ME/CFS Research Published 26 April – 2 May 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).

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.

Audio Commentary from Dr Katrina Pears

ME/CFS Research Published 26 April – 2 May 2022 

After a slow week last week, research has picked up again, with seven new ME/CFS studies and fourteen studies on Long Covid. There has been a range of different topics published this week. 

We highlight two of the studies below: 

Paper one (1) looks into neurocognitive impairment in ME/CFS, finding altered and reduced cortical volume and cortical thickness changes compared to healthy controls. Furthermore, the authors looked at these findings with clinical measures and autonomic measures (fatigue, heart-rate variability, sleep disturbance score, respiratory rate, and cognitive performance) and found a correlation between these findings. 

This is a very nicely presented study, however, this study is hugely limited by the small sample size (n=18) affecting its strength, as well as the need for a longitudinal study to show the progression in cortical volume and thickness changes. Furthermore, there is no explanation of what these findings mean to people with ME/CFS. 

Hopefully we will see these findings coming together in a larger study as we have seen several studies of late from this author which use neuroimaging and showing differences in the brains of people with ME/CFS (for example, these previous published studies: Thapaliya et al., 2020; Thapaliya et al., 2021; Thapaliya et al., 2022).  

Papers two (2) and six (6) both are preprint fairly large studies which cover the topic of Epstein-Barr virus (EBV), which we see come up a lot in ME/CFS research, with a number of studies suggesting that this virus plays an important part in the development of chronic illnesses. Both of these studies show very similar results, finding potential biomarker signatures to identify patients with ME/CFS. In summary: 

 Paper two (2): Sepúlveda et al. Paper seven (6): Cox et al. 
Sample size 92 ME/CFS patients and 50 health controls  351 ME/CFS patients and 77 health controls 
Methodology Re-analysing previous results and use of statistical methods.  Analysing blood samples for certain compounds. 
Specific findings Significant results were only found when samples were restricted to patients who could identify a disease onset which allowed two important antigens to be identified.   A range of complex interactions between different compounds in the blood, such as: – Increase in activin A (a glycoprotein with roles in inflammation and immunity) –  Increase in IL-21 (a cytokine with regulatory effects on the immune system) – These two findings correlated to levels of protein deoxyuridine-triphosphate nucleotidohydrolase (dUTPase) (an enzyme involved in pyrimindine metabolism) – These findings combined show abnormal activity of the lymphoid tissues (germinal center GC) which provide protection against infection.  
Implications Findings were established with pre-defined case criteria, allowing significant proteins to be identified. Combination of screening needed to identify ME/CFS, showed huge heterogeneity of patients and blood levels contribute to symptomology. 

In conclusion, both of these studies looked at a complex set of biological interactions, and both conclude that further work is needed to confirm these promising findings. As it stands, I feel a lot more work is needed to confirm a reliable biomarker for ME/CFS and to fully understand the connection to EBV. It would be interesting to know what results could be obtained if these studies were combined. 

You may also be interested in reading paper:  

  • Five (5) showing elevated levels of certain proteins (ATG13) involved in the removal of damaged cells, in order to regenerate new healthier cells (autophagy). 
  • Seven (7) on the impact on quality of life for people with ME/CFS, their partners and family members, and is highlighted on our website. The authors also provide a nice list of the strengths and limitations of their study. One of the researchers for this study was Dr Nina Muirhead, who is a doctor with ME/CFS and is working towards educating other doctors about ME/CFS. 

ME/CFS Research References and Abstracts  

1. Alteration of Cortical Volume and Thickness in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome 

Thapaliya K, Marshall-Gradisnik S, Staines D, Su J and Barnden L  
Front. Neurosci. 16:848730. 

Abstract 

Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) patients suffer from neurocognitive impairment.  

In this study, we investigated cortical volumetric and thickness changes in ME/CFS patients and healthy controls (HC). We estimated mean surface-based cortical volume and thickness from 18 ME/CFS patients who met International Consensus Criteria (ICC) and 26 HC using FreeSurfer.  

Vertex-wise analysis showed significant reductions in the caudal middle frontal gyrus (p = 0.0016) and precuneus (p = 0.013) thickness in ME/CFS patients compared with HC.  

Region based analysis of sub-cortical volumes found that amygdala volume (p = 0.002) was significantly higher in ME/CFS patients compared with HC.  

We also performed interaction-with-group regressions with clinical measures to test for cortical volume and thickness correlations in ME/CFS with opposite slopes to HC (abnormal).  

ME/CFS cortical volume and thickness regressions with fatigue, heart-rate variability, heart rate, sleep disturbance score, respiratory rate, and cognitive performance were abnormal.  

Our study demonstrated different cortical volume and thickness in ME/CFS patients and showed abnormal cortical volume and thickness regressions with key symptoms of ME/CFS patients. 

2. Revisiting IgG antibody reactivity to Epstein-Barr virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and its potential application to disease diagnosis 

Nuno Sepúlveda, João Malato, Franziska Sotzny, Anna D Grabowska, André Fonseca, Clara Cordeiro, Luís Graça, Przemyslaw Biecek, Uta Behrends, Josef Mautner, Francisco Westermeier, Eliana M Lacerda, Carmen Scheibenbogen 
medRxiv- Preprint 

Abstract 

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.  

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-analysed 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 be used to distinguish patients from healthy controls.  

A similar finding was obtained when comparing patients with noninfectious or unknown disease trigger to healthy controls. However, when data analysis was restricted to the comparison between HCs and patients with a putative infection at 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. When a bioinformatic analysis was performed on these epitopes, it revealed a potential molecular mimicry with several human proteins.  

To confirm these promising findings, a follow-up study will be conducted in a separate cohort of patients. 

3. Separating Patients with SEID from Those with CFS in the French ME/CFS Association, with Some Thoughts on Nomenclature 

Campagne, J.; Fornasieri, I.; Andreani, B.; Eginard, M.; de Korwin, J.-D. 
Diagnostics 2022, 12, 1095. 

Abstract 

In 2015, the American Institute of Medicine, now called the National Academy of Medicine, (IOM/NAM) proposed new diagnostic criteria for both Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and a new label: Systemic Exertion Intolerance Disease (SEID).  

This study aimed to evaluate the SEID criteria among members of the French Association of ME/CFS (ASFC) and their opinion about this new name.  

We sent an anonymous questionnaire to 494 ASFC members, using French-translated questions derived from the IOM/NAM tool kit. Among the 178/231 responding subjects who reported ME/CFS diagnosis, 150 (84%) met the criteria of SEID.  

For each set of questions, we identified some of them that significantly distinguished SEID from non-SEID patients concerning unrefreshing sleep, cognitive disorders, and orthostatic intolerance items.  

Forty-six percent of the respondents considered the “SEID” terminology as more appropriate than “CFS”, 39% considered it inappropriate, and 15% had no opinion. Some questions better identified the SEID criteria.  

The IOM/NAM SEID criteria captured a large part of ASFC members suffering from ME/CFS. However, this new SEID label was not well accepted by the subjects, nor were the other denominations, suggesting that a better term should be found. Pending development of specific markers, further work with patient communities is needed to find a more suitable label 

4. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE) 

Gunnar Gottschalk, Daniel Peterson, Konstance Knox, Marco Maynard, Ryan J. Whelan, Avik Roy 
Molecular and Cellular Neuroscience,202: 103731 

Abstract 

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown.  

Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy.  

A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls.  

Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells.  

Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells.  

Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS. 

5. Long-COVID post-viral chronic fatigue syndrome and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study 

Hussein Kadhem Al-Hakeim, Haneen Tahseen Al-Rubaye, Dhurgham Shihab Al-Hadrawi, Abbas F. Almulla, Michael Maes 
medRxiv- Preprint 

Abstract 

The immune-inflammatory response during the acute phase of COVID-19, as assessed using peak body temperature (PBT) and peripheral oxygen saturation (SpO2), predicts the severity of chronic fatigue, depression and anxiety (“physio-affective”) symptoms three to four months later.  

The present study was performed to characterize whether the effects of SpO2 and PBT on the physio-affective phenome of Long COVID are mediated by immune, oxidative and nitrosative stress (IO&NS) pathways.  

This study assayed SpO2 and PBT during acute COVID-19, and C-reactive protein (CRP), malondialdehyde (MDA), protein carbonyls (PCs), myeloperoxidase (MPO), nitric oxide (NO), zinc, and glutathione peroxidase (Gpx) in 120 Long COVID individuals and 36 controls.  

Cluster analysis showed that 31.7% of the Long COVID patients had severe abnormalities in SpO2, body temperature, increased oxidative toxicity (OSTOX) and lowered antioxidant defenses (ANTIOX), and increased total Hamilton Depression (HAMD) and Anxiety (HAMA) and Fibromylagia-Fatigue (FF) scores.  

Around 60% of the variance in the physio-affective phenome of Long COVID (a factor extracted from HAMD, HAMA and FF scores) was explained by OSTOX/ANTIOX ratio, PBT and SpO2.  

Increased PBT predicted increased CRP and lowered ANTIOX and zinc levels, while lowered SpO2 predicted lowered Gpx and increased NO production. Both PBT and SpO2 strongly predict OSTOX/ATIOX during Long COVID.  

In conclusion, the impact of acute COVID-19 on the physio-affective symptoms of Long COVID is partly mediated by OSTOX/ANTIOX, especially lowered Gpx and zinc, increased MPO and NO production and lipid peroxidation-associated aldehyde formation. Postviral physio-affective symptoms have an inflammatory origin and are partly mediated by neuro-oxidative toxicity. 

6. EBV/HHV-6A dUTPases contribute to Myalgic Encephalomyelitis/Chronic-Fatigue-Syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities 

Cox BS, Alharshawi K, Mena-Palomo I, Lafuse WP, Ariza ME. 
JCI Insight. 2022 Apr 28:e158193. [Epub ahead of print.] 

Abstract 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating multisystem illness of unknown etiology for which there is no cure and no diagnostic tests available.  

Despite increasing evidence implicating EBV and human herpesvirus-6A (HHV-6A) as potential causative infectious agents in a subset of ME/CFS patients, there are few mechanistic studies to address a causal relationship. 

In this study we examined a large ME/CFS cohort (n=351) and 77 controls and demonstrate a significant increase in activin A and IL-21serum levels, which correlated with seropositivity for antibodies to the EBV and HHV-6 protein deoxyuridine-triphosphate nucleotidohydrolase (dUTPase), but not CXCL13.  

These cytokines are critical for T follicular helper (TFH) cell differentiation, generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive TFH cell differentiation via an activin A-dependent mechanism.  

The lack of simultaneous CXCL13 increase with IL-21 indicates impaired TFH-function in ME/CFS.  

In vitro studies revealed that virus-dUTPases strongly induced activin A secretion while in vivo, EBV-dUTPase induced the formation of splenic marginal zone B and invariant NKTFH cells.  

Altogether, our data indicate abnormal germinal center (GC) activity in ME/CFS subjects and highlight a mechanism by which EBV and HHV6-dUTPases may alter GC and extrafollicular Ab responses. 

7. Impact of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) on the quality of life of people with ME/ CFS and their partners and family members: an online crosssectional survey 

Vyas J, Muirhead N, Singh R, et al. 
BMJ Open 2022; 12: e058128. 

Abstract 

Objectives: The aim of this study was to assess the impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the quality of life (QoL) of people with ME/CFS and their relative or partner (family member). 

Design: A patient-partner, multinational, subject-initiated, cross-sectional online survey. 

Setting: International survey using ME/CFS charities, support groups and social media. 

Participants: Participants were self-selected with recruitment via social media. Inclusion criteria were aged 18 years or over and reported diagnosis of ME/CFS by health professional. 1418 people with ME/CFS and their 1418 family members from 30 countries participated in the survey. Participants with ME/CFS had a mean age of 45.8 years (range 18–81) and were predominantly women (1214 (85.6%) of 1418). Family members had a mean age of 51.9 years (range 18–87) and were predominantly men (women: 504 (35.5%) of 1418). 991 (70%) family members were partners of the people with ME/CFS. 

Interventions: EuroQoL-5 Dimension (EQ-5D-3L), completed by people with ME/CFS, and Family Reported Outcome Measure (FROM-16) questionnaire, completed by family members. 

Results: The mean overall health status on a Visual Analogue Scale for people with ME/CFS was 33.8 (0=worst, 100=best). People with ME/CFS were most affected by ability to perform usual activities, pain, mobility, self-care and least impacted by anxiety. For family members, the overall mean FROM-16 score was 17.9 (0=no impact, 32=worst impact), demonstrating a major impact on QoL. Impact on QoL was significantly correlated between the person with ME/CFS and their family member (p<0.0001). Family members were most impacted emotionally by worry, frustration and sadness and personally by family activities, holidays, sex life and finances. 

Conclusions: To the best of our knowledge, this is the largest study on the impact of the QoL of persons with ME/CFS and their family members. While open participation surveys are limited by selection bias, this research has revealed a significant worldwide burden of ME/CFS on the QoL of people with ME/CFS and their family members. 

Strengths and limitations of this study: 

  • International study with patient and public involvement in the study design. 
  • Use of validated quality of life questionnaires for persons with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and their family members. 
  • Patients were only included in the data analysis if they reported a healthcare professional diagnosis of ME/CFS. 
  • However, recruitment was biased towards English-speaking participants 
  • Open participation can lead to sampling bias, limiting the generalisability of these findings. 

Long-COVID Research References   

  1. Persistent COVID-19 symptoms at least one month after diagnosis: A national survey 
  1. Long COVID: A growing problem in need of intervention 
  1. Long COVID-19: Psychological symptoms in COVID-19 and probiotics as an adjunct therapy 
  1. Cardiac tamponade – an unexpected “long COVID-19” complication 
  1. Long COVID: systemic inflammation and obesity as therapeutic targets 
  1. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study 
  1. Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism 
  1. Post-COVID-19 fatigue: the contribution of cognitive and neuropsychiatric symptoms 
  1. Post-viral mental health sequelae in infected persons associated with COVID-19 and previous epidemics and pandemics: Systematic review and meta-analysis of prevalence estimates 
  1. Long COVID in Children and Adolescents 
  1. The incidence and characteristics of chronic pain and fatigue after 12 months later admitting with COVID-19; The Post- COVID 19 syndrome 
  1. Restless legs syndrome is associated with long-COVID in women 
  1. Hormonal trends in patients suffering from long COVID symptoms 
  1. Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment 

Dr Katrina Pears
MEA Research Correspondent

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