Research Digest 01/12/22

Welcome to the 90th 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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The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Authors: Nunes JM, Kruger A, Proal A, Kell DB, Pretorius E (Stellenbosch University, South Africa)
Publication: Pharmaceuticals
Link: https://doi.org/10.3390/ph15080931

The authors’ previous study into Long COVID/Post-Acute Sequelae of COVID-19 (PASC) found that the patients’ platelet-poor plasma (PPP) was demonstrably hypercoagulable and that immune cells showed elevated activity. Due to the similar symptoms of PASC and ME/CFS, this study examined whether PPP from ME/CFS patients would be analogous.

Blood samples were taken from 15 healthy controls and 25 patients with ME/CFS (self-reported through a questionnaire based on the International Consensus Criteria). Whole blood (WB) and PPP were analysed using thromboelastography, examining viscoelasticity, microclotting, and platelet appearance.

The ME/CFS cohort demonstrated clots in WB that were greater in size and strength than those of healthy controls, and a hypercoagulable state was observed in both WB and PPP. PPP of ME/CFS patients, both treated and untreated with thrombin, contained substantial amounts of fibrinaloid microclots. Compared to those of the controls, the platelets of ME/CFS patients demonstrated a severe tendency to greater spread, clumping, and granulation, as well as hyperactivation.

The authors acknowledged that the small sample size, self-reported symptom severity and comorbidities in ME/CFS were limitations of their study.

Supplementary studies need to be undertaken to determine whether excessive clotting leads to ME/CFS symptoms such as hypoxia, exercise intolerance, and fatigue. Whilst these results were not as statistically significant as those the authors had previously found in Long COVID/PASC patients, nor those that had been described in diabetes and acute SARS-CoV2, the authors conclude that this area of research could lead to new treatment options for vascular and endothelial pathology in ME/CFS. The authors also recommend further research into the effect of ME/CFS plasma and fibrinogen microclots on healthy endothelium.

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Systemic antibody responses against human microbiota flagellins are overrepresented in chronic fatigue syndrome patients

Authors: Vogl T, Kalka IN, Klompus S, Leviatan S, Weinberger A, Segal E (Weizmann Institute of Science, Israel)
Publication: Science Advances
Link: https://www.science.org/doi/epdf/10.1126/sciadv.abq2422

Research has demonstrated the involvement of the immune system, inflammation, and dysbiosis of the gut in ME/CFS. This study took an agnostic approach to identify where the immune response to gut microflora differed between healthy and ME/CFS populations, and subsequently taught machine learning algorithms to perform predictions likely to provide the best diagnostic accuracy.

Serum and blood samples were obtained from the UK ME/CFS Biobank (UKMEB) of a cohort of 40 severe ME/CFS cases and an age-and-sex-matched cohort of 40 healthy controls. Phage immunoprecipitation sequencing (PhIP-Seq) was performed on these samples to identify immunoglobulin (Ig) epitope repertoires, which were then compared to a 244,000-variant phage display antigen library. This data was filtered to include only those antigens that were significantly bound. Statistical tests were performed to determine the distribution of binding across the cohorts, and then input into classifiers to predict further antigens of interest.

ME/CFS patients were found to have an overrepresentation of antibodies to the flagellins of intestinal microbiota species such as Lachnospiraceae, Clostridiales, and Eubaterium. Additionally, these patients had significantly decreased antibodies for the surface proteins and non-flagellin proteins of Bacteriodetes and Clostridiales species. Machine learning algorithms picked up increased antigens in the severe ME/CFS cohort that bound to proteins associated with hydrolases, sorting, and secretion; whilst antibodies against certain bacterial toxins were fewer. Algorithms were able to blindly distinguish between cases and controls with 25% greater accuracy when based on combined blood and Ig epitope repertoires, than when based on blood biomarkers alone.

The authors conclude that these results demonstrate that the immune system of severe ME/CFS patients is targeting beneficial gut bacteria, allowing for increased inflammation, immune dysregulation, and intestinal permeability. Patients with Crohn’s disease have similar immune responses, leading the authors to point to genetic and environmental effects creating the different phenotypes. Whilst the authors believe the results of this study could be improved upon by including stool samples and examining further immunoglobulins than IgG, they believe that testing antibody responses against gut microbiota, alongside standard blood tests, could provide an improved diagnosis of ME/CFS.

Figure: Schematic illustration of antibody responses against the respective proteins from Lachnospiraceae, Eubacteriaceae, and Bacteroidetes driving classification.

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Serum of Post-COVID-19 Syndrome Patients with or without ME/CFS Differentially Affects Endothelial Cell Function In Vitro

Authors: Flaskamp L, Roubal C, Uddin S, Sotzny F, Kedor C, Bauer S, … Seifert M (Charité-Universitätsmedizin Berlin, Germany).
Publication: Cells
Link: https://www.mdpi.com/2073-4409/11/15/2376

Following COVID-19 infection, a proportion of patients develop post-COVID syndrome (PCS), and a subgroup fulfils the diagnostic criteria for ME/CFS (PCS/CFS). Recent research has identified endothelial dysfunction in these patients. This study sought to investigate the mechanism causing endothelial dysfunction in PCS and PCS/CFS.
Participants were recruited from another ongoing observational study and included 17 PCS patients, 13 PCS/CFS patients (Canadian Consensus Criteria), and 14 healthy controls (HC). Participant blood samples were screened for serum anti-endothelial cell autoantibodies (AECA) and dysregulated cytokines. Human umbilical cord-derived venous endothelial cells (HUVEC) were treated with patient serum and the effects observed, and the angiogenic potential of sera was also measured. Analysis was completed to determine serum-mediated effects on endothelial cells in vitro.

The authors found AECA binding to endothelial cells was significantly increased in the PCS/CFS group, though there were no significant differences between the patient groups. PCS sera also enhanced angiogenesis compared with PCS/CFS and HC sera. It was also found that HUVEC secretion profiles differed, and the molecules involved in the inhibition of nitric oxide. The majority of cytokines measured did not appear dysregulated in either patient group.

Given differences between PCS and PCS/CFS patients, with altered AECA content and functional effects on endothelial cells, including angiogenic potential, the authors hypothesise that the PCS sera had a pro-angiogenic effect serving as a compensatory mechanism for endothelial dysfunction and that this effect is absent or insufficient in the PCS/CFS group accounting for the results observed.

Figure: representation of the suppressed angiogenic response in PCS versus PCS/CFS

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We failed Australians with chronic fatigue. Will we do the same with long COVID?

Authors: Mannix L
Publication: ABC News
Link: https://www.smh.com.au/national/we-failed-australians-with-chronic-fatigue-will-we-do-the-same-with-long-covid-20221101-p5bulg.html

If ME/CFS research had been properly funded, we would already understand a lot more about Long COVID than we do now. “ME/CFS is effectively a more severe form of long COVID. If there was no long COVID, these people would just be diagnosed with ME/CFS,” said the University of Melbourne’s Dr Chris Armstrong.

Instead, we are playing catch-up.

Anne Wilson, CEO of Emerge Australia, said that the keys now are: don’t reinvent the wheel and don’t make the same mistakes. Develop high-quality GP education, ensure access to necessary supports like NDIS, and fund research that builds on existing work on ME/CFS. And make long COVID a national health priority.

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