ME/CFS and Long Covid Research: 12 – 18 April 2022 

April 22, 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 by Dr Katrina Pears

ME/CFS Research Published 12 – 18 April 2022 

There have been five new ME/CFS studies and fourteen studies on Long Covid. There has been a range of different topics published this week but there is very little biomedical research. 

We highlight two of the studies below: 

Paper one (1) is a review on the use of molecular hydrogen (H2) as a treatment option. From the literature review carried out it is suggested that molecular hydrogen can help with mitochondrial dysfunction therefore help to alleviate fatigue, as well as having antioxidant and anti-inflammatory properties. However, there are very few studies that have been conducted on the use of molecular hydrogen for ME/CFS to fully evaluate its use, therefore this study only suggests this could be of benefit and needs further investigation. 

We have previously covered the use of hydrogen-enriched water as a treatment option, interestingly this study was not cited in this review. 

Paper two (2) looks at collecting data remotely (activity trackers) and using diaries to evaluate the fluctuating symptoms, activity and cardiac function of 148 individuals. We cannot access the full study as it is behind a paywall, but from what we can tell from the abstract it does not sound like a very strong study, for example: 

  • The term “uplifts and hassles” appears to be a term created for the study and not one we see in ME/CFS research. 
  • It doesn’t seem like any blood samples were taken. 
  • Published in Psychosomatic Medicine. 

This study showed that patients who reported non-improvements in health had greater autonomic dysfunction but their activity patterns didn’t differ. From this, the authors suggest “these findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS”, however, this seems like a big assumption with no biomedical investigations in the research.  

I am personally interested in paper ten (10) in the Long Covid reference section due to being a breastfeeding mother myself, which is a preliminary study to find whether or not breastfeeding may help change the outcomes of developing long covid in children. However, the study cannot find any association, it concludes that breastfeeding children is likely to reduce viral infections such as covid. There is a need to investigate the possible link between breastfeeding and protection against not only acute COVID-19 but also its long-term effects. 

As well as paper fourteen (14) which shows that Postural Orthostatic Tachycardia Syndrome (POTS) is uncommon in long covid, despite commonly reported orthostatic intolerance. 

ME/CFS Research References and Abstracts  

1. Molecular Hydrogen as a Medical Gas for the Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Possible Efficacy Based on a Literature Review 

Hirano S-i, Ichikawa Y, Sato B, Takefuji Y and Satoh F   
Front. Neurol. 13:841310 


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disorder that is characterized by fatigue that persists for more than 6 months, weakness, sleep disturbances, and cognitive dysfunction.  

There are multiple possible etiologies for ME/CFS, among which mitochondrial dysfunction plays a major role in abnormal energy metabolism.  

The potential of many substances for the treatment of ME/CFS has been examined; however, satisfactory outcomes have not yet been achieved. The development of new substances for curative, not symptomatic, treatments is desired.  

Molecular hydrogen (H2) ameliorates mitochondrial dysfunction by scavenging hydroxyl radicals, the most potent oxidant among reactive oxygen species.  

Animal experiments and clinical trials reported that H2 exerted ameliorative effects on acute and chronic fatigue. Therefore, we conducted a literature review on the mechanism by which H2 improves acute and chronic fatigue in animals and healthy people and showed that the attenuation of mitochondrial dysfunction by H2 may be involved in the ameliorative effects.  

Although further clinical trials are needed to determine the efficacy and mechanism of H2 gas in ME/CFS, our literature review suggested that H2 gas may be an effective medical gas for the treatment of ME/CFS. 

2. Non-improvement in chronic fatigue syndrome: relation to activity patterns, uplifts and hassles, and autonomic dysfunction 

Friedberg, Fred; Adamowicz, Jenna L.; Bruckenthal, Patricia; Milazzo, Maria; Ramjan, Sameera; Quintana, Daniel  
Psychosomatic Medicine: April 15, 2022 – Volume – Issue – 10.1097/PSY.0000000000001082 


Objective: To test a model of non-improvement in chronic fatigue syndrome (CFS) utilizing self-report activity patterns (e.g., “push-crash”), uplifts and hassles, and a biological measure of cardiac autonomic function. Activity pattern impacts on symptoms and objective measures of autonomic and physical activity were also examined. 

Methods: This prospective study in CFS collected all data remotely, including six months of weekly web diaries that recorded symptom ratings, activity patterns, and hassles and uplifts. In addition, six months of weekly heart monitoring and three months of daily waking actigraphy data were collected. Improvement or non-improvement status was assessed using semi-structured interviews at 6 months follow-up. 

Results: 148 individuals (87.2% female) were enrolled and 12.2% were lost to follow-up. Participants reporting non-improvement (n = 92), as compared to improvement (n = 38) showed greater autonomic dysfunction (lower heart rate variability [HRV], group difference = 5.93 (SE = 2.73) ms; p = .032) and lower mean intensity of behavioral uplifts (group difference = 0.14 (SE = 0.16); p = .043), but no significant differences in any activity pattern, including push-crash, limiting activity, and healthy pacing. 

Conclusions: This study provided evidence for linking patient-reported non-improvement to a biological variable indexing autonomic dysfunction and a behavioral measure indicating a deficit in psychological uplifts. These findings suggest a possible marker of illness trajectory that could potentially advance the biomedical underpinnings of CFS. 

3. Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS 

Soejima, Y.; Otsuka, Y.; Tokumasu, K.; Nakano, Y.; Harada, K.; Nakamoto, K.; Sunada, N.; Sakurada, Y.; Hasegawa, K.; Hagiya, H.; Ueda, K.; Otsuka, F.  
Medicina 2022, 58, 536.  


After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients.  

Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient’s fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection.  

Examination revealed a high Aging Male’s Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome.  

Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions.  

After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient’s symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness.  

Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome.  

In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH. 

4. The underlying sex differences in neuroendocrine adaptations relevant to Myalgic Encephalomyelitis Chronic Fatigue Syndrome 

Natalie Thomas, Caroline Gurvich, Katherine Huang, Paul R Gooley, Christopher W Armstrong  
Frontiers in Neuroendocrinology: 100995. In Press, Journal Pre-proof 


Introduction: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem disease characterised by severe and disabling new-onset symptoms of post-exertional malaise (PEM), fatigue, brain fog, and sleep dysfunction that lasts for at least six months.  

Accumulating evidence suggests that sex and endocrine events have a significant influence on symptom onset and moderation of ME/CFS, with female sex being one of the most consistent and credible predictive risk factors associated with diagnosis. Such sex differences suggest sex chromosomes and sex steroids may play a part in the development of the condition or moderation of symptoms, although this has yet to be explored in detail. 

Methods/Aims: This narrative review outlines sex differences in ME/CFS in terms of vulnerability factors and clinical phenotype and explores the known sex differences in neuroendocrine systems affected in ME/CFS and how this may relate to disease risk, onset, pathophysiology, and potential treatment avenues. 

Conclusions: There is clear evidence of a sex dimorphism with regards to prevalence (3:1 female preponderance), clinical phenotypes, and aetiological triggers prior to symptom onset of ME/CFS.  

Endocrinological events, particularly those throughout the female lifespan, are associated with ME/CFS and include reproductive menstrual cycle fluctuations, pregnancy, post-partum and perimenopause.  

Further, there is evidence for gonadal sex, adrenal stress and renal neuroendocrine systems as implicated in ME/CFS, including changes in estrogen, progesterone compounds, aldosterone, and cortisol levels, of which there are established sex differences.  

The broad effects of steroid hormones on the physiological systems may also speak to the diversity of ME/CFS symptomatology observed in patients. Further attention must be paid to sex, age, and steroid biology in ME/CFS. 

5. Health-related quality of life in Young People with Chronic fatigue syndrome/ Myalgic encephalomyelitis 

Similä, Wenche Ann 
Doctoral thesis 


Background: Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a disease that affects people of all ages. CFS/ME significantly limits the activity level of those affected, including in relation to physical activity, schooling, occupational life and social life.  

High levels of school absence among young people with CFS/ME result in loss of important learning and social development among peers. As such, there is increasing uncertainty about their future, and personal and socio-economic consequences could put them at risk of becoming disabled at a young age. Measurements of health-related quality of life (HRQoL), including being able to function in school, have shown that young people with CFS/ME score lower than their counterparts without CFS/ME. 

Aims: The overall aim of this project was to explore HRQoL among young people with CFS/ME, including the factors associated with HRQoL in relation to school and everyday life.  

More specifically, the aim was to firstly (Study1) examine HRQoL, including factors that are positively or negatively associated with HRQoL, in a cohort of young people with CFS/ME.  

Study 1, along with the previous literature, provided the basis for an in-depth study (Study 2) to investigate the positive and negative factors that young people with CFS/ME experience in school and everyday life.  

Based on the findings from Study 1 and Study 2, a third study (Study 3) was planned to explore teachers’, counsellors’ and school nurses’ experiences with educational and social adaptation at school for young people with CFS/ME. 

Method: To explore HRQoL and the factors associated with HRQoL among young people with CFS/ME (Studies 1 & 2), a cross-sectional survey- and interview-based study was conducted. The participants of the cross-sectional study were recruited to participate in the interview study.  

To explore the experiences of teachers, counsellors and school nurses with education and social adaptions at school for young people with CFS/ME (Study 3), an interview study was conducted with participants recruited among school personnel and school nurses in secondary school (educating students aged 13-16), high school (educating students aged 16-19) and educational psychological services (EPS). 

Results: A total of 63 participants were included in the cross-sectional study, 18 of whom participated in the interview study. A total of 12 participants were included in the interview study with the teachers, counsellors and school nurses. In the cross-sectional study (Study 1), young people with CFS/ME scored lower on HRQoL than their counterparts who were healthy or had other chronic diseases. Contact with school and teachers was associated with a higher HRQoL among young people with CFS/ME.  

This association could be due to that more contact resulted from adaptations of education and social life at school, or that fewer health problems due to CFS/ME had abled the young people to maintain the contact with school and teachers.  

In Study 2, it was found that an adapted plan for education and social life at school for young people with CFS/ME could increase the possibility of continuing schooling with peers. The lack of an adapted plan for education and social life at school could lead to increased school absence as well as loss of education, social contact and development among peers. Subsequently, this could lead to depressive thoughts and worry about the future.  

The school personnel and school nurses in Study 3 experienced that young people with CFS/ME lost confidence in school. The challenges experienced by school personnel included (1) understanding students’ needs before they received a diagnosis and before school personnel received information from healthcare providers and (2) maintaining the teacher–student relationship and (3) the continuity of teaching.  

In terms of measures for better management, early problematization of school absence, interdisciplinary collaboration on early measures, ensuring the maintenance of the teacher–student relationship and increasing CFS/ME-related competence in schools were proposed. These measures could contribute to prevent loss of function and school absence among young people with CFS/ME. 

Conclusion: HRQoL among young people with CFS/ME was associated with contact with school and teachers, but a causal relationship could not be proven.  

Interviews with young people with CFS/ME and school personnel suggested that interdisciplinary strategies for early adaptations to education and social life at school for young people with CFS/ME may benefit education and social development among peers for young people with CFS/ME. Lack of educational and social adaptations at school might lead to loss of education, social life and development among peers. 

Long-COVID Research References   

  1. Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review 
  1. Risk factors and multidimensional assessment of long COVID fatigue: a nested case-control study 
  1. Reducing fatigue-related symptoms in Long COVID-19: a preliminary report of a lymphatic drainage intervention 
  1. Increased risk of incident diabetes in patients with long COVID 
  1. Muscle dysfunction in the long coronavirus disease 2019 syndrome: Pathogenesis and clinical approach 
  1. Long COVID and Medicine's Two Cultures 
  1. Post-COVID-19 syndrome: persistent neuroimaging changes and symptoms 9 months after initial infection 
  1. Long-term outcomes of pediatric infections: from traditional infectious diseases to long Covid 
  1. Persistent symptoms after the first wave of COVID-19 in relation to SARS-CoV-2 serology and experience of acute symptoms: A nested survey in a population-based cohort 
  1. Modulating Role of Breastfeeding Toward Long COVID Occurrence in Children: A Preliminary Study 
  1. Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review 
  1. Long COVID and COVID-19 Omicron Variant in Children 
  1. Exploration of Occupational Problems and Concerns in Individuals with Long-Covid (Post-Acute Sequelae of SARS-CoV-2) 
  1. Orthostatic Intolerance in Adults Reporting Long COVID Symptoms Was Not Associated With Postural Orthostatic Tachycardia Syndrome 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent



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