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

June 8, 2021

Note: The round-up should have been published on Friday 04 June, but was delayed due to staff holiday. Please accept our apologies for any inconvenience.

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 June 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 15 May – 21 May 2021

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

Graded exercise therapy (GET) is a very controversial management technique for people with ME/CFS. The ME Association's position on GET is that we do not support its use as an intervention, and we welcomed its removal from the draft of the new NICE clinical guideline. This position has not altered as a result of this latest review (5).

White and Etherington attempt to examine concerns about GET via previously published trial data. The authors conclude that it, “probably is safe when properly prescribed and supervised.” They also say that more research is needed to establish the safest and most effective form of GET in ME/CFS.

The sixth paper (6) examined the pathology of ME/CFS and fibromyalgia (FM) due to the overlapping symptoms in the two conditions. The authors look at comparing the kynurenine pathway (which is involved in energy production in the body) in these two conditions.

It was found that the metabolites needed for this pathway differ between ME/CFS and FM patients, and also that there are differences in the metabolite ratios compared to healthy controls. The authors conclude that these findings may provide a target for treatment studies and prevention of developing these conditions in the future.

ME/CFS Research References and Abstracts

1. A proprietary herbal drug Young Yum Pill ameliorates chronic fatigue syndrome in mice

Yin C, Fu X, Chou J, Li J, Chen Y, Bai Y, Wu Y, Wu Y, Wang X, Yu Z-L
Phytomedicine, 2021, 153602 [Epub ahead of print]


Background: Chronic fatigue syndrome (CFS) is a complex disease with few effective and safe therapies. Young Yum Pill (YYP), a proprietary herbal drug, has been used to relieve CFS-like symptoms. The pharmacological basis of this application of YYP is unknown.

Purpose: This study aimed to investigate the pharmacological effects and mechanisms of action of YYP in a mouse model of CFS.

Study design and methods: A food restriction and exhaustive swimming-induced mouse CFS model was used to evaluate the effects of YYP. Lymphocyte proliferation was assessed by MTT assays. T-lymphocyte subsets were analyzed by flow cytometry. Serum biochemical parameters were determined using commercial kits. Protein levels were measured by immunoblotting.

Results: Intragastric administration of YYP (2.85, 5.70, 11.40 g/kg) daily for 21 consecutive days significantly prolonged swimming time and diminished body weight loss of CFS mice. Mechanistic investigations revealed that YYP increased thymus and spleen indices of CFS mice, enhanced proliferation of lipopolysaccharide- or concanavalin A-stimulated spleen lymphocytes, and increased CD3+CD4+ and CD3+CD8+ T-cells in the spleen. YYP increased glycogen content in gastrocnemius muscle and liver, and lowered levels of triglyceride, lactic acid and urea nitrogen in sera of CFS mice. YYP suppressed the elevation of serum level of malondialdehyde, the increase of activities of lactic dehydrogenase and creatine phosphokinase, and the decrease of activity of the serum antioxidant enzyme superoxide dismutase in CFS mice. Moreover, YYP upregulated protein level of activated AMPK in gastrocnemius muscle and liver of CFS mice.

Conclusions: YYP ameliorates CFS by reversing metabolic changes, reducing oxidative damage, and improving some immune function parameters in mice. This study provides pharmacological justifications for the use of YYP in treating fatigue, including CFS.

2. Identifying and Managing Suicidality in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Chu L, Elliott M, Stein E, Jason LA
Healthcare 2021, 9, 629.


Adult patients affected by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are at an increased risk of death by suicide. Based on the scientific literature and our clinical/research experiences, we identify risk and protective factors and provide a guide to assessing and managing suicidality in an outpatient medical setting. A clinical case is used to illustrate how information from this article can be applied.

Characteristics of ME/CFS that make addressing suicidality challenging include absence of any disease-modifying treatments, severe functional limitations, and symptoms which limit therapies. Decades-long misattribution of ME/CFS to physical deconditioning or psychiatric disorders have resulted in undereducated healthcare professionals, public stigma, and unsupportive social interactions. Consequently, some patients may be reluctant to engage with mental health care.

Outpatient medical professionals play a vital role in mitigating these effects. By combining evidence-based interventions aimed at all suicidal patients with those adapted to individual patients’ circumstances, suffering and suicidality can be alleviated in ME/CFS.

Increased access to newer virtual or asynchronous modalities of psychiatric/psychological care, especially for severely ill patients, may be a silver lining of the COVID-19 pandemic.

3. The Impact of Severe ME/CFS on Student Learning and K–12 Educational Limitations

Newton FR
Healthcare 2021, 9, 627


Children with ME/CFS who are severely ill are bedbound and homebound, and oftentimes also wheelchair-dependent. Very seriously affected children are often too sick for doctor’s office visits, let alone school attendance.

The most recent data estimate that 2–5% of children may be severely affected or bedridden. However, there is no recent research that confirms these numbers. The severely ill receive little help from their schools, and are socially isolated.

This article outlines several suggestions for the type of education that students with ME/CFS should be receiving and develops a preliminary sketch of the web of resources and emergent techniques necessary to achieve these outcomes.

4. Living with myalgic encephalomyelitis/chronic fatigue syndrome: Experiences of occupational disruption for adults in Australia

Bartlett C, Hughes JL, Miller L
British Journal of Occupational Therapy. May 2021


Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a poorly understood, highly stigmatised health condition that has widespread impacts on the individual. Currently, there is limited understanding of the ME/CFS experience from an occupational perspective within Australia. This study aimed to explore the lived experience of ME/CFS and subsequent disruption to occupational participation for adults living in Australia.

Methods: Using descriptive case study design, five participants with ME/CFS in Australia completed semi-structured interviews. Reflexive thematic analysis was used to analyse the qualitative data.

Findings: Themes identified were organised using the Person-Environment-Occupation model. Participants reported systemic changes to previous levels of physical, cognitive and affective functioning, resulting in significant occupational disruption and poor well-being. Occupational prioritisation was followed by a loss of occupations starting with leisure, then productivity and eventually self-care. Environmental barriers to participation included stigma and misunderstanding of ME/CFS, financial hardship, lack of appropriate health services and strains on personal support networks and relationships.

Conclusion: Changes to occupational performance following the onset of ME/CFS caused significant occupational disruption and resulted in limited participation which narrowed over time. There is a clear role for occupational therapy to intervene early to prevent significant negative impacts on occupational participation for people with ME/CFS.

5. Adverse outcomes in trials of graded exercise therapy for adult patients with chronic fatigue syndrome

White PD, Etherington J
Journal of Psychosomatic Research, 5 2021, 110533


• Participants were no worse after graded exercise therapy than control interventions.

• No more participants withdrew from graded exercise therapy than control interventions.

• More participants dropped out from trial follow up after graded exercise therapy.

• Graded exercise therapy probably is safe when properly prescribed and supervised.


Objectives: Graded exercise therapy (GET) is an effective treatment for chronic fatigue syndrome (CFS), but concerns have been raised about its safety. Two randomised controlled trials have not supported these concerns. We further assessed safety outcomes in all ten published trials of GET for CFS.

Methods: We undertook meta-analyses of three outcomes: Self-ratings of Clinical Global Impression (CGI) change scores of 6 or 7 (“much worse” or “very much worse”), numbers of participants withdrawing from treatments, and numbers of participants dropping out of trial follow up. We provide risk ratios (95% confidence intervals (CI)), comparing GET with control interventions.

Results: The 10 trials involved 1279 participants. CGI scores of 6 or 7 were reported by 14/333 (4%) participants after GET and 26/334 (8%) participants after control interventions (RR (CI): 0.62 (0.32, 1.17)). Withdrawals from treatment occurred in 64/535 (12%) participants after GET and 53/534 (10%) participants after control interventions (RR (CI):1.21 (0.86, 1.69)). Drop-outs from trial follow up occurred in 74/679 (11%) participants after GET and 41/600 (7%) participants after control interventions (RR (CI): 1.51 (1.03, 2.22)). The certainty of this evidence was rated low by GRADE, due to imprecision.

Conclusions: There was no evidence of excess harm with graded exercise therapy by either self-rated deterioration or by withdrawing from GET, in comparison to control interventions. More GET participants dropped out of trial follow up in comparison to control interventions. Future research should ascertain the most effective and safest form of graded exercise therapy.

6. Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls

Groven N, Reitan SK, Fors EA, Guzey IC
Psychneuroendocrinology 131, 105287


• Quinolinic acid differs between CFS and FM.

• The neuroprotective ratio kynurenic acid / 3-hydroxykykynurenine is lower in FM compared to healthy controls.

• The KAT II enzymatic activity (xanthurenic acid / 3-hydroxykynurenine) is lower in FM compared to healthy controls.

• BMI, fatigue and pain are related to kynurenine pathway metabolic concentrations.


Background: There is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the central nervous system (CNS), because of the neuroprotective or neurotoxic properties of certain metabolites, yet the role of each metabolite is not clear.

The pathology of Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) is currently under investigation, and the overlapping symptoms such as depression suggest that the CNS may be involved. These symptoms may be driven by enhanced neurotoxicity and/or diminished neuroprotection. However, the kynurenine metabolite status has not been well studied in these two possible related disorders of CFS and FM.

The objective of this study was to investigate the metabolites and ratios of the kynurenine pathway in CFS and FM compared to healthy controls and examine the possible correlations with symptoms of anxiety and depression.

Method: In this study, females aged 18–60 were included: 49 CFS patients; 57 FM patients; and 54 healthy controls. Blood plasma was analysed for the following metabolites involved in the kynurenine pathway: Tryptophan, kynurenine, kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid, xanthurenic acid (XA), 3-hydroxyanthranilic acid, quinolinic acid (QA) and picolinic acid. The concentrations of these metabolites, as well as the ratios of different metabolites indicating enzymatic activity, were compared between the groups. Findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results: QA differed between CFS and FM patients (β = .144, p = .036) and was related to higher levels of BMI (β = .017, p = .002). The neuroprotective ratio given by KA/QA was lower for CFS patients compared to healthy controls (β = −.211, p = .016). The neuroprotective ratio given by KA/HK was lower for FM patients compared to healthy controls, and this lower neuroprotective ratio was associated with increased symptoms of pain. The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (β = −.236, p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (β = −.015, p = .039). Symptoms of anxiety and depression were not associated with the metabolites or ratios studied.

Conclusion: Our study indicates associations between kynurenine metabolism and CFS and FM as well as characteristic symptoms like fatigue and pain. Forthcoming studies indicating a causative effect may place kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

7. Post-Exertional Malaise May Be Related to Central Blood Pressure, Sympathetic Activity and Mental Fatigue in Chronic Fatigue Syndrome Patients

Kujawski S, Słomko J, Hodges L, Pheby DFH, Murovska M, Newton JL, Zalewski P 
Journal of Clinical Medicine. 2021 May 26; 10 (11): 2327


Post-exertional malaise (PEM) is regarded as the hallmark symptom in chronic fatigue syndrome (CFS). The aim of the current study is to explore differences in CFS patients with and without PEM in indicators of aortic stiffness, autonomic nervous system function, and severity of fatigue.

One-hundred and one patients met the Fukuda criteria. A Chronic Fatigue Questionnaire (CFQ) and Fatigue Impact Scale (FIS) were used to assess the level of mental and physical fatigue. Aortic systolic blood pressure (sBPaortic) and the autonomic nervous system were measured with the arteriograph and Task Force Monitor, respectively.

Eighty-two patients suffered prolonged PEM according to the Fukuda criteria, while 19 did not. Patients with PEM had higher FIS scores (p = 0.02), lower central systolic blood pressure (p = 0.02) and higher mental fatigue (p = 0.03). For a one-point increase in the mental fatigue component of the CFQ scale, the risk of PEM increases by 34%. For an sBPaortic increase of 1 mmHg, the risk of PEM decreases by 5%. For a one unit increase in sympathovagal balance, the risk of PEM increases by 330%.

Higher mental fatigue and sympathetic activity in rest are related to an increased risk of PEM, while higher central systolic blood pressure is related to a reduced risk of PEM. However, none of the between group differences were significant after FDR correction, and therefore conclusions should be treated with caution and replicated in further studies.

8. Analysis of Gender Differences in HRV of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Using Mobile-Health Technology

Capdevila L, Castro-Marrero J, Alegre J, Ramos-Castro J, Escorihuela RM
Sensors (Basel, Switzerland). 2021 May 28;21(11):3746


In a previous study using mobile-health technology (mHealth), we reported a robust association between chronic fatigue symptoms and heart rate variability (HRV) in female patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

This study explores HRV analysis as an objective, non-invasive and easy-to-apply marker of ME/CFS using mHealth technology, and evaluates differential gender effects on HRV and ME/CFS core symptoms.

In our methodology, participants included 77 ME/CFS patients (32 men and 45 women) and 44 age-matched healthy controls (19 men and 25 women), all self-reporting subjective scores for fatigue, sleep quality, anxiety, and depression, and neurovegetative symptoms of autonomic dysfunction.

The inter-beat cardiac intervals are continuously monitored/recorded over three 5-min periods, and HRV is analyzed using a custom-made application (iOS) on a mobile device connected via Bluetooth to a wearable cardiac chest band.

Male ME/CFS patients show increased scores compared with control men in all symptoms and scores of fatigue, and autonomic dysfunction, as with women in the first study. No differences in any HRV parameter appear between male ME/CFS patients and controls, in contrast to our findings in women. However, we have found negative correlations of ME/CFS symptomatology with cardiac variability (SDNN, RMSSD, pNN50, LF) in men. We have also found a significant relationship between fatigue symptomatology and HRV parameters in ME/CFS patients, but not in healthy control men.

Gender effects appear in HF, LF/HF, and HFnu HRV parameters. A MANOVA analysis shows differential gender effects depending on the experimental condition in autonomic dysfunction symptoms and HF and HFnu HRV parameters. A decreased HRV pattern in ME/CFS women compared to ME/CFS men may reflect a sex-related cardiac autonomic dysfunction in ME/CFS illness that could be used as a predictive marker of disease progression.

In conclusion, we show that HRV analysis using mHealth technology is an objective, non-invasive tool that can be useful for clinical prediction of fatigue severity, especially in women with ME/CFS.

Long-COVID Research References

  1. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments
  2. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study
  3. Recovery from COVID-19: a sprint or marathon? 6-month follow-up data from online long COVID-19 support group members
  4. Living with long Covid: some reflections 14 months down the line
  5. Characteristics and predictors of acute and chronic post-COVID syndrome: A systematic review and meta-analysis
  6. Unravelling Pathophysiology of Neurological and Psychiatric Complications of COVID-19 Using Brain Organoids
  7. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments
  8. Legacy of COVID-19 infection in children: long-COVID will have a lifelong health/economic impact
  9. Skeletal muscle weakness in older adults home-restricted due to COVID-19 pandemic: a role for full-body in-bed gym and functional electrical stimulation
  10. Long COVID-19 Syndrome Precaution and Management
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