MEA Research Roundup

ME/CFS and Long Covid Research: 28 June – 04 July 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 Dr Katrina Pears

ME/CFS Research Published 28 June – 4 July 2022 

Firstly, I would like to apologies for no weekly roundup last week, as I was taking a week’s holiday. 

There have been five new ME/CFS studies and thirteen studies on Long Covid this week. 

We have also included a list of the titles of ME/CFS research which were published in the previous week, with six new research studies. 

We have highlighted two of the studies below from this week’s published research: 

Paper one (1) looks at using oxaloacetate for treating mental and physical fatigue. Oxaloacetate is an energy metabolite found in every cell of the human body, playing a key role in the process of providing energy to the mitochondria. 

The premise of this study looks promising, with a reduction of fatigue, both physically and mentally over the 6-weeks of treatment, however, when delving deeper into this study, quite a few flaws can be found. For example: 

  • The Chalder Fatigue Scale was used to measure fatigue, which does not provide fair representation of fatigue levels (more about problems with the Chalder Scale can be read here). 
  • No real control group was used as results were compared to a historical placebo group from a previous trail using a different drug, therefore the paper is incorrectly labelled as a controlled trial. 
  • The study was funded Terra Biological LLC which Alan Cash is the founder of and also the lead author on this paper. This questions if this research is to boost the marketing of the product especially as he was the sole researcher who analysed and interpreted results. 
  • A number of participants dropped out during the trail, and this might be to the huge cost associated with this treatment, for this 6-week course this ranges between £380 to £760. (See information here.) 
  • There are also concerns about the theoretical basis of this work, where cell biology can not make use of the extra oxaloacetate in the way implied in this study, especially in low does. (More information on the biochemistry can be found here.) 

In conclusion, in summarising the evidence available on this trail, I do not think this will lead to any new promising treatments. 

Paper two (2) is shows the clinical similarities between ME/CFS and Long Covid. From reading the study, I do not feel this tells us anything new, despite the authors claims of this being the first study to diagnose ME/CFS after covid, as well as showing the prevalence of ME/CFS in this set of patients, which was seen to be 16.8%. Although, a strong point of this study is that face-to-face examinations were used to fully rule out other conditions, however, this study is on a set of patients referred to one clinic only. 

The study did also show that fatigue and PEM (post-exertional malaise) are symptoms that are more important for ME/CFS than are other post COVID-19 condition symptoms. Other symptoms, such as dizziness, insomnia and headache were not so commonly reported in this study. However, I do not know how the prevalence of these symptoms fit with the overall ME/CFS population and if there are distinct subsets where ME/CFS develops after a covid infection. Therefore, more investigation is needed to show how symptoms vary. 

This study adds to the building evidence showing the striking resemblance between Long Covid and ME/CFS, which will hopefully lead to more research in this area. The ME Association takes the view that Long Covid and ME/CFS are both examples of a serious and debilitating condition that can follow any type of viral infection.  

You may also be interested in papers three (3) and four (4) which are from the well-known research group in the Netherlands, with the lead author van Campen. This research group is commonly seen to investigate cardiac function especially in relation to orthostatic intolerance. These two new studies are on deconditioning in orthostatic intolerance and resting heart rate in ME/CFS, respectively. 

ME/CFS Research References and Abstracts  

1. Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial 

Cash A, Kaufman DL.  
J Transl Med20, 295 (2022). 


Background: There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue. 

Methods: ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection. 

Results: 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks. 

Conclusions: Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. 

2. Clinical Characteristics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Diagnosed in Patients with Long COVID 

Tokumasu K, Honda H, Sunada N, Sakurada Y, Matsuda Y, Yamamoto K, Nakano Y, Hasegawa T, Yamamoto Y, Otsuka Y, Hagiya H, Kataoka H, Ueda K, Otsuka F. 
Medicina 2022, 58, 850 


Background and Objectives: COVID-19 can be serious not only in the acute phase but also after the acute phase and some patients develop ME/CFS. There have been few studies on patients with long COVID in whom ME/CFS was diagnosed by physicians based on standardized criteria after examinations and exclusion diagnosis and not based on only subjective symptoms. The purpose of this study was to elucidate the detailed characteristics of ME/CFS in patients with long COVID.  

Materials and Methods: A retrospective descriptive study was performed for patients who visited a COVID-19 aftercare clinic established in Okayama University Hospital during the period was from February 2021 to April 2022.  

Results: Clinical data were obtained from medical records for 281 patients, and 279 patients who met the definition of long COVID were included. The overall prevalence rate of ME/CFS diagnosed by three sets of ME/CFS criteria (Fukuda, Canadian and IOM criteria) was 16.8% (48.9% in male and 51.1% in females).  

The most frequent symptoms in ME/CFS patients were general fatigue and post-exertional malaise (89.4% of the patients), headache (34.0%), insomnia (23.4%), dysosmia (21.3%) and dysgeusia (19.1%). Dizziness, chest pain, insomnia and headache were characteristic symptoms related to ME/CFS.  

The male to female ratio in ME/CFS patients was equal in the present study, although ME/CFS was generally more common in women in previous studies. 

Given that patients with ME/CFS had more severe conditions in the acute phase of COVID-19, the severity of the acute infectious state might be involved in the pathophysiology of ME/CFS.  

Conclusion: The prevalence rate of ME/CFS and the characteristic sequelae in the long COVID condition were revealed in this study. 

3. Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance 

Van Campen, C (Linda) M.C.; Visser, Frans C. 
Medical Research Archivesv. 10, n. 6.  


Background: Orthostatic intolerance (OI) is a core finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Deconditioning is often proposed as an important determinant for OI.  

Deconditioning can be objectively classified using the predicted peak oxygen consumption (%VO2 peak) values as derived from cardiopulmonary exercise testing (CPET) and OI can be objectively quantified using cerebral blood flow (CBF) changes during tilt testing. Therefore, if deconditioning contributes to OI, a correlation between peak VO2 and the %CBF reduction is expected. 

Methods and results: 18 healthy controls (HC) and 122 ME/CFS patients without hypotension or tachycardia on tilt testing were studied.  

Deconditioning was classified as follows: %VO2 peak ≥85%= no deconditioning, %VO2 peak 65-85%= mild deconditioning, %VO2 peak<65%= severe deconditioning.  

HC had higher %VO2 peak compared to ME/CFS patients (p<0.0001). ME/CFS patients had significantly larger CBF reduction than HC (p<0.0001).  

No relation between the degree of deconditioning by the %VO2 peak and the %CBF reduction in ME/CFS patients was found.  

Moreover, we separately analyzed ME/CFS patients without an abnormal CBF reduction. Despite equal CBF reductions compared to HC and large differences between these patients and the patients with an abnormal CBF reduction, cardiac index (CI) changes (measured by suprasternal Doppler) were significantly less compared to ME/CFS patients with an abnormal CBF reduction (p<0.0001) but larger than in HC (p=0.004).  

Despite these different hemodynamic findings, %VO2 values were not different between the two patient groups, argumenting again against the causative role of hemodynamic abnormalities in deconditioning.  

Conclusion: In ME/CFS patients without hypotension or tachycardia there is no relation between the %VO2 peak during CPET and the %CBF and %CI reduction during tilt testing, whether or not patients have an abnormal CBF reduction during tilt testing. It suggests again that deconditioning does not play an important role in OI. 

4. The higher resting heart rate in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients compared to healthy controls: relation with stroke volumes 

Campen C and Visser F.  
Medical Research Archives 10 (6) 


Introduction: In patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) a higher-than-normal resting heart rate has been reported in a number of studies.  

As heart rate is linked to stroke volume, the present study explored the relationship between the supine heart rate and stroke volume index in healthy controls and in ME/CFS patients.  

Moreover, as patients with a postural orthostatic tachycardia syndrome (POTS) during tilt testing, have a higher supine heart rate than patients with a normal heart rate and blood pressure response during tilting, these two patient groups were also compared. 

Methods and results: From a database of individuals who had undergone tilt-testing, including supine Doppler measurements for stroke volume index calculation, we selected ME/CFS patients and healthy controls without evidence of hypotension or syncope.  

474 ME/CFS patients were analyzed, 314 with a normal heart rate and blood pressure response and 160 with POTS during tilt-testing, and 56 healthy controls.  

Resting stroke volume indices were similar between the 3 groups. All 3 groups had an inverse relation between the resting stroke volume index and resting heart rate (all p<0.0001).  

The slope of the relation was not significantly different between the 3 groups. Using the upper limit of the 95% prediction interval for the heart rate of healthy controls, 46 (15%) of patients with a normal heart rate and blood pressure response had a resting heart rate above the upper limit, 248 (85%) a heart rate between the upper and lower limit.  

In 47 (29%) patients developing POTS the resting heart rate was above the upper limit, and in 113 (71%) patients within the upper limit and lower limit. This distribution was significantly different between the two patient groups (p=0.0001). 

Conclusion: Patients and healthy controls showed a significant and inverse relation between the SVI and heart rate at rest.  

Already at rest heart rate in patients developing POTS during tilt-testing were higher compared to the patients with a normal heart rate and blood pressure response per unit of SVI, but the heart rate of the majority of all patients fell within the limits of normal of healthy controls.  

The difference of patients with heart rate above the upper limit versus between the upper limit and lower limit deserves further investigation and may have therapeutic implications. 

5. Identifying disrupted biological factors and patient-tailored interventions for chronic fatigue in adolescents and young adults with Q-Fever Fatigue Syndrome, Chronic Fatigue Syndrome and Juvenile Idiopathic Arthritis (QFS-study): study protocol for a randomized controlled trial with single-subject experimental case series design 

Anouk Vroegindeweij, Joost F. Swart, Jan Houtveen, Niels Eijkelkamp, Elise M. Van De Putte, Nico M. Wulffraat, Sanne L. Nijhof 
ResearchSqaure (Preprint) 


Background: Chronic fatigue with a debilitating effect on daily life is a frequently reported symptom among adolescents and young adults with a history of Q-fever infection (QFS).  

Persisting fatigue after infection may have a biological origin with psychological and social factors contributing to the disease phenotype. This is consistent with the biopsychosocial framework, which considers fatigue to be the result of a complex interaction between biological, psychological and social factors. In line, similar manifestations of chronic fatigue are observed in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) and Juvenile Idiopathic Arthritis (JIA).  

Cognitive behavioural therapy is often recommended as treatment for chronic fatigue, considering its’ effectiveness on the group-level. However, not everybody benefits on the individual level. More treatment success at the individual level might be achieved with patient-tailored treatments that incorporate the biopsychosocial framework.  

Methods: In addition to biological assessments of blood, stool, saliva, and hair, the QFS-study consists of a randomized controlled trial (RCT) in which a single-subject experimental case series (N = 1) design will be implemented using Experience Sampling Methodology in fatigued adolescents and young adults with QFS, CFS/ME and JIA (aged 12–29).  

With the RCT design, the effectiveness of patient-tailored PROfeel lifestyle advices will be compared against generic dietary advices in reducing fatigue severity at the group-level.  

Pre-post analyses will be conducted to determine relevance of intervention order. By means of the N = 1 design, effectiveness of both advices will be measured at the individual level.  

Discussion: The QFS-study is a comprehensive study exploring disrupted biological factors and patient-tailored lifestyle advices as intervention in adolescent and young adults with QFS and similar manifestations of chronic fatigue.  

Practical or operational issues are expected during the study, but can be overcome through innovative study design, statistical approaches, and recruitment strategies. Ultimately, the study aims to contribute to biological research and (personalized) treatment in QFS and similar manifestations of chronic fatigue. 

ME/CFS Research References Published 21 – 27 June 2022 

  1. Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 
  1. Semen raphani weakened the action of ginseng under chronic fatigue condition 
  1. Mental health screening in adolescents with CFS/ME 
  1. Why Should ACT Work When CBT Has Failed? a Study Assessing Acceptability and Feasibility of Acceptance and Commitment Therapy (ACT) for Paediatric Patients With Chronic Fatigue Syndrome/myalgic Encephalomyelitis (CFS/ME) 
  1. Dietary supplements, daily nutrient intake, and health-related quality of life among people with myalgic encephalomyelitis/chronic fatigue syndrome 
  1. Memory impairments in chronic fatigue syndrome patients 

Long-COVID Research References (28 June – 4 July 2022) 

  1. Disorders of gut-brain interaction in post-acute COVID-19 syndrome 
  1. Functional decline, long term symptoms and course of frailty at 3-months follow-up in COVID-19 older survivors, a prospective observational cohort study 
  1. Evidence of previous SARS-CoV-2 infection in seronegative patients with long COVID 
  1. Rationale for Nicotinamide Adenine Dinucleotide (NAD+) Metabolome Disruption as a Pathogenic Mechanism of Post-Acute COVID-19 Syndrome 
  1. Bridging Knowledge Gaps in the Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19 
  1. COVID fog demystified 
  1. Long COVID burden and risk factors in 10 UK longitudinal studies and electronic health records 
  1. High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19 
  1. Long COVID, audiovestibular symptoms and persistent chemosensory dysfunction: a systematic review of the current evidence 
  1. Disorders of gut-brain interaction in post-acute COVID-19 syndrome 
  1. Rapid improvement in severe long COVID following perispinal etanercept 
  1. Post-acute Sequelae of SARS-CoV-2 Infection: A Neglected Public Health Issue 
  1. A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



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