MEA Research Roundup

ME/CFS and Long Covid Research: 16 – 22 August 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 16 – 22 August 2022 

It’s certainly been a busy week for research, with no quiet period over the summer holidays. There have been eight new ME/CFS studies and sixteen studies on Long Covid. Paper five (5) included in this roundup is actually a book chapter, but it is included out of interest as it covers healthcare prevision in ME/CFS and Long Covid. 

We have highlighted two studies below: 

Paper three (3) is on impaired cation channel function, specifically transient receptor potential melastatin 3 (TRPM3) in natural killer cells (NK), which have been shown to be impaired in ME/CFS.  TRPM3 is a non-selective cation channel (positively charged ions) and is highly permeable to calcium (Ca2+) which is fundamental to many biological processes, such as cell division and apoptosis (programmed death of cells). It is the activity through this cation channel that was measured in this study, as well as determining whether the function differs between ME/CFS and Long Covid patients. 

Despite there being few laboratory studies looking at ME/CFS and Long Covid cells in detail simultaneously, this study was small, with 5 ME/CFS patients, 5 Long Covid and 5 healthy controls. Studies have previously supported this dysfunction of the TRPM3 cation channel function in ME/CFS. However, this study reinforced the biological similarities between ME/CFS and Long Covid, showing that ME/CFS patients and Long Covid patients were not significantly different but differed from healthy controls. However, much larger studies are needed to confirm this, and whether the findings differ in patients who have recovered from Covid-19, especially seeing that the majority of the population have had a Covid-19 infection. 

Paper six (6) is a preprint paper (hasn’t undergone peer-review so the science has not been verified) on autoimmune gene expression. This study is fairly exciting as it was conducted in the home environment where participants were posted a sample kit, meaning that the study could include participants with a range of different severities. In total there were 166 ME/CFS participants, with almost half being house or bed-bound and 83 controls. The study also looked at known viruses associated with ME/CFS, such as the herpesvirus (HHV) and Epstein-Barr virus (EBV). 

A range of interesting results were found, with up regulation of certain genes in the bedridden patients with ME/CFS, but also in those without ME/CFS but with other conditions making them bedbound. Surprisingly though only 7 patients with ME/CFS also had HHV and 1 had EBV. The main outcome from this study was the ability to identify between different severity levels of disease. 

Despite the results being promising in this study, it is confusing why in this study which aimed to look at autoimmune genes in ME/CFS that the researchers knowingly included participants who already had a known autoimmune disease diagnosis, which would ultimately effect results. Therefore, in order to make the implications clearer, a study without other autoimmune diseases included is needed. 

You may also be interested in reading paper two (2) in the Long Covid reference section which is on blood abnormalities in people with Long Covid. There is an easy to read article which has been published in Science on this research. 

ME/CFS Research References and Abstracts  

1. Generalized Worry in Patients With Chronic Fatigue Syndrome Following Cognitive Behavioral Therapy: A Prospective Cohort Study in Secondary Care 

Kalfas M, Smakowski A, Hirsch C, Simiao F, Chalder T.  

Behav Ther. 2022 Sep;53(5):828-842. 


  • Generalized worry is highly prevalent in Chronic Fatigue Syndrome (CFS). 
  • Worry was linked with greater fatigue, anxiety, and worse work and social adjustment. 
  • Avoidance behavior mediated the association of worry with work and social adjustment. 
  • Cognitive behavioral therapy may need to focus more on generalized worry in CFS. 


Research has shown that generalized anxiety disorder is commonly associated with Chronic Fatigue Syndrome (CFS).  

This prospective cohort study aimed to investigate the prevalence of generalized worry in CFS patients and its relationship with fatigue, anxiety and social functioning, before and after Cognitive Behavioral Therapy (CBT).  

Our cohort consisted of 470 patients diagnosed with CFS who received CBT at a secondary care, specialist clinic. Patients completed self-report measures investigating levels of generalized worry, fatigue, work and social adjustment, anxiety and depression at baseline (pretreatment), discharge from treatment, 3-month and 6-month follow up (posttreatment).  

Analysis indicated a high prevalence of generalized worry (72.4%) at assessment.  

A significant reduction in worry following CBT (M = -3.42, p < .001, 95% CIs: 2.26, 4.57) was observed at discharge, which remained stable at follow-up. Severe baseline worriers had greater overall fatigue score (M = 3.74, p = .026, 95% CIs: .33, 7.15) and worse overall work and social adjustment than mild worriers across time-points (M = 5.42, p = .035 95% CIs: .27, 10.58).  

Avoidance behavior mediated the association between generalized worry and work and social adjustment (95% bootstrap CIs: 013, .080).  

The majority of patients with CFS had comorbid generalized worry and severe worriers reported greater fatigue, anxiety, and worse work and social adjustment. This suggests that CFS patients may benefit from targeting generalized worry during CBT. 

2. 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 

Vroegindeweij A, Swart JF, Houtveen J, Eijkelkamp N, van de Putte EM, Wulffraat NM, Nijhof SL.  

Trials. 2022 Aug 19;23(1):683. 


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 behavioral 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. 

3. Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients 

Sasso EM, Muraki K, Eaton-Fitch N, Smith P, Lesslar OL, Deed G, Marshall-Gradisnik S. 

Mol Med. 2022 Aug 19;28(1):98. 


Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic condition associated with post-infectious onset, impaired natural killer (NK) cell cytotoxicity and impaired ion channel function, namely Transient Receptor Potential Melastatin 3 (TRPM3).  

Long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has resulted in neurocognitive, immunological, gastrointestinal, and cardiovascular manifestations recently recognised as post coronavirus disease 2019 (COVID-19) condition.  

The symptomatology of ME/CFS overlaps significantly with post COVID-19; therefore, this research aimed to investigate TRPM3 ion channel function in post COVID-19 condition patients. 

Methods: Whole-cell patch-clamp technique was used to measure TRPM3 ion channel activity in isolated NK cells of N = 5 ME/CFS patients, N = 5 post COVID-19 patients, and N = 5 healthy controls (HC). The TRPM3 agonist, pregnenolone sulfate (PregS) was used to activate TRPM3 function, while ononetin was used as a TRPM3 antagonist. 

Results: As reported in previous research, PregS-induced TRPM3 currents were significantly reduced in ME/CFS patients compared with HC (p = 0.0048). PregS-induced TRPM3 amplitude was significantly reduced in post COVID-19 condition compared with HC (p = 0.0039).  

Importantly, no significant difference was reported in ME/CFS patients compared with post COVID-19 condition as PregS-induced TRPM3 currents of post COVID-19 condition patients were similar of ME/CFS patients currents (p > 0.9999). Isolated NK cells from post COVID-19 condition and ME/CFS patients were resistant to ononetin and differed significantly with HC (p < 0.0001). 

Conclusion: The results of this investigation suggest that post COVID-19 condition patients may have impaired TRPM3 ion channel function and provide further evidence regarding the similarities between post COVID-19 condition and ME/CFS.  

Impaired TRPM3 channel activity in post COVID-19 condition patients suggest impaired ion mobilisation which may consequently impede cell function resulting in chronic post-infectious symptoms. Further investigation into TRPM3 function may elucidate the pathomechanism, provide a diagnostic and therapeutic target for post COVID-19 condition patients and commonalities with ME/CFS patients. 

4. Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study 

Joustra ML, Hartman CA, Bakker SJL, Rosmalen JGM.  

Psychosom Med. 2022 Aug 2. [Epub ahead of print.] 


Objective: This study examined cognitive task performance and self-reported cognitive functioning in individuals with chronic fatigue syndrome (CFS) and fibromyalgia (FM) in a population-based sample and investigated the role of mood and anxiety disorders as well as severity of the physical symptoms. 

Methods: This study was performed in 79,966 participants (Mean age: 52.9, SD = ±12.6 years, 59.2% women) from the Lifelines general-population. Symptoms consistent with the diagnostic criteria for CFS and FM were assessed using questionnaires.  

Two comparison groups were used: participants with self-reported medical disorders with well-defined pathophysiology (i.e., multiple sclerosis and rheumatic arthritis) and controls without these diseases.  

Objective task-performance was based on the computerized CogState cognitive battery and subjective cognitive symptoms using the concentration subscale of the Checklist Individual Strength. 

Results: Cognitive task performance was poorer in individuals with CFS vs. controls without disease and controls with a medical disorder, although the severity of cognitive dysfunction was mild.  

Participants meeting criteria for CFS (n = 2,461) or FM (n = 4,295) reported more subjective cognitive symptoms compared to controls without a medical disorder (d = 1.53, 95%CI = 1.49-1.57 for CFS; d = 1.25, 95%CI = 1.22-1.29 for FM) and participants with a medical disease (d = 0.62, 95%CI = 0.46-0.79 for CFS; d = 0.75, 95%CI = 0.70-0.80 for FM).  

These differences remained essentially the same when excluding participants with comorbid mood or anxiety disorders or adjusting for physical symptom severity. 

Conclusions: Subjective cognitive symptoms and to a lesser extent suboptimal cognitive task performance are more prevalent in individuals with CFS or FM compared to controls without these conditions. 

5. The Advantages of an Integrative Approach in the Primary Healthcare of Post-COVID-19 and ME/CFS Patients 

Diana Araja, Angelika Krumina, Uldis Berkis, Zaiga Nora-Krukle and Modra Murovska 

COVID-19 Pandemic, Mental Health and Neuroscience – New Scenarios for Understanding and Treatment [Working Title], IntechOpen, London. 


The coronavirus disease caused by the SARS-CoV-2 virus (COVID-19) pandemic has changed not only global epidemiological and economic developments but also the lives of every individual, with particular severity for patients.  

The number of acute illness cases grew rapidly, significantly increasing the workload of hospitals, and simultaneously, new chronic diseases emerged, such as persistent post-COVID-19 syndrome (PPCS), with unclear etiology, symptoms, and complexity—similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  

Accordingly, the burden of chronic diseases poses new long-term challenges for primary healthcare and requires new approaches to patient care.  

This chapter provides insight into the integrative approach to healthcare and focuses on potentially new solutions by implementing an integrative attitude to the treatment of post-COVID-19 and ME/CFS patients in primary healthcare.  

Integrative health coaching contributes the holistic approach to patients’ overall health and resilience through cognitive practice and patient active engagement. The findings of this chapter can enrich the person-centered approach and healthcare system strengthening through holistic measures and systems thinking. 

6. Autoimmune Gene Expression Proling of Fingerstick Whole Blood in Chronic Fatigue Syndrome 

Zheng Wang, Michelle F. Waldman, Tara J. Basavanhally, Aviva R. Jacobs et al. 

ResearchSquare [Preprint] 


Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating condition that can lead to severe impairment of physical, psychological, cognitive, social, and occupational functions.  

The cause of ME/CFS remains incompletely understood. There is no clinical diagnostic test for ME/CFS. Although many therapies have been used off-label to manage symptoms of ME/CFS, there are limited, if any, specific therapies or cure for ME/CFS.  

In this study, we investigated the expression of genes specific to key immune functions, and viral infection status in ME/CFS patients with an aim of identifying biomarkers for characterization and/or treatment of the disease.  

Methods: In 2021, one-hundred and sixty-six (166) patients diagnosed with ME/CFS and 83 healthy controls in the US participated in this study via a social media-based application (app). The patients and heathy volunteers consented to the study and provided self-collected finger-stick blood and first morning void urine samples from home.  

RNA from the fingerstick blood was tested using DxTerity’s 51-gene autoimmune RNA expression panel (AIP). In addition, DNA from the same fingerstick blood sample was extracted to detect viral load of 4 known ME/CFS associated viruses (HHV6, HHV7, CMV and EBV) using a real-time PCR method.  

Results: Among the 166 ME/CFS participants in the study, approximately half (49%) of the ME/CFS patients reported being house-bound or bedridden due to severe symptoms of the disease.  

From the AIP testing, ME/CFS patients with severe, bedridden conditions displayed significant increases in gene expression of IKZF2, IKZF3, HSPA8, BACH2, ABCE1 and CD3D, as compared to 2 patients with mild to moderate disease conditions.  

These six aforementioned genes were further upregulated in the 22 bedridden participants who suffer not only from ME/CFS but also from other autoimmune diseases.  

These genes are involved in T cell, B cell and autoimmunity functions. Furthermore, IKZF3 (Aiolos) and IKZF2 (Helios), and BACH2 have been implicated in other autoimmune diseases such as systemic lupus erythematosus (SLE) and Rheumatoid Arthritis (RA).  

Among the 240 participants tested with the viral assays, 9 samples showed positive results (including 1 EBV positive and 8 HHV6 positives).  

Conclusions: Our study indicates that gene expression biomarkers may be used in identifying or differentiating subsets of ME/CFS patients having different levels of disease severity.  

These gene targets may also represent opportunities for new therapeutic modalities for the treatment of ME/CFS. The use of social media engaged patient recruitment and at-home sample collection represents a novel approach for conducting clinical research which saves cost, time and eliminates travel for office visits. 

7. Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways 

Michael Maes, Haneen Tahseen Al-Rubaye, Abbas F. Almulla, Dhurgham Shihab Al-Hadrawi, Kristina Stoyanova, Marta Kubera and Hussein Kadhem Al-Hakeim 

IJERPH, 2022, vol. 19, issue 16, 1-21 


The physio-affective phenome of Long COVID-19 is predicted by (a) immune-inflammatory biomarkers of the acute infectious phase, including peak body temperature (PBT) and oxygen saturation (SpO2), and (b) the subsequent activation of immune and oxidative stress pathways during Long COVID.  

The purpose of this study was to delineate the effects of PBT and SpO2 during acute infection, as well as the increased neurotoxicity on the physical, psychological, social and environmental domains of health-related quality of life (HR-QoL) in people with Long COVID.  

We recruited 86 participants with Long COVID and 39 normal controls, assessed the WHO-QoL-BREF (World Health Organization Quality of Life Instrument-Abridged Version, Geneva, Switzerland) and the physio-affective phenome of Long COVID (comprising depression, anxiety and fibromyalgia-fatigue rating scales) and measured PBT and SpO2 during acute infection, and neurotoxicity (NT, comprising serum interleukin (IL)-1β, IL-18 and caspase-1, advanced oxidation protein products and myeloperoxidase, calcium and insulin resistance) in Long COVID.  

We found that 70.3% of the variance in HR-QoL was explained by the regression on the physio-affective phenome, lowered calcium and increased NT, whilst 61.5% of the variance in the physio-affective phenome was explained by calcium, NT, increased PBT, lowered SpO2, female sex and vaccination with AstraZeneca and Pfizer.  

The effects of PBT and SpO2 on lowered HR-QoL were mediated by increased NT and lowered calcium yielding increased severity of the physio-affective phenome which largely affects HR-QoL. In conclusion, lowered HR-Qol in Long COVID is largely predicted by the severity of neuro-immune and neuro-oxidative pathways during acute and Long COVID. 

8. The importance of school in the management of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): issues identified by adolescents and their families 

Clery, P., Linney, C., Parslow, R., Starbuck, J., Laffan, A., Leveret, J., & Crawley, E.  

Health & Social Care in the Community, 00, 1– 11. 


Paediatric Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) is a disabling condition. Schools play a key role in adolescents' experiences with managing ME/CFS. However, little is known about the experiences of adolescents with ME/CFS (and their families) in schools.  

This paper is an incidental qualitative study, which combines data from two independent ME/CFS studies: study 1 researched ethnic minority adolescents with ME/CFS; study 2 explored Acceptance and Commitment Therapy for adolescents with ME/CFS who had not recovered after one year. Participants included: adolescents with ME/CFS; their families; and medical professionals (ME/CFS specialists and non-specialists).  

Adolescents, their families, and ME/CFS medical professionals were recruited from a UK specialist paediatric ME/CFS service. Non-ME/CFS medical professionals were recruited from the same region. Semi-structured qualitative interviews and focus groups were undertaken. Participants' views on schools from each study were combined and thematic analysis was used to identify themes.  

Fifteen adolescents with ME/CFS (11–17 years old), sixteen family members, and ten medical professionals (GPs, school nurses and ME/CFS specialists) were interviewed.  

Four key themes were found: (1) adolescents identified school was important for aiding ME/CFS recovery, especially educationally and socially; (2) families described varying levels of support from schools and local authorities with help managing ME/CFS – some described significant practical and emotional difficulties to accessing education, whereas others recounted examples of positive supportive strategies, particularly when teachers had previous experience or knowledge of ME/CFS; (3) parents thought three-way communication between schools, healthcare and families could improve support; (4) participants felt schools were an appropriate place for knowledge building and raising awareness of ME/CFS amongst teachers and pupils, to aid improved supportive measures.  

In conclusion, this paper provides rich data that highlights the importance of education and the realistic fears and hurdles for adolescents with ME/CFS remaining engaged in education and the impact on their future.  

Some families described positive strategies in school, which were viewed as helpful to manage ME/CFS in the classroom. These strategies could be implemented alongside knowledge building initiatives and improved communication between healthcare and education. There is a need to further investigate useful strategies and determine how teachers can be best supported in implementing them. 

What is known about the topic: 

  • Paediatric Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) can negatively impact on school attendance and educational achievement. 
  • Liaison between healthcare and schools is important for recovery from ME/CFS. 
  • There is little qualitative research on the experience of adolescents with ME/CFS in schools. 

What this paper adds: 

  • This paper highlights the importance of education and the realistic fears and hurdles for young people with ME/CFS remaining engaged in education and the concerns about the impact on their future. 
  • Some adolescents with ME/CFS experienced difficulties with school, which they felt negatively impacted on their future potential whereas others described supportive experiences with schools recognising their individual needs and built their confidence inattending school. 
  • Adolescents and their families felt school support was particularly good when teachers had knowledge of ME/CFS, therefore there is a need to further investigate useful strategies and determine how teachers can be best supported by healthcare professionals in implementing them. 

Long-COVID Research References   

  1. Long COVID Symptomatology After 12 Months and Its Impact on Quality of Life According to Initial Coronavirus Disease 2019 Disease Severity 
  1. Distinguishing features of Long COVID identified through immune profiling 
  1. Muscle fatigability and post-acute COVID-19 syndrome: A case study 
  1. Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients 
  1. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2 
  1. Post COVID syndrome: A novel challenge and threat to international health 
  1. NeuroCOVID-19: a critical review 
  1. Prevention and early treatment of the long-term physical effects of COVID-19 in adults: design of a randomised controlled trial of resistance exercise-CISCO-21 
  1. Screening and assessment for post-acute COVID-19 syndrome (PACS), guidance by personal pilots and support with individual digital trainings within intersectoral care: a study protocol of a randomized controlled trial 
  1. STIMULATE-ICP-CAREINEQUAL (Symptoms, Trajectory, Inequalities and Management: Understanding Long-COVID to Address and Transform Existing Integrated Care Pathways) study protocol: Defining usual care and examining inequalities in Long Covid support 
  1. Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis 
  1. A service evaluation of a community project combining psychoeducation and mind-body complementary approaches to support those with Long Covid in the UK 
  1. Predictors of post-COVID-19 and the impact of persistent symptoms in non-hospitalized patients 12 months after COVID-19, with a focus on work ability 
  1. Sex-dependent characteristics of Neuro-Long-COVID: Data from a dedicated neurology ambulatory service 
  1. Autonomic and neuropathic complaints of long-COVID objectified: an investigation from electrophysiological perspective 
  1. Cardiac impairments in postacute COVID-19 with sustained symptoms: A review of the literature and proof of concept 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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