MEA Research Roundup

ME/CFS and Long Covid Research: 19 – 25 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 by Dr Katrina Pears

ME/CFS Research Published 19 – 25 July 2022 

There have been six new ME/CFS studies and fourteen studies on Long Covid.  

None of the studies particularly caught our eyes this week, with a lack of biological studies and a large number of review articles. Several of the studies listed this week are not directly on ME/CFS (they cover a range of chronic illnesses) these are studies: one (1), two (2), three (3) and six (6). 

We have highlighted two of the studies below: 

Paper one (1) is a pre-print study (therefore it has not been peer-reviewed and the science verified) and is on non-pharmacological therapies for post-viral syndromes (PVS). The review identified five non-pharmacological treatments, these were: Pilates, music therapy, telerehabilitation (use of the television to delivery services rehabilitation at home), resistance exercises and neuromodulation (technological intervention working on the nerves).  The authors concluded that these have all shown promise in those who have experienced PVS. 

Despite the extremely large number of UK based researchers involved in this review (21 in total), there seems to be gaps in their knowledge and the breadth of this review. For example, the biggest gap being the definition of post-viral syndromes used, where they only included studies where the original virus could be identified. Therefore, this ruled out ME/CFS and included long-covid, Epstein-Barr virus (EBV) and Chikungunya virus. The knock on effect of this, meant their eligible criteria for their systematic review only included five studies in total (with five therapies being presented). Which is definitely not enough studies to make an informed decision about non- pharmacological treatments which should be used.  

If ME/CFS was included in this review, we would have probably seen a very different review, especially when nonpharmacological therapies were focused on. In conclusion, we cannot take much from this study of the nonpharmacological therapies mentioned to help manage fatigue. 

Paper four (4) is another review article looking at the role of antigen persistence in three similar long-term illnesses: ME/CFS, Long Covid and Gulf War Illness (GWI)

This review article gives a nice overview of the three long-term illnesses covered  before explaining the authors theory of the “Persistent Antigen Hypothesis”. From my understanding, in brief this can be summarized as a mismatch in the antigens, leading to antigens not being eliminated and persisting the body. The authors list this as causing a number of issues, such as: 

  • direct tissue damage  
  • the tissue damage induces chronic inflammation produced by a persistent immune response, including cytokine production 
  • ongoing breakdown of proteins which can lead to autoimmunity  
  • antigen persistence can alter differentiation of pathogen-specific T cells resulting in functional exhaustion and defective immunological memory. 

This review covers a range of topics relating to the immune system, and shows that immune dysfunction is present in all three conditions. Persistent antigens are shown to be a problem in a number of other illnesses, such as HIV, hepatitis B and C, Epstein-Barr virus (EBV), with recent data showing this is the case following a Covid infection. However, I’m not sure how strong the theories presented in this review are for ME/CFS, as to date there is a lack of evidence showing that antigen persistence exists in ME/CFS. Therefore, currently this is another hypothesis to add to the collection on what causes ME/CFS. 

ME/CFS Research References and Abstracts  

1. Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review  

Joht Singh Chandan, Kirsty R Brown, Nikita Simms-Williams, Nasir Z Bashir, Jenny Camaradou, Dominic Heining, Grace M Turner, Samantha Cruz Rivera, Richard Hotham, Sonica Minhas, Krishnarajah Niratharakumar, Manoj Sivan, Kamlesh Khunti, Devan Raindi, Steven Marwaha, Sarah E. Hughes, Christel McMullan, Tom Marshall, Melanie J Calvert, Shamil Haroon, Olalekan Lee Aiyegbusi 

medRxiv 2022.06.07.22276080 [Preprint] 


Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises evidence for the effectiveness of non-pharmacological treatments for symptoms of PVS. It also summarises the symptoms and health impacts of PVS in individuals recruited to studies evaluating treatments. 

Methods and findings: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo.  

The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1st January 2001 to 29th October 2021.  

We anticipated that there would be few RCTs specifically pertaining to Long COVID, so we also included observational studies only if they assessed interventions in individuals where the viral pathogen was SARS-COV-2.  

Relevant outcome data were extracted, study quality appraised using the Cochrane Risk of Bias tool, and the findings were synthesised narratively. Quantitative synthesis was not planned due to substantial heterogeneity between the studies.  

Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. 

Conclusions: In this study, we observed a lack of robust evidence evaluating non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS as well as what may work for certain sub-groups of patients with differential symptom presentation. 

2. Exploring the management approaches of cytokines including viral infection and neuroinflammation for neurological disorders 

Md. Mominur Rahman, Sadia Afsana Mim, Mst. Afroza Alam Tumpa, Md. Taslim Sarker, Muniruddin Ahmed, Badrah S. Alghamdi, Abdul Hafeez, Athanasios Alexiou, Asma Perveen, Ghulam Md Ashraf, 

Cytokine, Volume 157, 2022, 155962 


Considerable evidence supports that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in various neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. 

The purpose of this study is to discuss the recent research on treating cytokine storm and amyloids, including stroke, Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's condition, Multi-sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS).  

Neuroinflammation observed in neurological disorders has a pivotal role in exacerbating Aβ burden and tau hyperphosphorylation, suggesting that stimulating cytokines in response to an undesirable external response could be a checkpoint for treating neurological disorders.  

Furthermore, the pro-inflammatory cytokines help our immune system through a neuroprotective mechanism in clearing viral infection by recruiting mononuclear cells.  

This study reveals that cytokine applications may play a vital role in providing novel regulation and methods for the therapeutic approach to neurological disorders and the causes of the deregulation, which is responsible for neuroinflammation and viral infection.  

However, it needs to be further investigated to clarify better the mechanisms of cytokine release in response to various stimuli, which could be the central point for treating neurological disorders. 


  • The innate immune response is the first line of protection after people are infected. 
  • Controlling cytokine production and inflammatory response are considered treatment strategies for neurological diseases
  • Regarding the diagnosis, multidisciplinary intervention should be taken several times for management and treatments. 

3. Response Shift After Cognitive Behavioral Therapy Targeting Severe Fatigue: Explorative Analysis of Three Randomized Controlled Trials 

Müller F, Verdam MGE, Oort FJ, Riper H, van Straten A, Verdonck-de Leeuw IM, Sprangers MAG, Knoop H.  

Int J Behav Med. 2022 Jul 22.  


Background: Cognitive behavioral therapy (CBT) is an evidence-based intervention for severe fatigue. Changes in patients' fatigue scores following CBT might reflect not only the intended relief in fatigue but also response shift, a change in the meaning of patients' self-evaluation. Objectives were to (1) identify the occurrence of response shift in patients undergoing CBT, (2) determine the impact of response shift on the intervention effect, and (3) investigate whether changes in fatigue-related cognitions and perceptions, targeted during CBT, are associated with response shift. 

Methods: Data of three randomized controlled trials testing the efficacy of CBT in individuals with chronic fatigue syndrome (CFS, n = 222), cancer (n = 123), and diabetes (n = 107) were re-analyzed. Fatigue severity was measured with 8 items from the Checklist Individual Strength, a valid and widely used self-report questionnaire. Structural equation modelling was applied to assess lack of longitudinal measurement invariance, as indication of response shift. 

Results: As expected, in all three trials, response shift was indicated in the CBT groups, not the control groups. Response shift through reprioritization was indicated for the items “Physically, I feel exhausted” (CFS) and “I tire easily” (cancer, diabetes), which became less vs. more important to the measurement of fatigue, respectively. However, this did not affect the intervention effects. Some changes in cognitions and perceptions were associated with the response shifts. 

Conclusions: CBT seems to induce response shift through reprioritization across patient groups, but its occurrence does not affect the intervention effect. Future research should corroborate these findings and investigate whether patients indeed change their understanding of fatigue. 

4. At the Root of 3 “Long” Diseases: Persistent Antigens Inflicting Chronic Damage on the Brain and Other Organs in Gulf War Illness, Long-COVID-19, and Chronic Fatigue Syndrome 

James LM, Georgopoulos AP.  

Neuroscience Insights. January 2022. 


Several foreign antigens such as those derived from viruses and bacteria have been linked to long-term deleterious effects on the brain and other organs; yet, health outcomes subsequent to foreign antigen exposure vary depending in large part on the host’s immune system, in general, and on human leukocyte antigen (HLA) composition, in particular.  

Here we first provide a brief description of 3 conditions characterized by persistent long-term symptoms, namely long-COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and Gulf War Illness (GWI), followed by a brief overview of the role of HLA in the immune response to foreign antigens.  

We then discuss our Persistent Antigen (PA) hypothesis and highlight associations between antigen persistence due to HLA-antigen incongruence and chronic health conditions in general and the 3 “long” diseases above in particular.  

This review is not intended to cover the breadth and depth of symptomatology of those diseases but is specifically focused on the hypothesis that the presence of persistent antigens underlies their pathogenesis. 

5. Mechanism of Action of Bu Zhong Yi Qi Decoction in the Treatment of Chronic Fatigue Syndrome based on Network Pharmacology and Molecular Docking 

Jie Zhang, Xiaoju Liu, Xin Li, Zhenhao Ying, Wei Liu 

Pharmacological Research – Modern Chinese Medicine, 2022, 100139 


Objective: Bu Zhong Yi Qi (BZYQ) decoction is a classic prescription in Chinese history that has an obvious effect on improving fatigue symptoms. The objective was to investigate the substance basis and mechanism of BZYQ in the treatment of chronic fatigue syndrome (CFS) at the molecular level based on network pharmacology and molecular docking technology. 

Method: The active components and their targets of Huangqi, Baizhu, Renshen, Gancao, Danggui, Chaihu, Chenpi, Shenma in BZYQ were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database and the Encyclopedia of Traditional Chinese Medicine (ETCM). The UniProt database was used to calibrate the target information in BZYQ.  

CFS target genes were obtained from the GeneCards and DisGeNET databases. Cytoscape 3.7.2 software and the STRING 11.0 database were used to construct a protein–protein interaction (PPI) network and screen core targets.  

Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Subsequently, the binding affinity of BZYQ with key target receptors was assessed by molecular docking analysis. 

Result: BZYQ consists of 329 active components, 198 targets, and 6490 CFS-related targets. There were 180 common targets of BZYQ and CFS, including nitric oxide synthase Ⅱ (NOS2), estrogen receptor beta (ESR2), interleukin-2 (IL2), interleukin-6 (IL6), interleukin-1 beta (IL1B), MAP kinase-activated protein kinase 3 (MAPK3), vascular endothelial growth factor A (VEGFA), nitric oxide synthase Ⅲ (NOS3), and matrix metallopeptidase 2 (MMP2).  

More than 600 GO terms were obtained (Biological Process 630; Cellular Component: 95; Molecular Function:152) and 185 related signaling pathways, involving the AGE-RAGE signaling pathway in diabetic complications, pathways in cancer, TNF signaling pathway, lipid and atherosclerosis, cAMP signaling pathway, VEGF signaling pathway, calcium signaling pathway, and NF-kappa B signaling pathway. 

Conclusion: BZYQ achieves the purpose of treating CFS through the interaction mechanism of multiple components, multiple targets and multiple pathways.  

It advances the study of BZYQ to the clinical stage, expounds the effective mechanism of Traditional Chinese Medicine from an overall perspective, and provides ideas at the molecular level for future experimental study. 

6. The Depressing Truth about Depression Scales for People with Chronic Invisible Illness 

Pederson CL and Wagner BM 

J Health Sci Educ Vol 6(1): 1-6 


Background: Depression screening instruments are commonly used in research and the clinic.  

Aim: This study seeks to determine whether several common depression scales might be contaminated by somatic symptoms, thus overestimating depression in people with chronic invisible illness.  

Method: 685 chronically ill women with postural orthostatic tachycardia syndrome, chronic fatigue syndrome/myalgic encephalomyelitis, mast cell activation syndrome, Ehlers-Danlos syndrome and/or fibromyalgia took the Beck Depression Inventory-II (BDI-II). For a broader look at major self-report scales that assess depression in adults, we also investigated seven additional instruments listed on the American Psychological Association webpage.  

Results: In this sample, 38.5% appeared to have major depression as measured by the BDI-II, but this number decreased to 8% when somatic symptoms were removed. Further, there was a 31.2% increase in the number of participants in the minimal depression category of the BDI-II-Mood. Finally, 75% of the adult depression scales that we assessed had at least 40% of the score related to somatic symptoms.  

Conclusion: Care must be taken when assessing depression in people with chronic invisible illnesses to prevent artificial over-inflation of scores based on somatic complaints. 

Long-COVID Research References   

  1. Combining L-Arginine with Vitamin C Improves Long-COVID Symptoms: The Nationwide Multicenter LINCOLN Study 
  1. Neuropsychiatric sequelae of long COVID-19: Pilot results from the COVID-19 neurological and molecular prospective cohort study in Georgia, USA 
  1. ‘Long COVID’: Symptom persistence in children hospitalised for COVID-19 
  1. Therapeutic Approaches to the Neurologic Manifestations of COVID-19 
  1. Developing a long covid phenotype for post-acute COVID-19 in a national primary care sentinel cohort: an observational retrospective database analysis 
  1. SARS-CoV-2 infection in hamsters and humans results in lasting and unique systemic perturbations post recovery 
  1. COVID-19 Vaccine and Long COVID: A Scoping Review 
  1. Post–COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection 
  1. Postural Orthostatic Tachycardia Syndrome as a Sequela of COVID-19 
  1. Tackling Long COVID using international host genetics research collaboration 
  1. Effects of Long COVID on Sleep Health 
  1. Symptoms and risk factors for long COVID in non-hospitalized adults 
  1. Long COVID and the cardiovascular system – elucidating causes and cellular mechanisms in order to develop targeted diagnostic and therapeutic strategies: A joint Scientific Statement of the ESC Working Groups on Cellular Biology of the Heart and Myocardial & Pericardial Diseases  
  1. Modafinil: A Review and Its Potential Use in the Treatment of Long COVID Fatigue and  Neurocognitive Deficits  

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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