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  5. Research Digest 27/10/22

Research Digest 27/10/22

Welcome to the 89th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Phenotypic characteristics of peripheral immune cells of Myalgic Encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study

Authors: Jahanbani F, Maynard RD, Sing JC, Jahanbani S, Perrino JJ, Spacek DV, … Snyder MP (Stanford University School of Medicine, USA)
Publication: PLoS ONE
Link: http://doi.org/10.1371/journal.pone.0272703
 
As ME/CFS is known to be associated with immunological changes and mitochondrial dysfunction, this study sought to examine changes in the morphology of mitochondria and other organelles, as well as physiological alteration of activated and inactive immune cells in ME/CFS patients, and to compare these to biologically relevant sequences of exome.
 
The cohort consisted of four males: a pair of identical twins (one with moderate ME/CFS and one healthy), plus one patient suffering severe ME/CFS and one age- and gender-matched healthy control. The ME/CFS patients were diagnosed by the Canadian Consensus Criteria, International Consensus Criteria, and Institute of Medicine criteria. Samples of blood were taken and separated into T cells and peripheral blood mononuclear cells (PBMCs), which were then each separated into two sub-samples, one of which was stimulated to activate the immune response. These samples were closely examined under transmission electron microscopy (TEM) for numerical and morphological changes. Whole exome sequencing was performed using target probes to enhance coverage in difficult-to-sequence regions within sets of biomedically and medically relevant genes to filter for variants.
 
Whilst the number of mitochondria per cell did not differ between patient and control, the proportion of swollen mitochondria and those with abnormal characteristics, increased with disease severity. Activated T cells showed higher levels of apoptotic and necrotic cell death proportional to disease severity. A subset of the activated PBMCs of the severe ME/CFS patient showed large numbers of intracellular lipid droplet-like organelles. Rosette-like adhesion of activated platelets corresponded to disease severity. Whole exome sequencing revealed a gene associated with Niemann-Pick disease (NPD), an illness associated with lipid storage dysfunction, in the patient with severe ME/CFS, that was not present in the rest of the cohort.
 
This study suggests distinct dysfunction in the immune cells of ME/CFS patients, particularly immune cells that have been activated, as well as showing specific organelle abnormalities. The authors acknowledge that their study lacks statistical power due to the sample size however, they hope that replication with a larger cohort, using other cell death assays and with more measurement points, will yield a greater understanding of the morphological changes in immune cells in ME/CFS.

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No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Authors: Ueland M, Hajdarevic R, Mella O, Strand EB, Sosa DD, Saugstad OD… & Viken MK (Oslo University Hospital, Norway).
Publication: Translational Psychiatry
Link: http://www.nature.com/articles/s41398-022-02046-1.pdf
 
Many studies have reported on the involvement of the immune system in ME/CFS disease processes, and some genetic association studies also suggested possible hereditary components. The authors have previously completed a small-scale study that found an association with the human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. This study aimed to replicate these previous findings on a larger scale in the T-cell receptor alpha (TRA) locus, where the HLA molecules and T-cell receptors interact.
 
Participants for this study included 409 ME/CFS patients (Canadian Consensus Criteria) and 810 healthy controls from the Norwegian Bone Marrow Donor Registry. Data was also collected from the ME/CFS UK Biobank with 2105 ME/CFS patients and 4786 healthy controls. Genotyping investigation was completed with numerous Single Nucleotide Polymorphisms (SNPs) in the TRA locus, including the two variants previously reported to be associated with ME/CFS: rs11157573 and rs17255510.
 
The authors found no associations in the Norwegian population group, and no cohort showed associations with the previously reported SNPs. Although other SNPs showed some indications of association, none remained statistically significant after correction for multiple testing. The authors noted that these results failed to identify any reliable association with variants in the TRA locus.
 
The authors conclude that the study size utilised was below the optimal level which may have interfered with results and that TRA involvement in the pathogenesis of ME/CFS should not be ruled out based on these results. The authors propose that further studies and meta-analyses are needed to further investigate this area. 

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Combination of whole-body cryotherapy with static stretching exercises reduces fatigue and improves functioning of the autonomic nervous system in Chronic Fatigue Syndrome

Authors: Kujawski S, Słomko J, Godlewska BR, Agnieszka Cudnoch‑Jędrzejewska A, Murovska M, Newton JL, … Zalewski P (Warsaw Medical University, Poland)
Publication: Journal of Translational Medicine
Link: http://link.springer.com/content/pdf/10.1186/s12967-022-03460-1.pdf

Intensive cooling of the skin surface associated with the application of a cryogenic factor at temperatures of −120 °C has been shown to initiate a number of physiological changes within the cardiovascular and autonomic systems. The benefits of cryotherapy have been relatively well explored in a number of contexts such as sporting injuries, muscle damage, inflammation or sleep problems and have shown to improve health-related quality of life in fibromyalgia patients.
 
The aim of this study was to explore the tolerability and effect of static stretching (SS) and whole-body cryotherapy (WBC) upon fatigue, daytime sleepiness, cognitive functioning and objective and subjective autonomic nervous system functioning in those with ME/CFS.
 
 
This study recruited 32 participants with ME/CFS (Fukuda criteria) and 18 healthy controls for a SS and WBC program, consisting of five sessions per week over two weeks. The participants were exposed to extremely low temperatures in a WBC chamber for 0.5 to 2.5 min, and exposure time increased incrementally (1–3 days for 0.5 min, 4–5 days for 1 min, 6–7 days for 1.5 min, 8–9 days for 2 min, 10 days for 2.5 min). Immediately after leaving the cryogenic chamber, patients underwent kinesiotherapy lasting 30 min. Kinesiotherapy procedures included breathing exercises and passive stretching exercises of the muscles of the major joints.
 
A significant decrease in fatigue was recorded in the ME/CFS group in response to SS + WBC. Certain domains of cognitive functioning (speed of processing visual information and cognitive flexibility) also improved in response to SS + WBC in both ME/CFS and HC groups.
 
The authors conclude that the study confirmed that WBC is well tolerated by those with ME/CFS and leads to symptomatic improvements associated with changes in cardiovascular and autonomic function. The authors noted significant cognitive improvements must be considered against the learning effect associated with repeated testing. The authors attempted to mitigate this effect by applying the same tests to both ME/CFS and control groups. However, as both groups improved, at least a partial learning effect cannot be overlooked.

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Activity monitoring and patient-reported outcome measures in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients

Authors: Rekeland IG, Sørland K, Bruland O, Risa K, Alme K, Dahl O, … and Fluge Ø (Haukeland University Hospital, Norway).
Publication: Plos One
Link: http://doi.org/10.1371/journal.pone.0274472
 
ME/CFS clinical trials have been hampered by many methodological issues, including inconsistent outcome measures and selection criteria. The aim of this study was to improve future trials by assessing the potential of activity trackers as outcome measures. The authors used activity trackers to: (i) explore natural symptom variations, (ii) the feasibility of continuous activity monitoring and (iii) compare activity data with patient-reported outcomes (PROMS).
 
This study included twenty-seven participants (25 female, 2 male) with mild, moderate or severe ME/CFS (Canadian Consensus Criteria) and a mean age of 42.3 years. Participants wore a Fitbit tracker continuously for six months and wore a SenseWear activity bracelet for seven days at baseline, at three and six months. At baseline and follow-up, they completed the Short Form 36 Health Survey (SF-36) and the DePaul Symptom Questionnaire–Short Form (DSQ-SF) to measure symptoms and function.
 
The mean number of steps per day decreased with increasing ME/CFS severity, which is consistent with other studies. Scores on five of the six SF-36 domains (physical function, bodily pain, general health, social function, and vitality) were low. Scores in the mental health domain were close to those of the general population. There were significant associations between steps per day and physical and social function domains, as well as the DSQ-SF. The resting heart rate was stable over the six-month study period.

The authors acknowledged that their small sample size was a limitation of their study, which did not allow firm conclusions to be drawn.  The authors also noted that the Fitbit devices recorded a significantly higher number of steps than SenseWear and that participants reported that the Fitbit devices at times recorded steps when the participant was engaged in an activity other than walking (such as knitting or cooking).  

The authors conclude that the use of activity trackers has potential for improved outcomes in future clinical trials. Given the complexity of ME/CFS, the authors recommend the combined use of both continuous activity monitoring and self-report measures of symptoms and function.

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Advocates disappointed at lack of funding for Long COVID research and support services

Publication: ABC News
Link: http://www.abc.net.au/news/2022-10-27/disappointment-after-no-mention-of-long-covid-in-budget/101584806

Emerge Australia’s CEO, Anne Wilson, responds to the lack of funding for ME/CFS and Long COVID services in the federal budget.

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