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Research Digest 23/2/23

Welcome to the 92nd 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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Exosome-associated mitochondrial DNA from patients with myalgic encephalomyelitis/chronic fatigue syndrome stimulates human microglia to release IL-1β

Authors: Tsilioni I, Natelson B, Theoharides TC (Tufts University, USA)

Publication: European Journal of Neuroscience


While some evidence suggests that ME/CFS may be an autoimmune disease with neuroinflammation, cytokine studies have yielded inconsistent results. Previous research has demonstrated links between brain disorders and cytokines, such as IL-1β, but to date, no such study has been completed in ME/CFS. The authors compared mitochondrial DNA (mtDNA) associated with serum exosomes in healthy controls (HC) and in ME/CFS patients before (ME/CFS-BE) and after (ME/CFS-AE) exercise and used these exosomes to stimulate cultured human microglia to determine their pathogenicity.

This study included a small sample of female participants with ME/CFS (Fukuda criteria) and a small number of age- and sex-matched healthy controls (HC) having no history of physical trauma. ME/CFS participants had blood serum drawn before (ME/CFS-BE) and after (ME/CFS-AE) a maximal exercise test performed on an electronically braked cycle ergometer. HC serum was purchased. The serum samples were analysed using transmission electron microscopy (TEM), Western blot analysis, DNA extraction, and stimulation of human microglia by the serum-derived exosomes.

ME/CFS-BE samples showed significantly lower levels of total exosome-associated protein compared to healthy controls, with ME/CFS-AE levels even more significantly lowered. In contrast, exosome-associated mtDNA increased after exercise, as did the ratio of mtDNA to protein. Cultured human microglia exposed to ME/CFS-AE exosomes released nearly 1.5 times more IL-1β than HC or (ME/CFS-BE).

This is the first study to examine extracellular vesicles and their contents before and after exercise in ME/CFS. The results give weight to the notion of a pro-inflammatory state in ME/CFS patients, particularly post-exertion. The authors have previously suggested that this neuroinflammation could be localized in mast cells in the hypothalamus, causing dysfunctional homeostasis, however, this study did not examine exosome markers to determine the cells of origin. They suggest that IL-1β, rather than being an indicator of the severity or duration of the disease, may simply be a sign of the presence of the disease, and mtDNA is a mediator of the auto-inflammatory response.

Figure: Exosome-associated protein in healthy controls (HC) and ME/CFS patients before exercise (BE) or after exercise (AE). Each dot represents individual subjects.

Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults – A Systematic Review and Meta-analysis

Authors: Durstenfeld MS, Sun K, Tahir P, Peluso MJ, Deeks SG, Aras MA, … Hsue PY (University of California, USA).

Publication: Cardiology


A frequently reported symptom of Long-COVID is reduced exercise capacity. Cardiopulmonary exercise testing (CPET) is the gold standard in measuring exercise capacity and assisting in the diagnosis of causes of exercise limitation. This is achieved by examining oxygen consumption at rest and during exercise. This systematic review sought to summarise the findings of existing literature in this area.

The authors completed two literature searches and a total of 38 studies were included in the review.  Studies were only included if participants experiencing Long-COVID symptoms were at least three months post-infection. Two blinded reviewers independently assessed each study to determine whether it met the inclusion criteria. A meta-analysis was completed on the study results, of a total of 2160 participants.

The authors found that exercise capacity (as measured by peak oxygen consumption) was reduced in individuals experiencing symptoms consistent with long-COVID when compared to individuals who were not experiencing ongoing symptoms 3 months post-infection. The authors found that deconditioning and peripheral limitations were commonly reported in studies, as well as dysfunctional breathing and chronotropic incompetence.

The authors acknowledged that distinguishing deconditioning from other issues such as mitochondrial dysfunction or disrupted oxygen delivery was difficult without adjunctive testing and noted that none of the studies which included adjunctive cardiac testing concluded that deconditioning was responsible for observed results.

The authors also noted that there were multiple limitations to the studies included in this systematic review, including small sample sizes, selection bias, lack of appropriate statistical methods, variable interpretation of CPET results, and inadequately addressed confounding variables. They recommend CPET be used as a maximal test with adjunctive cardiac testing to assess chronotropy. They also recommend careful assessment following CPET to adequately assess post-exertional malaise.

Based on the available evidence, the authors conclude that CPET was effective in providing insight into the mechanisms for reduced exertion tolerance and exercise capacity between individuals experiencing Long-COVID symptoms and those experiencing no symptoms. The authors hypothesise that the differences in exertion tolerance may be due to altered autonomic function, endothelial dysfunction, and muscular or mitochondrial pathology.

Tissue-specific signature of HHV-6 infection in ME/CFS

Authors: Kasimir F,  Toomey D,  Liu Z , Kaiping AC, Ariza ME, Prusty BK (Julius-Maximilians-University of Würzburg, Germany)

Publication: Frontiers in Molecular Biosciences


Human herpesviruses (HHVs) are a common family of viruses that lie dormant after infection and are known to reside in a large proportion of the population. These viruses have been identified as a possible pathogen associated with many neurological diseases, including multiple sclerosis, Alzheimer’s disease and ME/CFS. Renewed interest in Epstein-Barr virus (EBV) (Epstein-Barr) and human herpesvirus 6 (HHV-6) was sparked by the search for answers to Long Covid symptoms. The aim of this study was to look for evidence of HHV-6 and EBV viruses in ME/CFS post-mortem brain tissue.

This was a small study with three ME/CFS patients and three non-ME/CFS controls who had other clinical diagnoses (anorexia, non-Hodgkin’s lymphoma and breast cancer).

Immunofluorescence and FISH (Fluorescence in situ hybridization) were used to identify HHV-6 and EBV in post-mortem brain tissue samples from different regions of the brain.

Two out of the three ME/CFS patients showed evidence of HHV-6 reactivation in multiple brain tissue samples, compared with none of the control samples. All ME/CFS samples were positive for EBV while all non-ME/CFS controls were negative. There was also evidence of co-infection of EBV and HHV-6 in two ME/CFS samples. 

The authors note that the small size is a limitation of this study and that ME/CFS post-mortem brain tissues are difficult to obtain.

The authors conclude that a lot more research is needed but it is possible that HHV-6 viral infection in brain tissues could cause some of the ME/CFS characteristics and that HHV-6 and EBV warrant further investigation.

‘We’re all vulnerable’: One in 10 people will end up with long COVID, new study says

Authors: McMillan A

Publication: Sydney Morning Herald


A new report suggests there may already be as many as 65 million people living with Long COVID globally, with an estimated 10% of those infected with COVID-19 developing the condition. Health experts are recommending a rethink of Australia’s approach to managing COVID-19 infections.

Professor Brendan Crabb, CEO of the Burnet Institute, described the report as “jaw-dropping”.

“Our clear national policy is to protect the aged, protect those who are immunocompromised, but in the rest of us, allow the transmission to go pretty much unchecked,” he said. “But if you factor in Long COVID, then we’re all vulnerable.” He is encouraging political leaders to “change the narrative” around COVID-19 infection and to encourage mitigation measures like masks, air ventilation and vaccine boosters.

‘We can learn a lot about long COVID from years of diagnosing and treating chronic fatigue syndrome

Authors: Annesley S, Josev E and Tavoletti, M.

Publication: The Conversation


Authored by Emerge Australia’s Research Manager, Michelle Tavoletti and ME/CFS researchers Sarah Annesley (LaTrobe University) and Elisha Josev (Murdoch Children’s Research Institute), this article outlines the many lessons that ME/CFS can offer Long COVID researchers and clinicians in diagnosing and managing the condition.


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