MEA Research Roundup

ME/CFS and Long Covid Research: 16  – 23 January 2023

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  – 23 January 2023 

Research has picked up this week, with six new ME/CFS studies and twelve new Long Covid studies. 

We have highlighted one of the ME/CFS studies in detail below: 

Paper five (5) is on altered fatty acid oxidation in immune cells (lymphocytes). The study isolated three types of immune cells from blood which help to fight off infections: natural killer (NK), CD4+ (helper) T cells and CD8+ (killer) T cells in ME/CFS and healthy controls. Participates were recruited from different clinics in America, but were mainly by one of the authors, a physician specialising in ME/CFS (Dr Peterson).  

Analysis of these cells was carried out in vitro (experimental work performed outside of a living organism, such as in a test tube). The cells underwent a range of tests, oxygen consumption was measured and different drugs were injected which inhibit or promote different metabolic pathways, for example, the drug Etomoxir inhibits fatty acid oxidation and the response was measured. 

In the body the energy metabolism (fuel) used by these cells is tightly moderated, therefore looking at the fatty acids being used by these cells (whether they increase or decrease) can tell you a lot about function or dysfunction of the immune cells. 

The study found: 

  • All three types of cells increased their use of lipids (fatty acids) and levels of relevant proteins compared to controls, particularly during times of high energy demand and activation. 
  • Fatty acid utilisation by CD4+ T cells was found to correlate with illness duration. 
  • The findings support the theory of an altered bioenergetic state in immune cells. 
  • The authors hypothesise that the reduced cytotoxicity which has previously been found in ME/CFS (the degree to which a substance can cause damage to a cell) (for example Eaton-Fitch et al., 2019) could be due to lipid accumulation and fatty acid oxidation. 
  • The authors also propose, from looking at the metabolic profile of these cells, that the T cells are in an exhausted state and that this might contribute to symptoms experienced. 

This study was limited in size and was not consistent with the sample sizes in which immune cell fatty acids were characterised, as such there were at least 8 and as many as 20 samples used in each experiment. The legends of each graph presented need to be carefully read to find the sample size. This means that some results will have more meaning and significance than others. Some data showed outliers (result differing from the rest of the group) which question the difference between the groups, as well as one graph showing an extreme difference from one patient at two different time points.  

It is hard to find much to critique this study for, however there are no details of the diagnosis criteria used and only a small range of fatty acids were investigated so it would be interesting to know the utilisation of different sized fatty acids. 

Overall, this is a very nice, clearly presented study with a lot of new data which gives lots of new avenues which could be investigated, this could also open up new avenues for future treatment.  

There is a short video available by the first author of this research which briefly explains the concepts in this study, however, fairly complex information is given on the methods used. 

You may also be interested in reading: 

  • Paper three (3) which is on persistent viral infections in the development and severity of ME/CFS, which focuses on the role of human herpesviruses (HHV) (namely HHV6, HHV7 and parvovirus B19). This study concludes that these viruses are important in the development and severity of ME/CFS, this adds to the growing evidence of the role of HHVs which is presented in our latest Research Review
  • This also links in with Paper two (2) in the Long Covid Reference section on treating Epstein-Barr virus (EBV) to reduce Long Covid symptoms. Unfortunately, we can not access the full study. 

ME/CFS Research References and Abstracts  

1. A randomized controlled trial protocol for persistent physical symptoms associated with indoor environment or chronic fatigue: Effectiveness of video-based functional case conceptualization and web-program for improving quality of life 

Selinheimo S, Keinonen K, Vuokko A, Liesto S, Sainio M, Lappalainen R, Paunio T.  

Front Psychol. 2023 Jan 6;13:923532. 


Introduction: Persistent physical symptoms (PPS) refer to symptoms that cannot be fully explained by structural bodily pathology or by environmental factors. Their impact on daily functioning varies from mild to severe disability. So far, evidence-based treatments for PPS have resulted in only small to moderate effects.  

Treatment protocols with a stronger orientation toward personalized approaches are needed to improve the efficacy and applicability of treatment. In this study, we aim to assess the effect of an online individual case conceptualization with web-based program for PPS. This study is conducted among two focus groups: patients with indoor air-related symptoms and patients with chronic fatigue syndrome. 

Methods and analyses: Using a randomized controlled design (RCT) with two parallel groups in a 1:1 ratio, we will compare individual video-based case conceptualization with a web-based program based on Acceptance and Commitment Therapy (ACT), combined with treatment as usual, with treatment as usual only. The web-based program consists of ten modules, each lasting 1 week and including training. The planned sample size is 124 eligible patients without attrition.  

The primary outcome will be the health-related quality of life as measured by the 15D questionnaire. The secondary outcome measures will include questionnaires on psychiatric and physical symptoms, illness perceptions, psychological flexibility, and work ability.  

We will also use national registers to obtain information on the use of healthcare and social benefits to complete patient-reported outcomes. Data collection began in August 2020 and will continue until 2023. 

Discussion: This trial will provide information on the effects and usefulness of an online administrated individual case conceptualization and an ACT-based web-program on PPS. 

2. Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro-Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection 

Al-Hakeim HK, Al-Rubaye HT, Almulla AF, Al-Hadrawi DS, Maes M.  

J Clin Med. 2023 Jan 8;12(2):511. 


Background: Long-term coronavirus disease 2019 (long COVID) is associated with physio-somatic (chronic fatigue syndrome and somatic symptoms) and affective (depression and anxiety) symptoms. The severity of the long COVID physio-affective phenome is largely predicted by increased peak body temperature (BT) and lowered oxygen saturation (SpO2) during the acute infectious phase.  

This study aims to delineate whether the association of BT and SpO2 during the acute phase and the long COVID physio-affective phenome is mediated by neurotoxicity (NT) resulting from activated immune-inflammatory and oxidative stress pathways. 

Methods: We recruited 86 patients with long COVID (3-4 months after the acute phase) and 39 healthy controls and assessed serum C-reactive protein (CRP), caspase 1, interleukin (IL) 1β, IL-18, IL-10, myeloperoxidase (MPO), advanced oxidation protein products (AOPPs), total antioxidant capacity (TAC), and calcium (Ca), as well as peak BT and SpO2 during the acute phase. 

Results: Cluster analysis revealed that a significant part (34.9%) of long COVID patients (n = 30) show a highly elevated NT index as computed based on IL-1β, IL-18, caspase 1, CRP, MPO, and AOPPs. Partial least squares analysis showed that 61.6% of the variance in the physio-affective phenome of long COVID could be explained by the NT index, lowered Ca, and peak BT/SpO2 in the acute phase and prior vaccinations with AstraZeneca or Pfizer. The most important predictors of the physio-affective phenome are Ca, CRP, IL-1β, AOPPs, and MPO. 

Conclusion: The infection-immune-inflammatory core of acute COVID-19 strongly predicts the development of physio-affective symptoms 3-4 months later, and these effects are partly mediated by neuro-immune and neuro-oxidative pathways. 

3. The persistent viral infections in the development and severity of myalgic encephalomyelitis/chronic fatigue syndrome 

Rasa-Dzelzkaleja, S., Krumina, A., Capenko, S. et al.  

J Transl Med 21, 33 


Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disease with an unexplained aetiology in which viral infections are possible trigger factors. 

The aim of this study was to determine the involvement of human herpesvirus (HHV)-6A/B, HHV-7, and parvovirus B19 (B19V) in the etiopathogenesis of ME/CFS. 

Methods: 200 patients with clinically diagnosed ME/CFS and 150 apparently healthy individuals were enrolled in this study. Single-round, nested, and quantitative real-time polymerase chain reactions (PCR) were used to detect the presence and load of HHV-6A/B, HHV-7, and B19V. HHV-6A and HHV-6B were distinguished by PCR and restriction analysis. Immunoenzymatic assays were applied to estimate the presence of virus-specific antibodies and the level of cytokines. 

Results: HHV-6A/B, HHV-7, and B19V specific antibodies were detected among patients and healthy individuals in 92.1% and 76.7%, 84.6% and 93.8%, and 78% and 67.4% of cases. HHV-6B had 99% of HHV-6 positive patients. 

Latent HHV-6A/B, HHV-7, and B19V infection/co-infection was observed in 51.5% of the patients and 76.7% of the healthy individuals, whereas active–45% of the ME/CFS patients and 8.7% of healthy individuals. HHV-6A/B load in patients with a persistent infection/co-infection in a latent and active phase was 262 and 653.2 copies/106 cells, whereas HHV-7 load was 166.5 and 248.5 copies/106 cells, and B19V-96.8 and 250.8 copies/106 cells, respectively. 

ME/CFS patients with persistent infection in an active phase had a higher level of pro-inflammatory cytokines (interleukin(IL)-6, tumor necrosis factor-alpha(TNF-α) and IL-12) and anti-inflammatory (IL-10) than with a persistent infection in a latent phase. A significant difference was revealed in the levels of TNF-α, IL-12, and IL-10 among the patient groups without infection, with latent infection/co-infection, active single, double and triple co-infection. The levels of TNF-α, IL-12, and IL-10 are significantly higher in patients with severe compared with a moderate course of ME/CFS. 

Conclusions: Significantly more persistent HHV-6A/B, HHV-7, and B19V infection/co-infection in an active phase with a higher viral load and elevated levels of pro- and anti-inflammatory cytokines among patients with ME/CFS than healthy individuals indicate the importance of these infections/co-infections in ME/CFS development. The presence of these infections/co-infections influences the ME/CFS clinical course severity. 

4. Effects of Yijinjing Qigongin Alleviating Fatigue, Sleep Quality and Health Status on Patients with Chronic Fatigue Syndrome: A Randomized, Controlled, and Parallel Group Clinical Study 

Xie F, Dong W, Guan C, Yao F.  

Complement Med Res. 2023 Jan 19. [Epub ahead of print.] 


Background: Chronic fatigue syndrome (CFS) is a chronic disease characterized by various symptoms such as pathological fatigue, cognitive dysfunction, and inability to recover energy after waking up.  

The Yijinjing, a kind of health care practice from ancient China, consists of 12 movements, and it is considered as one of the complementary and alternative medicine (CAM) for health maintenance, health care and disease healing. In this study, multiple scales were used to evaluate the effects of Yijinjjing intervention on the clinical symptoms of CFS. 

Patients and methods: Forty patients with CFS were randomly assigned to Yijinjing group and the cognitive behavior therapy (CBT) group separately. The Yijinjing intervention was practiced 6 times per week, among which one exercise should be guided by the teacher of the faculty in the university, and another 5 times should be finished at home over 12 consecutive weeks.  

Similarly, the control group received cognitive education, including popular science lectures and psychological counseling related to CFS prevention and treatment for 12 weeks. Multidimensional Fatigue Inventory-20 (MFI-20), Short Form 36-item Health Survey (SF-36) and Pittsburgh Sleep Quality Index (PSQI) were assessed before and after intervention. 

Results: Intra-group analysis showed that the differences in MFI-20, SF-36, and PSQI were statistically significant (p<0.05) after the intervention of 12 weeks Yijinjing intervention. Compared with the CBT group, the differences in MFI-20 and PSQI of the Yijinjing group were statistically significant (p<0.05), but SF-36 was superior to the CBT group in terms of physical function, bodily pain, general health and vitality (p<0.05). 

Conclusion: Yijinjing can significantly improve sleep disorders, fatigue and quality of life in patients with CFS, and is superior to behavioral cognitive education in pain and vitality.  

5. Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome 

Maya J, Leddy SM, Gottschalk CG, Peterson DL, Hanson MR. 

International Journal of Molecular Sciences. 2023; 24(3):2010.  


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction.  

To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation.  

We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation.  

In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells.  

We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data.  

These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action. 

6. The Cognitive and Behavioural Responses to Symptoms Questionnaire (CBRQ): Development, reliability and validity across several long-term conditions 

Picariello F, Chilcot J, Chalder T, Herdman D, Moss-Morris R.  

Br J Health Psychol. 2023 Jan 23. [Epub ahead of print.] 


Objectives: Cognitive and behavioural responses to symptoms can worsen or maintain the severity of symptoms across long-term conditions (LTCs). Although the Cognitive and Behavioural Responses Questionnaire (CBRQ) has been used in research, its original development and psychometric properties as a transdiagnostic measure have not been reported. Our aim was to evaluate the psychometric properties of the CBRQ and a recently proposed short version, across different LTCs. 

Design: Psychometric validation study. 

Methods: Confirmatory factor analysis (CFA) tested the factor structure of the CBRQ in two datasets from the CBRQ's original development; (chronic fatigue syndrome, N = 230; and multiple sclerosis, N = 221) and in additional groups: haemodialysis (N = 174), inflammatory bowel disease (N = 182) and chronic dizziness (N = 185). Scale reliability and construct validity were assessed. The factor structure of the shortened CBRQ (CBRQ-SF) was also assessed. 

Results: CFA revealed that a 7-or 8-factor structure had generally appropriate fit supporting the originally proposed 7 factors (Fear avoidance, Damage beliefs, Catastrophising, Embarrassment avoidance, Symptom focusing, All-or-nothing behaviour and Avoidance/Resting behaviour). Omega coefficients indicated satisfactory internal reliability. Correlations with related constructs suggested construct validity. The scale appeared sensitive to change. The CBRQ-SF also displayed good psychometric quality, with a better model fit than the CBRQ. 

Conclusions: The CBRQ and the shortened version were shown to be reliable and valid at assessing a range of cognitive and behavioural responses to symptoms, highlighting the multi-symptom, transdiagnostic properties of this questionnaire. Further research is necessary to determine the test-retest reliability and sensitivity to change of the CBRQ and CBRQ-SF and a thorough evaluation of the content validity of the items. 

Long-COVID Research References  

  1. Chinese medicine for residual symptoms of COVID-19 recovered patients (long COVID)-A double-blind, randomized, and placebo-controlled clinical trial protocol 
  1. Epstein-Barr Virus Testing-to-Treatment in Long COVID Patients: A Review and Recommendation 
  1. Characterising patterns of COVID-19 and long COVID symptoms: evidence from nine UK longitudinal studies 
  1. Is the post-COVID-19 syndrome a severe impairment of acetylcholine-orchestrated neuromodulation that responds to nicotine administration? 
  1. Prediction of Long COVID Based on Severity of Initial COVID-19 Infection: Differences in predictive feature sets between hospitalized versus non-hospitalized index infections 
  1. Sleep Assessment in Long COVID Clinics- A Necessary Tool for Effective Management 
  1. Diagnosis and management of post-COVID (Long COVID) in children: a moving target 
  1. Association between long COVID, functional activity, and health-related quality of life in older adults 
  1. A multidisciplinary approach to screen the post-COVID-19 conditions 
  1. Within and between-day variation and associations of symptoms in Long Covid: Intensive longitudinal study 
  1. Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection 
  1. Diagnosis and management of post-COVID (Long COVID) in children: a moving target 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
Shopping Basket