Research round up

ME/CFS Research Published 14 – 20 August 2021 

August 27, 2021

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).

All research relating to ME/CFS can be located in the ME Association: Index of ME/CFS Published Research. It is a FREE resource, available to anyone, and updated at the beginning of each month.

The Index provides an A-Z of published research studies, selected key documents and articles, listed by subject matter, on myalgic encephalomyelitis, myalgic encephalopathy, and/or chronic fatigue syndrome (ME/CFS).

You can use it to easily locate and read any research that you might be interested in regard to, e.g., epidemiology, infection, neurology, post-exertional malaise etc.

You can also find the Research Index in the Research section of the website together with a list of Research Summaries that provide more detailed lay explanations of the more interesting work that has been published to date.

It’s been a slightly busier week, with seven new research studies on ME/CFS and fourteen studies on Long Covid. We highlight two on ME/CFS from the selection below:   

The second study (2) is a review that examines Long Covid and ME/CFS. It concludes that there are a number of similar “biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state.” Individually these abnormalities have not been well studied in Long Covid but are reported in other neurological diseases. The study speculates what might be causing them and provides a good foundation for further studies.  

The sixth study (6) provides additional support to the view that metabolic dysfunction may be a cause of ME/CFS symptoms. Furthermore, compared to other research in our field, this study is of a reasonable size – using 83 patients with ME/CFS and 35 health controls – although it would still require a much larger study to confirm the results. We will provide a summary review explaining these results in due course.  

The third (3) and seventh (7) studies are also worth reading… 

ME/CFS Research References and Abstracts  

1. Fine mapping of the major histocompatibility complex (MHC) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suggests involvement of both HLA class I and class II loci  

Hajdarevic R, Lande A, Rekeland I, Rydland A, Strand EB, Sosa DD, Creary LE, Mella O, Egeland T, Saugstad OD, Fluge Ø, Lie BA, Viken MK. Brain Behav Immun. 2021 Aug 14;98:101-109. [Epub ahead of print.]  


The etiology of myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is unknown, but involvement of the immune system is one of the proposed underlying mechanisms.  

Human leukocyte antigen (HLA) associations are hallmarks of immune-mediated and autoimmune diseases. We have previously performed high resolution HLA genotyping and detected associations between ME/CFS and certain HLA class I and class II alleles.  

However, the HLA complex harbors numerous genes of immunological importance, and there is extensive and complex linkage disequilibrium across the region. In the current study, we aimed to fine map the association signals in the HLA complex by genotyping five additional classical HLA loci and 5,342 SNPs in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian Consensus Criteria, and 480 healthy Norwegian controls.  

SNP association analysis revealed two distinct and independent association signals (p ≤ 0.001) tagged by rs4711249 in the HLA class I region and rs9275582 in the HLA class II region. Furthermore, the primary association signal in the HLA class II region was located within the HLA-DQ gene region, most likely due to HLA-DQB1, particularly the amino acid position 57 (aspartic acid/alanine) in the peptide binding groove, or an intergenic SNP upstream of HLA-DQB1.  

In the HLA class I region, the putative causal locus might map outside the classical HLA genes as the association signal spans several genes (DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotype.  

Taken together, our results implicate the involvement of the MHC, and in particular the HLA-DQB1 gene, in ME/CFS. These findings should be replicated in larger cohorts, particularly to verify the putative involvement of HLA-DQB1, a gene important for antigen-presentation to T cells and known to harbor alleles providing the largest risk for well-established autoimmune diseases.   

2. Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome  

Paul BD, Lemle MD, Komaroff AL, Snyder SH. Proc Natl Acad Sci U S A. 2021 Aug 24;118(34):e2024358118.  


Although most patients recover from acute COVID-19, some experience postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC). One subgroup of PASC is a syndrome called “long COVID-19,” reminiscent of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  

ME/CFS is a debilitating condition, often triggered by viral and bacterial infections, leading to years-long debilitating symptoms including profound fatigue, post exertional malaise, unrefreshing sleep, cognitive deficits, and orthostatic intolerance. Some are skeptical that either ME/CFS or long COVID-19 involves underlying biological abnormalities.  

However, in this review, we summarize the evidence that people with acute COVID-19 and with ME/CFS have biological abnormalities including redox imbalance, systemic inflammation and neuroinflammation, an impaired ability to generate adenosine triphosphate, and a general hypometabolic state. These phenomena have not yet been well studied in people with long COVID-19, and each of them has been reported in other diseases as well, particularly neurological diseases.  

We also examine the bidirectional relationship between redox imbalance, inflammation, energy metabolic deficits, and a hypometabolic state. We speculate as to what may be causing these abnormalities. Thus, understanding the molecular underpinnings of both PASC and ME/CFS may lead to the development of novel therapeutics.  

3. A Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/CFS  

Mackay A. A. Front Neurol. 2021 Aug 2;12:701419.   


A significant proportion of COVID-19 patients are suffering from prolonged Post-COVID-19 Fatigue Syndrome, with characteristics typically found in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no clear pathophysiological explanation, as yet, has been provided.  

A novel paradigm for a Post-COVID-19 Fatigue Syndrome is developed here from a recent unifying model for ME/CFS. Central to its rationale, SARS-CoV-2, in common with the triggers (viral and non-viral) of ME/CFS, is proposed to be a physiologically severe stressor, which could be targeting a stress-integrator, within the brain: the hypothalamic paraventricular nucleus (PVN).  

It is proposed that inflammatory mediators, released at the site of COVID-19 infection, would be transmitted as stress-signals, via humoral and neural pathways, which overwhelm this stress-center. In genetically susceptible people, an intrinsic stress-threshold is suggested to be exceeded causing ongoing dysfunction to the hypothalamic PVN's complex neurological circuitry. 

In this compromised state, the hypothalamic PVN might then be hyper-sensitive to a wide range of life's ongoing physiological stressors. This could result in the reported post-exertional malaise episodes and more severe relapses, in common with ME/CFS, that perpetuate an ongoing disease state.  

When a certain stress-tolerance-level is exceeded, the hypothalamic PVN can become an epicenter for microglia-induced activation and neuroinflammation, affecting the hypothalamus and its proximal limbic system, which would account for the range of reported ME/CFS-like symptoms.  

A model for Post-COVID-19 Fatigue Syndrome is provided to stimulate discussion and critical evaluation. Brain-scanning studies, incorporating increasingly sophisticated imaging technology should enable chronic neuroinflammation to be detected, even at a low level, in the finite detail required, thus helping to test this model, while advancing our understanding of Post-COVID-19 Fatigue Syndrome pathophysiology.  

4. Potential of Activin B as a Clinical Biomarker in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)  

Gravelsina S, Nora‐Krukle Z, Vilmane A, Svirskis S, Vecvagare K, Krumina A, Murovska M. Biomolecules 2021, 11, 1189.  


Reliable serum biomarkers are of immense need for diagnostic purposes of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)—a disabling and complex disease for which diagnosis is mainly based on clinical symptoms.  

The aim of this study was to evaluate a possible diagnostic potential of activin B by directly comparing 134 cases of ME/CFS with 54 healthy controls.  

Analyses of human activin B level in plasma samples were performed using a validated human activin B ELISA assay. The results of the study show that activin B levels did not differ statistically significantly between ME/CFS patients and healthy controls (p = 0.6511). No gender or age‐related differences in activin B levels were observed in the ME/CFS group and healthy controls.  

The level of activin B tended to decrease with increasing visual analogue scale score (r = −0.2004; p = 0.5085) nevertheless the results obtained so far does not support the clinical utility of activin B as a biomarker for ME/CFS.  

5. Psychological Factors in Fibromyalgia and Chronic Fatigue Syndrome: Implications in Counseling  

Ojha A & Kumar D. Bharatiya Journal of Counselling Psychology, 1(1).  


The condition of Chronic Fatigue Syndrome (CFS) includes, fatigue and exhaustibility, muscle pain, muscle weakness, sore throat, fever, headache, impaired memory, concentration difficulties and sleep disorder.  

Whereas Fibromyalgia (FM) include symptoms such as aches, pain, stiffness and powerlessness in the muscles, fatigue, exhaustibility, headache, swelling, numbness, bowel problems, and sleeping difficulties. 

Sometimes, fibromyalgia patients report anxiety, tension, insomnia, and depressive mood, while some patients reported psychiatric disorders such as major depressive and anxiety disorders.  

Fibromyalgia (FM) often categorized, as a ‘functional somatic syndrome’, or sometimes, ‘somatization disorder’. Both CFS and FM share the symptomatology to a large extent.  

Patients with fibromyalgia also meet the criteria for chronic fatigue syndrome whereas individuals with chronic fatigue syndrome also manifest concurrent fibromyalgia. 

In absence of any biomedical test or a stable physiological marker, researchers also conceptualize chronic fatigue syndrome as a psychiatric disorder, or manifestation of a psychiatric condition such as somatization disorder.  

The present paper is a review of the studies conducted in the area to understand the nature, clinical picture and causal factors for these conditions. It is also aimed to provide the information about the underlying mechanism of CFS and FM to counsellors to incorporate this body of knowledge while counselling with the similar kind of problems.   

6. A map of metabolic phenotypes in patients with myalgic encephalomyelitis/chronic fatigue syndrome  

Hoel F, Hoel A, Pettersen IK, Rekeland IG, Risa K, Alme K, Sørland K, Fosså A, Lien K, Herder I, Thürmer HL, Gotaas ME, Schäfer C, Berge RK, Sommerfelt K, Marti HP, Dahl O, Mella O, Fluge Ø, Tronstad KJ. JCI Insight. 2021 Aug 23;6(16):149217.  


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease usually presenting after infection. Emerging evidence supports that energy metabolism is affected in ME/CFS, but a unifying metabolic phenotype has not been firmly established.  

We performed global metabolomics, lipidomics, and hormone measurements, and we used exploratory data analyses to compare serum from 83 patients with ME/CFS and 35 healthy controls.  

Some changes were common in the patient group, and these were compatible with effects of elevated energy strain and altered utilization of fatty acids and amino acids as catabolic fuels. 

In addition, a set of heterogeneous effects reflected specific changes in 3 subsets of patients, and 2 of these expressed characteristic contexts of deregulated energy metabolism.  

The biological relevance of these metabolic phenotypes (metabotypes) was supported by clinical data and independent blood analyses. 

In summary, we report a map of common and context-dependent metabolic changes in ME/CFS, and some of them presented possible associations with clinical patient profiles.  

We suggest that elevated energy strain may result from exertion-triggered tissue hypoxia and lead to systemic metabolic adaptation and compensation. Through various mechanisms, such metabolic dysfunction represents a likely mediator of key symptoms in ME/CFS and possibly a target for supportive intervention.  

7. Salivary DNA Loads for Human Herpesviruses 6 and 7 Are Correlated With Disease Phenotype in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome  

Lee JS, Lacerda EM, Nacul L, Kingdon CC, Norris J, O'Boyle S, Roberts CH, Palla L, Riley EM, Cliff JM. Front Med (Lausanne). 2021 Aug 6;8:656692.  


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex chronic condition affecting multiple body systems, with unknown cause, unclear pathogenesis mechanisms, and fluctuating symptoms which may lead to severe debilitation.  

It is frequently reported to have been triggered by an infection, but there are no clear differences in exposure to, or seroprevalence of, any particular viruses between people with ME/CFS and healthy individuals.  

However, herpes viruses have been repeatedly hypothesized to underlie the chronic relapsing/remitting form of ME/CFS due to their persistence in a latent form with periodic reactivation. It is possible that ME/CFS is associated with herpes virus reactivation, which has not been detectable previously due to insufficiently sensitive testing methods.  

Saliva samples were collected from 30 people living with ME/CFS at monthly intervals for 6 months and at times when they experienced symptom exacerbation, as well as from 14 healthy control individuals.  

The viral DNA load of the nine humanherpes viruses was determined by digital droplet PCR. Symptoms were assessed by questionnaire at each time point.  

Human herpesvirus (HHV) 6B, HHV-7, herpes simplex virus 1 and Epstein-Barr virus were detectable within the saliva samples, with higher HHV-6B and HHV-7 viral loads detected in people with ME/CFS than in healthy controls.  

Participants with ME/CFS could be broadly separated into two groups: one group displayed fluctuating patterns of herpesviruses detectable across the 6 months while the second group displayed more stable viral presentation. 

In the first group, there was positive correlation between HHV-6B and HHV-7 viral load and severity of symptom scores, including pain, neurocognition, and autonomic dysfunction. The results indicate that fluctuating viral DNA load correlates with ME/CFS symptoms: this is in accordance with the hypothesis that pathogenesis is related to herpesvirus reactivation state, and this should be formally tested.  

Herpesvirus reactivation might be a cause or consequence of dysregulated immune function seen in ME/CFS. The sampling strategy and molecular tools developed here permit such large-scale epidemiological investigations.  

Long-COVID Research References   

  1. Clinical characteristics of paediatric COVID-19 patients followed for up to 13 months  
  1. Inflammation-type dysbiosis of the oral microbiome associates with the duration of COVID-19 symptoms and long-COVID  
  1. Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination  
  1. Failure to prescribe: UK workers with occupational long covid-19 have been ignored  
  1. Autonomic dysfunction in SARS-COV-2 infection acute and long-term implications COVID-19 editor's page series  
  1. Occupational Therapy for the Long Haul of Post-COVID Syndrome: A Case Report  
  1. GPs need awareness about post-covid ME/CFS  
  1. Children rarely get ‘long COVID'  
  1. Chronic SARS-CoV-2, a Cause of Post-acute COVID-19 Sequelae (Long-COVID)?  
  1. Risk Predictors and Symptom Features of Long COVID Within a Broad Primary Care Patient Population Including Both Tested and Untested Patients  
  1. Persistence of symptoms after improvement of acute COVID19 infection, a longitudinal study  
  1. Charting a course for the management of long COVID  
  1. Long covid clinics should be run as research hubs  
  1. Neurologic Manifestations and Complications of COVID-19  


 Katrina Pears, Research Correspondent, ME Association  

Shopping Basket