysis in Patients with End-Stage Renal Disease 

Asad HN, Al-Hakeim HK, Moustafa SR, Maes M.  
CNS Neurol Disord Drug Targets. [Epub ahead of print.] 


Background: End-stage renal disease (ESRD) is associated with fatigue and physio-somatic symptoms. 

Objective: To delineate the associations between severity of fatigue and physio-somatic symptoms and glomerular filtration rate, inflammatory biomarkers, and Wnt/catenin-pathway proteins. 

Methods: The Wnt-pathway related proteins β-catenin, Dickkopf-related protein 1 (DKK1), R-spondin-1, and sclerostin were measured by ELISA technique in 60 ESRD patients and 30 controls. The Fibromyalgia and Chronic Fatigue Syndrome (FF) Rating Scale was used to assess the severity of FF symptoms. 

Results: ESRD is characterized by a significant increase in the total FF score, muscle tension, fatigue, sadness, sleep disorders, gastro-intestinal (GI) symptoms, and a flu-like malaise. The total-FF score was significantly correlated with serum levels of urea, creatinine, and copper (positively), and β-catenin, eGFR, hemoglobin, albumin, and zinc (inversely).  

The total-FF score was associated with the number of total dialysis and weekly dialysis sessions, and these dialysis characteristics were more important in predicting FF scores than eGFR measurements.  

Partial Least Squares analysis showed that the FF score comprised two factors that are differently associated with biomarkers: a) 43.0% of the variance in fatigue, GI symptoms, muscle tension, sadness, and insomnia is explained by hemoglobin, albumin, zinc, β-catenin, and R-spondin-1; and b) 22.3% of the variance in irritability, concentration and memory impairments by increased copper and cations/chloride ratio, and male sex. 

Conclusion: ESRD patients show high levels of fatigue and physio-somatic symptoms, which are associated with hemodialysis and mediated by dialysis-induced changes in inflammatory pathways, the Wnt/catenin pathway, and copper. 

6. Volumetric differences in hippocampal subfields and associations with clinical measures in myalgic encephalomyelitis/chronic fatigue syndrome 

Thapaliya K, Staines D, Marshall-Gradisnik S, Su J, Barnden L.  
J Neurosci Res. [Epub ahead of print.] 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients suffer from a cognitive and memory dysfunction. Because the hippocampus plays a key role in both cognition and memory, we tested for volumetric differences in the subfields of the hippocampus in ME/CFS.  

We estimated hippocampal subfield volumes for 25 ME/CFS patients who met Fukuda criteria only (ME/CFSFukuda ), 18 ME/CFS patients who met the stricter ICC criteria (ME/CFSICC ), and 25 healthy controls (HC).  

Group comparisons with HC detected extensive differences in subfield volumes in ME/CFSICC but not in ME/CFSFukuda . ME/CFSICC patients had significantly larger volume in the left subiculum head (p < 0.001), left presubiculum head (p = 0.0020), and left fimbria (p = 0.004).  

Correlations of hippocampus subfield volumes with clinical measures were stronger in ME/CFSICC than in ME/CFSFukuda patients.  

In ME/CFSFukuda patients, we detected positive correlations between fatigue and hippocampus subfield volumes and a negative correlation between sleep disturbance score and the right CA1 body volume.  

In ME/CFSICC patients, we detected a strong negative relationship between fatigue and left hippocampus tail volume. Strong negative relationships were also detected between pain and SF36 physical scores and two hippocampal subfield volumes (left: GC-ML-DG head and CA4 head).  

Our study demonstrated that volumetric differences in hippocampal subfields have strong statistical inference for patients meeting the ME/CFSICC case definition and confirms hippocampal involvement in the cognitive and memory problems of ME/CFSICC patients. 

7. A distinctive profile of family genetic risk scores in a Swedish national sample of cases of fibromyalgia, irritable bowel syndrome, and chronic fatigue syndrome compared to rheumatoid arthritis and major depression 

Kendler, K., Rosmalen, J., Ohlsson, H., Sundquist, J., & Sundquist, K. 
Psychological Medicine, 1-8.  


Background: Functional somatic disorders (FSD) feature medical symptoms of unclear etiology. Attempts to clarify their origin have been hampered by a lack of rigorous research designs. We sought to clarify the etiology of the FSD by examining the genetic risk patterns for FSD and other related disorders. 

Methods: This study was performed in 5 829 186 individuals from Swedish national registers. We quantified familial genetic risk for FSD, internalizing disorders, and somatic disorders in cases of chronic fatigue syndrome (CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS), using a novel method based on aggregate risk in first to fifth degree relatives, adjusting for cohabitation. We compared these profiles with those of a prototypic internalizing psychiatric – major depression (MD) – and a somatic/autoimmune disorder: rheumatoid arthritis (RA). 

Results: Patients with FM carry substantial genetic risks not only for FM, but also for pain syndromes and internalizing, autoimmune and sleep disorders. The genetic risk profiles for IBS and CFS are also widely distributed although with lower average risks. By contrast, genetic risk profiles of MD and RA are much more restricted to related conditions. 

Conclusion: Patients with FM have a relatively unique family genetic risk score profile with elevated genetic risk across a range of disorders that differs markedly from the profiles of a classic autoimmune disorder (RA) and internalizing disorder (MD). A similar less marked pattern of genetic risks was seen for IBS and CFS. FSD arise from a distinctive pattern of genetic liability for a diversity of psychiatric, autoimmune, pain, sleep, and functional somatic disorders. 

8. Metabolomics study of the effect of Danggui Buxue Tang on rats with chronic fatigue syndrome 

Miao X, Li S, Xiao B, Yang J, Huang R.  
Biomed Chromatogr. 2022 Apr 4:e5379. [Epub ahead of print.]  


Danggui Buxue Tang (DBT), a traditional Chinese medicine formula for “invigorating qi and enriching blood”, has been reported to produce a good effect on chronic fatigue syndrome (CFS).  

However, the related mechanism remains largely unresolved. In this study, a metabolomics approach with gas chromatography coupled to mass spectrometry combined with pattern recognition was devised to estimate the extent to which DBT alleviated CFS induced by food restriction and force swimming in rats.  

After four weeks of treatment, the endurance capability of rats was significantly better and the motionless time was significantly shorter in the DBT group than in CFS model group.  

Moreover, the activities of SOD and GSH-Px were increased, while the levels of MDA, IL-6 and TNF-α were decreased in the DBT treatment group. Fifteen significantly changed metabolites were observed in the serum of rats with CFS, which was reversed markedly by DBT treatment.  

Metabolic pathway analysis showed that DBT could possibly alleviate CFS in rats by regulating phenylalanine, tyrosine and tryptophan biosynthesis, glycine, serine and the metabolism of threonine, glycerolipid, glyoxylate, dicarboxylate and tyrosine.  

It was observed that the metabolism of glycine, serine and threonine was most closely related to the improvement of CFS by DBT treatment. This study showed that DBT could improve CFS effectively and metabolomics was a powerful means to gain insights into the traditional Chinese medicine formulas against CFS. 

Long-COVID Research References   

  1. “Like before, but not exactly”: the Qualy-REACT qualitative inquiry into the lived experience of long COVID 
  1. Representation of long COVID syndrome in the awareness of the population is revealed by Google Trends analysis 
  1. Persisting olfactory dysfunction in post-COVID-19 is associated with gustatory impairment: Results from chemosensitive testing eight months after the acute infection 
  1. Dietary Recommendations for Post-COVID-19 Syndrome 
  1. Histopathology of Persistent Long COVID Toe: A Case Report 
  1. Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates 
  1. New Clinical Phenotype of the Post-Covid Syndrome: Fibromyalgia and Joint Hypermobility Condition 
  1. Long COVID (post-COVID-19 condition) in children: a modified Delphi process 
  1. Long COVID and neuropsychiatric manifestations (Review) 
  1. Obesity and lipid metabolism disorders determine the risk for development of long COVID syndrome: a cross-sectional study from 50,402 COVID-19 patients 
  1. Cardiopulmonary Rehabilitation in Long-COVID-19 Patients with Persistent Breathlessness and Fatigue: The COVID-Rehab Study 
  1. COVCOG 1: Factors Predicting Physical, Neurological and Cognitive Symptoms in Long COVID in a Community Sample. A First Publication From the COVID and Cognition Study 
  1. COVCOG 2: Cognitive and Memory Deficits in Long COVID: A Second Publication From the COVID and Cognition Study 
  1. Post COVID fatigue: Can we really ignore it? 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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