MEA Research Roundup

ME/CFS and Long Covid Research: 11 – 17 October 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 11 – 17 October 2022 

Research has picked up again this week. There have been seven new ME/CFS studies and fifteen studies on Long Covid. 

We have highlighted two studies below: 

Paper one (1) is about redefining the Institute of Medicine’s criteria for ME/CFS to include neurocognitive impairment or orthostatic intolerance (OI) as core symptoms. This study debates whether OI is a core symptom, or OI comes hand-in-hand with neurocognitive impairment. In order to help understand this, 240 participants filled in questionnaires to examine how they fit the IOM criteria. 

Unsurprisingly, 93.4% of participants reported neurocognitive impairment, but the presence of OI without neurocognitive impairment only identified a further 1.7-4.5% of participants to meet the criteria. Therefore, this study showed that neurocognitive impairment and OI are not interchangeable symptoms (especially for diagnosis). 

Unfortunately, this study is behind a paywall so we cannot evaluate its strength in detail, particularly how participants were selected. However, from the abstract it doesn’t look like there was a control group included and also this study used self-reported symptoms only. We don’t know from the abstract if OI symptoms had been confirmed, which could lead to over reporting. However, the conclusion of the study does express the need to have a uniform method for defining OI. 

After reading comments on this study on the Science for ME forum, there is a huge variety of neurocognitive impairment symptoms caused with or without OI, further showing they are distinct entities. Such as; improved neurocognitive function when lying down, to brain fog resolving in some when lying down. Furthermore, problems with OI are not always present with the initial onset of illness and develop later on. These comments further demonstrate the huge variation in ME/CFS and the need for biomarkers as no symptoms are clearly defined. 

Paper seven (7) is also on orthostatic intolerance (OI) and comparing patients with Long Covid to those with ME/CFS with a post-viral Epstein-Barr (EBV) onset and ME/CFS patients with an insidious onset of the disease. This piece of research is from the well-known research group van Campen and Visser who focus on OI and cerebral blood flow studies.  

This study was disappointingly small with only 14 participants in each group who underwent OI assessment (including tilt test), cerebral blood flow measurements and cardiac index measurements.  

Interestingly, POTS (Postural tachycardia syndrome) was present in all Long Covid patients (100%), 43% of ME/CFS post-EBV patients and 50% of ME/CFS with insidious onset of disease. However, no significant differences between the groups were found (i.e. all results were similar for the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test). This means that the results are comparable between groups, further providing evidence for the similarities of ME/CFS and Long Covid. 

I do enjoy seeing studies by this research group, as they are often well thought out and provide interesting results. It is disappointing, however, to see the small sample size in this study, it is probably unlikely that a larger study would change the statistical significance of the results but it would increase its strength. It is also difficult to compare Long Covid patients who have had the illness for under two years, to those with ME/CFS with over 10 years duration, as you would expect changes or compensation in cardio function with reduced activity. However, this is also the first study I’ve come across where Long Covid patients have been compared to those with a known trigger of disease onset in ME/CFS, which does add strength to the study.  

You may also be interested in reading: 

  • Paper two (2) which looks for biomarkers for ME/CFS, which allowed disease severity to be distinguished between when looking at the HHV-6 load. Although, results could be due to the severely ill not being able to eliminate the virus. 
  • Paper four (4) which looks into the co-diagnosis of ME/CFS with fibromyalgia (FM), which also coincides with our recent report on the Royal Society of Medicine’s webinar on FM. 

ME/CFS Research References and Abstracts  

1. Orthostatic intolerance and neurocognitive impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 

Gaglio, Caroline L., Islam, Mohammed F., Cotler, Joseph and Jason, Leonard A. 

Epidemiologic Methods, vol. 11, no. 1, 2022, pp. 20210033. 


Objectives: The Institute of Medicine (IOM 2015. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington: The National Academies Press) suggested new criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which requires an endorsement of either neurocognitive impairment or orthostatic intolerance (OI) in addition to other core symptoms.  

While some research supports the inclusion of OI as a core symptom, others argue that overlap with neurocognitive impairment does not justify the either/or option.  

The current study assessed methods of operationalizing OI using items from the DePaul Symptom Questionnaire (DSQ-1 and -2) as a part of the IOM criteria. Evaluating the relationship between OI and neurocognitive symptoms may lead to a better understanding of diagnostic criteria for ME/CFS. 

Methods: Two-hundred and forty-two participants completed the DSQ. We examined how many participants met the IOM criteria while endorsing different frequencies and severities of various OI symptoms. 

Results: Neurocognitive impairment was reported by 93.4% of respondents. OI without concurrent neurocognitive symptoms only allowed for an additional 1.7–4.5% of participants to meet IOM criteria. 

Conclusions: Neurocognitive symptoms and OI overlap in ME/CFS, and our results do not support the IOM’s inclusion of neurocognitive impairment and OI as interchangeable symptoms. Furthermore, our findings highlight the need for a uniform method of defining and measuring OI via self-report in order to accurately study OI as a symptom of ME/CFS. 

2. Biomarkers in the diagnostic algorithm of myalgic encephalomyelitis/ chronic fatigue syndrome 

Gravelsina S, Vilmane A, Svirskis S, Rasa-Dzelzkaleja S, Nora-Krukle Z, Vecvagare K, Krumina A, Leineman I, Shoenfeld Y and Murovska M.  

Front. Immunol. 13:928945.  


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease that is mainly diagnosed based on its clinical symptoms. Biomarkers that could facilitate the diagnosis of ME/CFS are not yet available; therefore, reliable and clinically useful disease indicators are of high importance.  

The aim of this work was to analyze the association between ME/CFS clinical course severity, presence of HHV-6A/B infection markers, and plasma levels of autoantibodies against adrenergic and muscarinic acetylcholine receptors.  

A total of 134 patients with ME/CFS and 33 healthy controls were analyzed for the presence of HHV-6A/B using PCRs, and antibodies against beta2-adrenergic receptors (β2AdR) and muscarinic acetylcholine receptors (M3 AChR and M4 AChR) using ELISAs.  

HHV-6A/B U3 genomic sequence in whole-blood DNA was detected in 19/31 patients with severe ME/CFS, in 18/73 moderate ME/CFS cases, and in 7/30 mild ME/CFS cases. Severity-related differences were found among those with a virus load of more than 1,000 copies/106 PBMCs.  

Although no disease severity-related differences in anti-β2AdR levels were observed in ME/CFS patients, the median concentration of these antibodies in plasma samples of ME/CFS patients was 1.4 ng/ml, while in healthy controls, it was 0.81 ng/ml, with a statistically significant increased level in those with ME/CFS (p = 0.0103).  

A significant difference of antibodies against M4 AChR median concentration was found between ME/CFS patients (8.15 ng/ml) and healthy controls (6.45 ng/ml) (p = 0.0250).  

The levels of anti-M4 plotted against disease severity did not show any difference; however, increased viral load correlates with the increase in anti-M4 level. ME/CFS patients with high HHV-6 load have a more severe course of the disease, thus confirming that the severity of the disease depends on the viral load—the course of the disease is more severe with a higher viral load.  

An increase in anti-M4 AchR and anti-β2AdR levels is detected in all ME/CFS patient groups in comparison to the control group not depending on ME/CFS clinical course severity.  

However, the increase in HHV-6 load correlates with the increase in anti-M4 level, and the increase in anti-M4 level, in turn, is associated with the increase in anti-β2AdR level.  

Elevated levels of antibodies against β2AdR and M4 receptors in ME/CFS patients support their usage as clinical biomarkers in the diagnostic algorithm of ME/CFS. 

3. The Hindi Version of International Consensus Criteria: A Cross-cultural Adaptation and Validation Study for Myalgic Encephalomyelitis in Post-COVID Patients 

Shah M, Kakar A, Gogia A.  

J Assoc Physicians India 2022;70(10):59–63. 


Context: Fatigue is the most prominent feature of long COVID. With the increasing burden of long COVID cases post-acute phase of illness after recurrent waves of the pandemic, understanding its pathophysiology is of paramount importance.  

Such fatigue and post-viral illness could be associated with features of neuroimmune exhaustion and thus be a part of a larger syndrome such as myalgic encephalomyelitis (ME).  

Identifying the proportion of patients having ME from those experiencing fatigue would bring us one step closer to understanding the pathophysiology. International consensus criteria (ICC) originally published in English (ICC-E) is a valid and reliable tool for identifying cases of ME. However, a validated Hindi version of ICC-E is not available.  

Aims: To develop and validate an equivalent version of ICC-E in the native Hindi language (ICC-H) to suit Indian patients and health care workers even at peripheries and to make conducting large scales surveys more feasible.  

Subjects and methods: Once permission from the ethics board was granted, guidelines given by MAPI Research Trust were followed and ICC-H was developed from ICC-E, in the following steps: (a) translation to Hindi, (b) back translation, (c) comparison between the translated and back-translated version performed by experts, and (d) pre-pilot test in the intended population. The ICC-H was applied to 53 bilingual individuals knowing both Hindi and English.  

Statistical analysis used: The distribution of Hindi and English questionnaires was analyzed using the Chi-square test and Spearman’s correlation coefficient was used for correlation between answers of each question. Results: The score of individual items and its global score was highly correlated with each other (p<0.001). The scores of individual components and global scores of ICC-H at baseline and original ICC-E after 4 weeks did not differ significantly.  

Conclusion: This study shows that the ICC-H is a valid and reliable instrument for the assessment of ME. ICC-H can be used for Hindi speaking population for identifying cases of ME. 

4. Influence of Codiagnosis of Chronic Fatigue Syndrome and Habitual Physical Exercise on the Psychological Status and Quality of Life of Patients with Fibromyalgia 

Hinchado MD, Otero E, Navarro MDC, Martín-Cordero L, Gálvez I, Ortega E.  

J Clin Med. 2022 Sep 28;11(19):5735. 


Fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) are two diseases that are frequently codiagnosed and present many similarities, such as poor tolerance to physical exercise. Although exercise is recommended in their daily routine to improve quality of life, little is known about how CFS codiagnosis affects that.  

Using scientifically validated questionnaires, we evaluated the psychological state and quality of life of patients with FM (n = 70) and how habitual physical exercise (HPE) reported by patients with only FM (FM-only n = 38) or codiagnosed with CFS (FM + CFS, n = 32) influences those aspects. An age-matched reference group of “healthy” women without FM (RG, n = 70) was used.  

The FM-only group presented a worse psychological state and quality of life compared to RG, with no influence of CFS codiagnosis. The patients of the FM-only and FM + CFS groups who perform HPE presented better levels of stress and state anxiety, but with no differences between them. Depression and trait anxiety improved only in women with just FM.  

CFS codiagnosis does not worsen the psychological and quality of life impairment of FM patients and does not have a great influence on the positive effect of HPE. 

5. The Relationship Between Chronic Fatigue Syndrome and Depression: Mediating Roles of Executive Functions in Patients with Relapsing-Remitting Multiple Sclerosis 

Saffariantoosi M, Sadeghi-Firoozabadi V, Fathabadi J, Naser Moghadasi A. 

Practice in Clinical Psychology 2022; 10 (4)  


This study aimed to investigate the relationship between chronic fatigue syndrome (CFS) and depression with the mediating role of executive functions (EFs) in patients with relapsing-remitting multiple sclerosis (RRMS).  

The statistical population of this descriptive correlational study included all patients with RRMS who were referred to Tehran neurologists in the summer of 2021 and among them, 208 samples who were eligible to enter the study, were selected via available sampling methods.  

To collect data, Krupp et al.'s (1988) Fatigue Severity Scale (FSS), Nejati's Cognitive Abilities (NCA), and Beck Depression Inventory (II-BDI) were used. Pearson correlation method and structural equation modeling (SEM) were used to analyze the data.  

Of the seven subscales of EFs, the subscales of working memory, inhibitory control, selective attention, planning, and cognitive flexibility, which are called “cold” processes of EFs, were approved as mediators at the level (P <0.001), but the subscales of cognitive functioning, decision-making and controlled attention, which are hot functions and require emotional awareness and regulation of personal social behaviors and decision-making with emotional and personal interpretation and empathy, were not approved as mediating roles.  

The results also showed that in patients with RRMS, there was a significant relationship between CFS and depression, between CFS and EFs, and between EFs and depression (P <0.001). The results of the present study can be used in cognitive rehabilitation to improve EFs and consequently improve depression in patients with MS. 

6. Experiences of carers of youth, adult children and spouses with ME/CFS 

Baken DM, Ross KJ, Hodges LD, Batten L.  

Chronic Illn. 2022 Oct 18:17423953221121696. [Epub ahead of print.] 


Objectives: The debilitating nature of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) means that family members often take on a caring role. This study compared the experiences of people caring for three groups: youth, young adults, spouses. 

Methods: An opportunistic sample of 36 carers completed an online survey of open-ended questions asking about their experiences. Thematic analysis was used to consider the three sets of responses separately and Thematic Comparison was used to identify points of connection and disconnection across the sets. 

Results: The themes identified were very similar to those identified in past studies. Two super-ordinate themes were identified: “Lack of knowledge and understanding” and “Holistic Impact”. Though most sub-ordinate themes were evident across all three groups, important differences were found. The sub-ordinate themes “Caring Blindly”, “Emotional and physical health cost”, and “Impact on the whole family” were more evident amongst carers of youth while the theme “Worry for the future” was more evident from carers of young adults and spouses. 

Discussion: Differences seemed to be related to both the time since diagnosis and the life stage. A longitudinal study would help to understand how carer experiences change over the life course of caring for someone with ME/CFS. 

7. Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients 

van Campen CMC, Visser FC.  

Healthcare. 2022; 10(10):2058. 


Background: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease.  

Methods: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients.  

Results: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test.  

Conclusion: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS 

Long-COVID Research References  

  1. Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis 
  1. Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study 
  1. A new clinical challenge: supporting patients coping with the long-term effects of COVID-19 
  1. Persistence of Neutrophil extracellular traps and anti-cardiolipin auto-antibodies in post-acute phase COVID-19 patients 
  1. Post-COVID syndrome, inflammation, and diabetes 
  1. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity 
  1. SARS-CoV-2, long COVID, prion disease and neurodegeneration 
  1. Headaches and Dizziness as Disabling, Persistent Symptoms in Patients with Long COVID-A National Multicentre Study 
  1. Long COVID Risk and Pre-COVID Vaccination: An EHR-Based Cohort Study from the RECOVER Program 
  1. Long COVID: An inevitable sequela of SARS-CoV-2 infection 
  1. Negative correlation between ACE2 gene expression levels and loss of taste in a cohort of COVID-19 hospitalized patients: New clues to long-term cognitive disorders 
  1. Long-COVID in people with intellectual disabilities: A call for research of a neglected area 
  1. The Glittre-ADL test in non-hospitalized patients with post-COVID-19 syndrome and its relationship with muscle strength and lung function 
  1. A new clinical challenge: supporting patients coping with the long-term effects of COVID-19 
  1. Beyond COVID-19 and SARS-CoV-2, cardiovascular outcomes of “long covid” from a pathological perspective – a look back and road ahead 

Dr Katrina Pears,
Research Correspondent.
The ME Association.

Dr Katrina Pears - MEA Research Correspondent
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