Research Roundup: ME/CFS Research Published 11 – 17 September 2021

September 23, 2021

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).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

 ME/CFS research is slowly starting to pick up again after the summer break, with five new research studies on ME/CFS and seven studies on Long Covid. We highlight two on ME/CFS from the selection below:    

The third study (3) looks at ME/CFS and joint hypermobility, as these conditions have always been thought to be associated (not causal, joint hypermobility doesn’t cause ME/CFS).  

The authors hypothesised that patients with joint hypermobility would have an earlier onset of ME/CFS, as well as increased severity. The study used 55 patients, unfortunately we cannot view the full article, but from the abstract it does not look like there was a control group, or comparison to patients with joint hypermobility but without ME/CFS or healthy controls.  Using a sample set of only people with ME/CFS and joint hypermobility is a limiting factor of this study.  

Of the sample set used in this study, no significant findings were found, concluding that despite joint hypermobility being a risk factor, joint hypermobility defined in this study was not associated with clinical characteristics of ME/CFS. 

The fourth study (4) looked into corticotropin-releasing factor receptor type 2 (CRFR2) which is a protein found in mammalian cells. When the system that involves the protein CRFR2 is under threat, the release of serotonin (5HT) is affected (the key hormone that stabilizes our mood, feelings of well-being, and happiness), 

The authors hypothesize that the abnormalities found in ME/CFS patients “could all originate from a single pathway, involving the corticotropinreleasing factor (CRF, also known as corticotropin-releasing hormone or CRH) system and its regulation of serotonin (5HT) in the limbic system, which controls the response to homeostatic threat.” 

This was a small study, using only 14 ME/CFS patients (again no healthy controls) but the findings support “the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.” (i.e. treatment with an acute dose of CRFR2.) 

ME/CFS Research References and Abstracts  

1. Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome  

Lutz L, Rohrhofer J, Zehetmayer S Stingl M, Untersmayr E  
Biomolecules 2021, 11, 1359  


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multi-systemic disease characterized by debilitating fatigue that is not relieved by rest. The causes of the disease are still largely unexplained, and no causative treatment is currently available. Changes in the immune response are considered as fundamental in the development of ME/CFS.  

Thus, we aimed to evaluate the immunological profile of ME/CFS patients in a retrospective data analysis.  

As part of the routine workup for ME/CFS patients, a differential blood count, leukocyte subtyping, and quantification of immunoglobulins and IgG subclasses, as well as a complement analysis, was performed.  

Out of 262 ME/CFS patients, 64.9% had a reduction or deficiency in at least one of the listed immune parameters. In contrast, 26.3% showed signs of immune activation or inflammation. A total of 17.6% of the ME/CFS patients had an unclassified antibody deficiency, with IgG3 and IgG4 subclass deficiencies as the most common phenotypes. Reduced MBL (mannose-binding lectin) levels were found in 32% of ME/CFS patients, and MBL deficiency in 7%.  

In summary, the present results confirmed the relevance of immune dysfunction in ME/CFS patients underlining the involvement of a dysfunctional immune response in the disease. Thus, immune parameters are relevant disease biomarkers, which might lead to targeted therapeutic approaches in the future. 

2. Clinical Profile and Aspects of Differential Diagnosis in Patients with ME/CFS from Latvia 

Krumina, A.; Vecvagare, K.; Svirskis, S.; Gravelsina, S.; Nora-Krukle, Z.; Gintere, S.; Murovska, M.  
Medicina2021, 57, 958. 


Background and objectives: There is still an uncertainty regarding the clinical symptomatology and the diagnostic criteria in terms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), as different diagnostic criteria exist. Our aim is to identify the core symptoms of ME/CFS in the outpatient setting in Riga; to distinguish symptoms in patients with ME/CFS and those with symptoms of fatigue; and to investigate patient thoughts on the onset, symptoms, treatment and effect of ME/CFS.  

Materials and methods: Total of 65 Caucasian patients from an ambulatory care setting were included in the study. Questionnaires, specialist evaluation of the patients and visual analogue scale (VAS) measurements were used to objectify the findings.  

Results: The study showed that ME/CFS with comorbidities is associated with a more severe disease. A negative correlation was found regarding an increase in age and number of current symptoms, as well as an increase in VAS score and the duration of fatigue and age in the ME/CFS without comorbidities group.  

Conclusions: Comorbidities tend to present with a more severe course of ME/CFS. Fatigue, myalgia, arthralgia and sleep disturbances tend to be more prevalent in the ME/CFS patients compared to the non-ME/CFS patients. VAS score has a tendency to decrease with age and duration of fatigue. Nonsteroidal anti-inflammatory drugs are the most commonly used pharmacological drug class that reduces ME/CFS symptoms. 

3. The Presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Influenced by the Presence or Absence of Joint Hypermobility 

Vogel SK, Primavera IR, Marden CL, Jasion SE, Cranston EM, Flaherty MAK, Violand RL, Rowe PC. 
J Pediatr. 2021 Sep 16:S0022-3476(21)00887-8. [Epub ahead of print.] 


Objective: To examine demographic and clinical characteristics of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with and without joint hypermobility We hypothesized that JH+ patients would have an earlier onset of ME/CFS symptoms as well as increased severity, greater number of co-morbid conditions, and lower health related quality of life. 

Study design: From an observational cohort study of 55 individuals meeting the Fukuda criteria for ME/CFS, we compared groups using a Beighton score cut-off of 4 or higher to indicate JH. Chart data were collected to examine the age and type of onset of ME/CFS, and the presence of comorbid conditions. The impact on quality of life was assessed through questionnaires that included the Peds QL, Functional Disability Inventory, Peds QL Multidimensional Fatigue Scale, and Anxiety Subscale of the Symptom Checklist 90. 

Results: There was no significant difference between groups in mean (SD) age at onset of ME/CFS (13.3 [3.3] years vs 13.3 [2.3] years; P = .92), sex, frequency, and severity of ME/CFS symptoms, orthostatic intolerance symptoms, or comorbid conditions. There was no significant difference between groups in measures of health-related quality of life using a Beighton score cut-off of 4 or a cut-off of 5 to define joint hypermobility. 

Conclusions: Despite being a risk factor for the development of ME/CFS, JH as defined in this study was not associated with other clinical characteristics of the illness. 

4Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Pereira G, Gillies H, Chanda S, Corbett M, Vernon SD, Milani T, Bateman L.  
Front Syst Neurosci. 2021 Sep 1;15:698240. [eCollection 2021] 


Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2. 

Materials and methods: This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms. 

Results: ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by -7.5 ± 1.9 (or -25.7%, p = 0.009), with all monitored symptoms improving. 

Conclusion: The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study. 

5Long COVID: Is it really myalgic encephalomyelitis? Bibliographic review and considerations 

Espinosa Rodríguez P, Martínez Aguilar A, Ripoll Muñoz MP, Rodríguez Navarro MÁ.  
Semergen. 2021 Sep 13:S1138-3593(21)00091-5. Spanish. [Epub ahead of print.] 
Article in Spanish  


Clinical sequelae of a disease as widespread as COVID-19 can be of great importance for primary care due to their prevalence and the morbidity they entail.  

The definition of long COVID and the establishment of its temporality are various, but some authors consider possible that this syndrome is actually myalgic encephalomyelitis.  

Similarities are observed when comparing the International Consensus Criteria for the diagnosis of myalgic encephalomyelitis with the symptoms described for long COVID. Blood tests, pulse oximetry, chest radiography, and thoracic ultrasound are recommended in patients with persistent symptoms after acute infection.  

Management in both conditions consists of treating the main symptoms. The possibility that COVID-19 can lead to a chronic condition such as myalgic encephalomyelitis makes long-term follow-up of patients who have suffered from this infection essential. 

Long-COVID Research References   

  1. Long COVID: current definition 
  2. Covid-19: Long covid must be recognised as occupational disease, says BMA 
  3. “Post-COVID syndrome”: The focus is on musculoskeletal pain 
  4. Long COVID or post COVID-19 syndrome 
  5. How Common Is Long COVID in Children and Adolescents? 
  6. Follow-Ups on Persistent Symptoms and Pulmonary Function Among Post-Acute COVID-19 Patients: A Systematic Review and Meta-Analysis 
  7. Association Between Psychological Distress, Cognitive Complaints, and Neuropsychological Status After a Severe COVID-19 Episode: A Cross-Sectional Study 

Katrina Pears, Research Correspondent, ME Association 

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