The ME Association ME/CFS (& Long Covid) Weekly Research Round-up

July 3, 2021

The weekly research round-up now includes recent publications about ME/CFS and about Long Covid. We highlight several 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 and available to anyone.

This extensive library of research is normally updated at the end of each month, but with the change in staff, it will be updated again by 01 August 2021.

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 Published 19 June – 25 June 2021 

Six new research studies on ME/CFS have been published during this period and we have also included twelve studies on Long Covid. We highlight one on ME/CFS from the selection below: 

The second paper (2) looks at biomarkers which could be used in the future diagnosis of ME/CFS. The study looks at the function of two molecules which are involved in normal bodily function and their role in ME/CFS; a protein fibroblast involved in glucose homeostasis and lipid metabolism and a prohormone which is strongly associated with increased cardiovascular risk. The study used 21 ME/CFS patients and 20 matched healthy controls.  

Plasma showed significantly decreased total antioxidant capacity and increased lipoperoxide levels in ME/CFS patients and significantly increased levels of certain inflammatory cytokines, indicating low-grade systemic inflammation status. The circulating protein fibroblast and prohormone were also significantly higher in ME/CFS.  

In ME/CFS patients significant correlations (connection between two factors) were found between prohormone levels and inflammatory cytokines. The authors hypothesise that elevated protein fibroblast and prohormone levels and the association between prohormone levels and inflammation may be promising novel diagnostic and therapeutic targets in ME/CFS, but larger studies will be required before any firm conclusions might be drawn.

ME/CFS Research References and Abstracts 

1. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel the pathogenesis of post-acute COVID-19 syndrome 

Komaroff AL, Lipkin WI. Trends in Molecular Medicine. 2021 Jun 7:S1471-4914(21)00134-9. [Online ahead of print] 


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause chronic and acute disease. Post-acute sequelae of SARS-CoV-2 infection (PASC) include injury to the lungs, heart, kidneys, and brain that may produce a variety of symptoms. PASC also includes a post-coronavirus disease 2019 (COVID-19) syndrome (‘long COVID') with features that can follow other acute infectious diseases and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Here we summarize what is known about the pathogenesis of ME/CFS and of ‘acute' COVID-19, and we speculate that the pathogenesis of post-COVID-19 syndrome in some people may be similar to that of ME/CFS. We propose molecular mechanisms that might explain the fatigue and related symptoms in both illnesses, and we suggest a research agenda for both ME/CFS and post-COVID-19 syndrome. 

2. Are Circulating Fibroblast Growth Factor 21 and N-Terminal Prohormone of Brain Natriuretic Peptide Promising Novel Biomarkers in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome? 

 Domingo JC, Cordobilla B, Ferrer R, Giralt M, Alegre-Martín J, Castro-Marrero J. Antioxidants & Redox Signal. 2021 Jun 20;34(18):1420-1427. 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, disabling, and complex multisystem illness of unknown etiology. The protein fibroblast growth factor 21 (FGF21) regulates glucose homeostasis and lipid metabolism, and the protein N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is strongly associated with an elevated cardiovascular risk; however, little is known about their role in ME/CFS patients.

To address this gap, we explored the association between FGF21 and NT-proBNP and oxidative stress and inflammatory markers in ME/CFS. Twenty-one ME/CFS patients and 20 matched healthy controls were included in the study. Participants filled out validated self-reported questionnaires on their current health status covering demographic and clinical characteristics.

Plasma showed significantly decreased total antioxidant capacity and increased lipoperoxide levels (p = 0.009 and p = 0.021, respectively) in ME/CFS. These ME/CFS patients also had significantly increased levels of inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-10, TNF-α, and C-reactive protein) (p < 0.05 for all) but not for IL-8 (p = 0.833), indicating low-grade systemic inflammation status.

Circulating FGF21 and NT-proBNP levels were significantly higher (p < 0.0001 and p = 0.005, respectively) in ME/CFS patients than in healthy controls. Significantly positive correlations were found between NT-proBNP levels and IL-1β and IL-6 (p = 0.04 and p = 0.01) in ME/CFS patients but not between FGF21 and these cytokines. In contrast, no significant correlations were found for either FGF21 or NT-proBNP in controls.

These findings lead to the hypothesis that elevated FGF21 and NT-proBNP levels and the association between NT-proBNP and inflammation may be promising novel diagnostic and therapeutic targets in ME/CFS. 

3. Systematic Review of Mind-Body Interventions to Treat Myalgic Encephalomyelitis / Chronic Fatigue Syndrome  

Khanpour Ardestani, S.; Karkhaneh, M.; Stein, E.; Punja, S.; Junqueira, D.R.; Kuzmyn, T.; Pearson, M.; Smith, L.; Olson, K.; Vohra, S. Medicina 2021, 57, 652. 


Background and Objectives:Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic condition distinguished by disabling fatigue associated with post-exertional malaise, as well as changes to sleep, autonomic functioning, and cognition. Mind-body interventions (MBIs) utilize the ongoing interaction between the mind and body to improve health and wellbeing.  

Purpose: To systematically review studies using MBIs for the treatment of ME/CFS symptoms.

Materials and Methods: MEDLINE, EMBASE, CINAHL, PsycINFO, and Cochrane CENTRAL were searched (inception to September 2020). Interventional studies on adults diagnosed with ME/CFS, using one of the MBIs in comparison with any placebo, standard of care treatment or waitlist control, and measuring outcomes relevant to the signs and symptoms of ME/CFS and quality of life were assessed for inclusion. Characteristics and findings of the included studies were summarized using a descriptive approach.  

Results: 12 out of 382 retrieved references were included. Seven studies were randomized controlled trials (RCTs) with one including three reports (1 RCT, 2 single arms); others were single-arm trials.

Interventions included mindfulness-based stress reduction, mindfulness-based cognitive therapy, relaxation, Qigong, cognitive-behavioural stress management, acceptance and commitment therapy and isometric yoga. The outcomes measured most often were fatigue severity, anxiety/depression, and quality of life. Fatigue severity and symptoms of anxiety/depression were improved in nine and eight studies respectively, and three studies found that MBIs improved quality of life. 

Conclusions: Fatigue severity, anxiety/depression and physical and mental functioning were shown to be improved in patients receiving MBIs. However, small sample sizes, heterogeneous diagnostic criteria, and a high risk of bias may challenge this result. Further research using standardized outcomes would help advance the field.  

4. Medical Care Situation of People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in Germany.  

Froehlich, L.; Hattesohl, D.B.R.; Jason, L.A.; Scheibenbogen, C.; Behrends, U.; Thoma, M. Medicina 2021, 57, 646.  


Background and Objective: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe illness with the hallmark symptom of Post-Exertional Malaise (PEM). Currently, no biomarkers or established diagnostic tests for ME/CFS exist.

In Germany, it is estimated that over 300,000 people are affected by ME/CFS. Research from the United States and the UK shows that patients with ME/CFS are medically underserved, as they face barriers to medical care access and are dissatisfied with medical care.

The first aim of the current research was to investigate whether patients with ME/CFS are medically underserved in Germany in terms of access to and satisfaction with medical care. Second, we aimed at providing a German-language version of the DePaul Symptom Questionnaire Short Form (DSQ-SF) as a tool for ME/CFS diagnostics and research in German-speaking countries. 

Materials and Methods: The current research conducted an online questionnaire study in Germany investigating the medical care situation of patients with ME/CFS. The questionnaire was completed by 499 participants who fulfilled the Canadian Consensus Criteria and reported PEM of 14 h or longer.   

Results:Participants frequently reported geographic and financial reasons for not using the available medical services. Furthermore, they reported low satisfaction with medical care by the physician they most frequently visited due to ME/CFS. The German version of the DSQ-SF showed good reliability, a one-factorial structure and construct validity, demonstrated by correlations with the SF-36 as a measure of functional status.  

Conclusions: Findings provide evidence that patients with ME/CFS in Germany are medically underserved. The German-language translation of the DSQ-SF provides a brief, reliable and valid instrument to assess ME/CFS symptoms to be used for research and clinical practice in German-speaking countries. Pathways to improve the medical care of patients with ME/CFS are discussed.  

5. Graded Exercise Therapy for Patients with Chronic Fatigue Syndrome in Secondary care: a benchmarking study.  

Smakowski A, Adamson J, Turner T, Chalder T. Disability & Rehabilitation. 2021 Jun 22. 


Objective: We investigated the effectiveness of Graded Exercise Therapy (GET) delivered to patients with Chronic Fatigue Syndrome (CFS/ME) in a routine, specialist clinic by measuring patient-reported outcome data collected prospectively over several timepoints alongside therapy. Benchmarking analyses were used to compare our results with those found in randomized control trials (RCTs). 

Method:Data was collected from patients, with a diagnosis of CFS/ME, who had been referred to a specialist clinical service in South London. Measures included Chalder fatigue questionnaire, physical functioning subscale of the short-form health questionnaire and the work and social adjustment scale. Change on each measure was calculated over time using linear mixed-model analyses. Within group effect sizes were calculated and compared with previous RCT’s.

Results:Fatigue scores were significantly reduced by session 4 (-5.18, 95%CIs -7.90, -2.45) and at follow-up (-4.73, 95%CIs -7.60, -1.85). Work and social adjustment and physical functioning progressively improved over the course of therapy, reaching significance at discharge, and maintained at follow-up (WSAS -4.97, 95%CIs -7.97, -1.97; SF-36 10.75, 95%CIs 2.19, 19.31). 

Conclusions: GET is an effective treatment for CFS/ME within clinical practice. However, effect sizes were smaller in routine clinical practice than RCT’s suggesting that avenues for augmentation need to be considered.  

Long-COVID Research References  

  1. Persistent symptoms in Swedish children after hospitalisation due to COVID-19 
  2. SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals 
  3. The Conundrum of ‘Long-COVID-19': A Narrative Review 
  4. Long COVID in a prospective cohort of home-isolated patients 
  5. Acute and persistent symptoms in non-hospitalized PCR-confirmed COVID-19 patients 
  6. Reducing fatigue-related symptoms in Long COVID-19: finding an intervention that works 
  7. Learning to manage long covid 
  8. Getting to grips with long covid 
  9. The Neurological Manifestations of Post-Acute Sequelae of SARS-CoV-2 infection 
  10. A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection 
  11. Massage Therapy in the Time of COVID-19 
  12. COVID-19 and Chronic Disease: The Impact Now and in the Future 

Katrina Pears, Research Correspondent, ME Association

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