MEA Research Roundup

ME/CFS and Long Covid Research: 05 – 11 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 5 – 11 July 2022 

There have been seven new ME/CFS studies and twelve studies on Long Covid this week. 

We have highlighted two of the studies below: 

Paper one (1) is on memory problems alongside the effects of depression, sleep, age and intelligence. Results showed a trend for impaired memory performance, but only certain tests confirmed this, particularly related to speed, reaction times, writing speed and the recall of shapes. It was also found that other symptoms and factors investigated did not change the effect on memory in CFS patients compared to controls. The overall conclusion was that effects on memory are small. 

This is the second paper of this nature (previously published paper here) that we have seen from this author, Andrew Smith based at Cardiff University. However, there are a few things that make me question the strength of this piece of research: 

  • only one author leading and investigating this research which is very unusual and limits what can be studied, 
  • limited background and knowledge of ME/CFS of the researcher (researcher has no prior history of investigating ME/CFS), 
  • CFS is used throughout the paper and ME is not mentioned which questions knowledge, 
  • no details of the diagnostic criteria used, or which clinic patients were recruited from, 
  • small sample which varied in each test, ranging from 21 CFS patients to 24, which limits finding significant results, 
  • unusual choice of journal to publish in further questioning the strength of the research. 

In conclusion, there are a few things which make me question the strength of this study, and larger studies are needed to fully show if problems with memory are minimal in ME/CFS. 

Paper four (4) looks at producing a template to increase the participation of severely and very severely affected ME/CFS patients in research, particularly seeing as research is very limited in this area. The author of this research is Helen Baxter who alongside Dr Nigel Speight and Dr William Weir were awarded the Howes Goudsmit Prize for their contributions to Severe ME research (more information here). 

This recently published research by Helen Baxter gives recommendations about how researchers should engage with people with severe ME, which are bullet pointed at the end of the research paper. These include: questionnaires in a way that is most accessible to the individual (i.e. paper copy, online etc), allow input/assistance from family members/careers and no time limits/pressures. Understandably, this research was conducted on an extremely small sample size, with only five participates, further reinforcing the need for this study. Hopefully, this will help to educate researchers and increase participate of this underrepresented group. 

You may also be interested in reading in the Long Covid reference section of paper one (1) on Low Does Naltrexone (LDN). This study has been conducted in Ireland, with results showing a reduction in symptoms. LDN has been discussed in relation to ME/CFS for a number of years; a previously written research summary about LDN can be found here, although results have previously been disappointing. 

ME/CFS Research References and Abstracts  

1. Chronic fatigue syndrome, depression, sleep, age, intelligence and memory 

Smith AP 

World Journal of Pharmaceutical and Medical Research 8 (7): 50-59 


Background: Memory problems are frequently reported by Chronic Fatigue Syndrome (CFS) patients. These self-reports are often not confirmed using objective memory tests. Indeed, conflicting results have been obtained in previous studies examining the performance of CFS patients on a variety of memory tasks.  

Results have shown that CFS patients perform working and semantic memory more slowly but show no decrease in accuracy. The present study examined whether sleep disturbances, depression, age and intelligence may modify the effects of CFS on memory.  

Methods: CFS patients were recruited from a specialist clinic and compared with healthy controls. Three experiments were carried out.  

The first used memory tasks designed to examine the different components of working memory.  

The second used working memory and semantic memory tasks and also examined psychomotor speed.  

The third used the “Doors and People” task, which measures immediate recall and forgetting of names and visual shapes.  

Measures of intelligence, insomnia and depression were also recorded.  

Results: The CFS patients reported frequent memory problems and showed a trend of impaired memory performance.  

However, only the differences in speed scores and the recall of shapes were significant.  

Depression, insomnia, age and intelligence did not significantly modify the performance of the CFS patients.  

Conclusions: CFS patients reported frequent memory problems, but objective testing largely failed to confirm this.  

The CFS patients were slower at several tasks (Digit-Symbol Substitution; Semantic Processing; writing and simple reaction time), and this slowing may be involved in the poorer immediate recall of shapes.  

Depression, insomnia, age and intelligence did not change the CFS effects. Future research should use large sample sizes as the effect sizes of being in the CFS group were small. 

2. Effects of Shenxian Congee on Chronic Fatigue Syndrome Rats by NF-κB Signaling Pathway 

Lianci He, Dingxi Bai, Chenxi Wu, Yizhu Zhong, Shi Chen, Xinru Bao, Jing Gao, Chaoming Hou 

Pakistan J. Zool., pp 1-9, 2022. 


The purpose of this study was to study the effect of Shenxian congee (SXC) in rats with chronic fatigue syndrome (CFS) on NF-κB signalling pathway and the expression of related factors. To reveal the relevant signal transduction mechanism in the treatment of CFS.  

Seventy two male SD rats were randomly divided into 6 groups with 12 rats in each group. Namely: control group (CON), low dose Shenxian Congee group (SXC-L), medium dose Shenxian Congee group (SXC-M), high dose Shenxian Congee group (SXC-M), fluoxetine hydrochloride group (influenza group, FLU) and chronic fatigue syndrome (CFS) group.  

In addition to the CON group, the remaining five groups established CFS rat models through forced swimming test and chronic restraint stress.  

After 28 days, the three groups received different concentrations of SXC (1.62 g/ml, 0.81 g/ml and 0.41 g/ml), FLU group received 0.21 mg/ml fluoxetine.  

CFS group and CON group received the same volume of normal saline.  

All groups received treatment for 28 days.  

The rats’ body weight, fatigue time, activity and mobility, and mRNA and protein levels of interleukin-1 beta (IL-1β), tumour necrosis factor alpha (TNF-α), transforming growth factor β-activated kinase 1 (TAK1), TAB, IκB kinase (IKKα), IκBα, NF-κBp65 and cyclooxygenase-2 in the serum were measured.  

Compared with the CON group, the CFS group had decreased weight and decreased activity and mobility (P < 0.05).  

Compared with the CFS group, the three SXC groups and the FLU group all had varying levels of increased body weight, horizontal motion, vertical motion and fatigue time (P < 0.05).  

The SXC downregulated the mRNA and/or protein expression of IL-1β, TNF-α, TAK1, TAB, IKKα and NF-κBp65 and increased the mRNA expression of IκBα protein (P < 0.05). To conclude in the CFS model, SXC inhibits the transmission of NF-κB signaling pathway by down-regulating the expression of inflammatory cytokines and protein targets, and has an immunoregulatory effect on chronic fatigue syndrome.  

3. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? 

Sun Y, Koyama Y, Shimada S.  

Front Aging Neurosci. 2022 Jun 16;14:903455. 


As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied.  

The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle.  

In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms. Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways.  

The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis.  

In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation. 

4. Ensuring the Voice of the Very Severely Affected Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patient Is Heard in Research—A Research Model 

Baxter, H  

Healthcare 2022, 10, 1278 


Most of the research about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has focused on ambulant patients who are able to attend clinics. It is estimated that 25% of people with ME/CFS are severely, or very severely, affected and are housebound or bedbound; some require tube feeding.  

Due to the severity of their illness, these patients have largely been excluded from research and are often described as ‘hard to reach.’  

A questionnaire was devised to gather data about their experiences of accessing tube feeding.  

By making the necessary reasonable adjustments, such as direct outreach and the option to complete the questionnaire by telephone or texting, very severely affected patients were enabled to participate and provided invaluable contributions.  

This study aimed to act as a model for future researchers. 

5. Could the kynurenine pathway be the key missing piece of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) complex puzzle? 

Kavyani B, Lidbury BA, Schloeffel R, Fisher PR, Missailidis D, Annesley SJ, Dehhaghi M, Heng B, Guillemin GJ.  

Cell Mol Life Sci. 2022 Jul 11;79(8):412. 


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex and debilitating disease with a substantial social and economic impact on individuals and their community.  

Despite its importance and deteriorating impact, progresses in diagnosis and treatment of ME/CFS is limited. This is due to the unclear pathophysiology of the disease and consequently lack of prognostic biomarkers.  

To investigate pathophysiology of ME/CFS, several potential pathologic hallmarks have been investigated; however, these studies have failed to report a consistent result.  

These failures in introducing the underlying reason for ME/CFS have stimulated considering other possible contributing mechanisms such as tryptophan (TRP) metabolism and in particular kynurenine pathway (KP).  

KP plays a central role in cellular energy production through the production of nicotinamide adenine dinucleotide (NADH).  

In addition, this pathway has been shown to mediate immune response and neuroinflammation through its metabolites.  

This review, we will discuss the pathology and management of ME/CFS and provide evidence pertaining KP abnormalities and symptoms that are classic characteristics of ME/CFS. Targeting the KP regulation may provide innovative approaches to the management of ME/CFS. 

6. The Facilitation of Clinical and Therapeutic Discoveries in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome and Related Diseases: A Protocol for the You + ME Registry Research Platform 

Ramiller A, Mudie K, Seibert E, Whittaker S.  

JMIR Res Protoc. 2022 Jun 5. [Epub ahead of print.] 


Background: ME/CFS (Myalgic Encephalomyelitis / Chronic Fatigue Syndrome) is a chronic, complex, heterogeneous disease that affects millions and lacks both diagnostics and treatments. Big data, or the collection of vast quantities of data that can be mined for information, has transformed the understanding of many complex illnesses like cancer and multiple sclerosis, by dissecting heterogeneity, identifying subtypes, and enabling the development of personalized treatments. It is possible that big data can reveal the same for ME/CFS. 

Objective: To describe the protocol for the You + ME Registry, present preliminary results related to participant enrollment and satisfaction, and discuss the limitations of the registry as well as next steps. 

Methods: Solve M.E. developed and launched the You + ME Registry to collect longitudinal health data from people with ME/CFS, people with Long COVID (LC) and control volunteers using rigorous protocols designed to harmonize with other groups collecting data from similar groups of people. 

Results: The Registry now has over 4,200 geographically-diverse participants (3,033 people with ME/CFS, 833 post-COVID, and 473 control volunteers) with an average of 72 new people registered every week. It has qualified as “great” using a Net Promotor Score, indicating registrants are likely to recommend to a friend. Analyses of collected data are currently underway and preliminary findings are expected in the near future. 

Conclusions: The Registry is an invaluable resource because it integrates with a symptom tracking app, as well as a biorepository, to provide a robust and rich dataset that is available to qualified researchers. Accordingly, it facilitates collaboration that may ultimately uncover causes and help accelerate the development of therapies. 

7. Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to Disease Diagnosis 

Sepúlveda N, Malato J, Sotzny F, Grabowska AD, Fonseca A, Cordeiro C, Graça L, Biecek P, Behrends U, Mautner J, Westermeier F, Lacerda EM, Scheibenbogen C.  

Front Med (Lausanne). 2022 Jun 24;9:921101. 


Infections by the Epstein-Barr virus (EBV) are often at the disease onset of patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, serological analyses of these infections remain inconclusive when comparing patients with healthy controls (HCs). In particular, it is unclear if certain EBV-derived antigens eliciting antibody responses have a biomarker potential for disease diagnosis.  

With this purpose, we re-analyzed a previously published microarray data on the IgG antibody responses against 3,054 EBV-related antigens in 92 patients with ME/CFS and 50 HCs.  

This re-analysis consisted of constructing different regression models for binary outcomes with the ability to classify patients and HCs. In these models, we tested for a possible interaction of different antibodies with age and gender. When analyzing the whole data set, there were no antibody responses that could distinguish patients from healthy controls.  

A similar finding was obtained when comparing patients with non-infectious or unknown disease trigger with healthy controls.  

However, when data analysis was restricted to the comparison between HCs and patients with a putative infection at their disease onset, we could identify stronger antibody responses against two candidate antigens (EBNA4_0529 and EBNA6_0070).  

Using antibody responses to these two antigens together with age and gender, the final classification model had an estimated sensitivity and specificity of 0.833 and 0.720, respectively.  

This reliable case-control discrimination suggested the use of the antibody levels related to these candidate viral epitopes as biomarkers for disease diagnosis in this subgroup of patients. To confirm this finding, a follow-up study will be conducted in a separate cohort of patients. 

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

  1. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study 
  1. EWAS of post-COVID-19 patients shows methylation differences in the immune-response associated gene, IFI44L, three months after COVID-19 infection 
  1. Neuropathic Corneal Pain as Debilitating Manifestation of LONG-COVID 
  1. Studying the Effect of Long COVID-19 Infection on Sleep Quality Using Wearable Health Devices: Observational Study 
  1. Effect of Oral Nirmatrelvir on Long COVID Symptoms: 4 Cases and Rationale for Systematic Studies 
  1. Rapid improvement in severe long COVID following perispinal etanercept 
  1. Immune response to SARS-CoV-2 in severe disease and long COVID-19 
  1. Using Logistic Regression to Predict Long COVID Conditions in Chronic Patients 
  1. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation 
  1. Searching for Factors Influencing the Severity of the Symptoms of Long COVID 
  1. Long COVID and symptom trajectory in a representative sample of Americans in the first year of the pandemic 
  1. Patient-led integrated cognitive behavioural therapy for management of long COVID with comorbid depression and anxiety in primary care – A case study 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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