Welcome to the 107th edition of Emerge Australia’s Research Digest, where we delve into recent research and media releases shaping our understanding of ME/CFS and long COVID. In this issue, we focus on pivotal studies and insightful reports that shed light on the blood-brain disruption in those with long COVID, and MRI studies that show similar neurochemical profiles in ME/CFS and long COVID. Furthermore, we highlight the Federal government’s announcement of $1.1m to enable the National Health and Medical Research Council to develop much-needed ME/CFS clinical guidelines in Australia.
Contributing Digesters: Jyothsna, Solène, Shan and Simone.
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Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment
Authors: Greene C, Connolly R, Brennan D, Laffan A, O’Keefe E, Zaporojan L, … Campbell M (University of Medicine and Health Sciences, Ireland)
Publication: Nature Neuroscience
Link: http://www.nature.com/articles/s41593-024-01576-9.pdf
Brain fog, a common symptom of COVID-19, includes headaches, fatigue, malaise, and altered consciousness. It may result from the blood-brain barrier (BBB) breakdown, allowing serum components and cytokines into the brain. This study investigated BBB breakdown in COVID-19 and its role in brain fog in long COVID.
The study participants included 76 adults aged 18 and above who had had COVID-19, both with and without neurological symptoms, and 25 healthy controls. Those with pre-existing neurological conditions were excluded. Blood samples were taken, and markers of inflammatory response, coagulation, and BBB dysfunction were profiled. To study BBB more directly, dynamic contrast-enhanced MRI (DCE-MRI) scans were undertaken on ten people who had recovered from COVID-19, 11 people with long COVID, and 11 people with long COVID with brain fog.
Significant differences in inflammatory markers like IFN-γ, G-CSF, and protein S were found between controls and those who had COVID-19, especially in moderate and severe cases. Higher levels of S100β, bFGF, IL-13, and MCP-1 were linked to COVID-19 severity, age, and comorbidities in those with brain fog.
DCE-MRI scans revealed increased BBB leakage and structural changes in long COVID patients with brain fog, especially in the temporal and frontal lobes, compared to long COVID patients without brain fog and recovered patients. Elevated levels of IL-1RA, IL-1β, and TGF-β, along with higher blood coagulation markers, were also found in long COVID patients with brain fog. Transcriptome analysis showed increased activity in pathways related to T cell differentiation and TGFβ signalling, and decreased activity in platelet function genes. Blood cells from brain fog patients showed increased adhesion to brain endothelial cells, indicating ongoing inflammation and BBB dysfunction.
The authors suggested the need for long-term research to understand BBB changes and develop treatments to protect BBB integrity in long COVID patients. The authors acknowledge the limitations of their study, including small sample size and the absence of cerebrospinal fluid samples, but conclude that their findings provide valuable insights and they recommend further investigation with larger groups.
Imbalanced brain neurochemicals in long COVID and ME/CFS: a preliminary study using MRI
Authors: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Eftekhari Z, Inderyas M, Barnden L (Griffith University, Australia)
Publication: The American Journal of Medicine
Link: https://doi.org/10.1016/j.amjmed.2024.04.007
long COVID and ME/CFS patients experience similar symptoms that may be related to imbalances in brain neurochemicals. This cross-sectional study investigated: (1) whether neurochemical differences exist in the posterior cingulate cortex of long COVID and ME/CFS patients compared to healthy controls using Magnetic Resonance Spectroscopy (MRS) imaging; and (2) whether these neurochemical differences correlate with symptom severity.
All participants were aged between 18 and 65 years old. In total, 17 patients with long COVID (as defined by the WHO clinical case definition), 17 patients with ME/CFS (fulfilling the Canadian Consensus Criteria or International Consensus criteria), and 10 aged-matched healthy controls (with no chronic disease and no previous COVID infection) were enrolled. Symptom severity was assessed with the Research Registry questionnaire of the National Centre for Neuroimmunology and Emerging Diseases. Quality of life and functional capacity were assessed with the 36-Item Short-Form Health Survey, where each item was scored on a scale of 0 to 100, and then averaged as previously published.
long COVID patients had significantly higher glutamate and N-acetyl-aspartate (NAA) compared with healthy controls, while ME/CFS patients only had significantly higher glutamate compared with healthy controls. There were no significant biochemical differences between patients with long COVID and ME/CFS. Elevated glutamate levels may be due to proinflammatory cytokines and activation of glial cells in both diseases. Elevated levels of NAA in long COVID may come from a compensatory response to lower brain metabolic efficiency.
Brain neurochemical levels and self-reported severity measures appeared to be associated with both diseases. In long COVID, glutamine and creatine negatively correlated with the duration of the disease, while glutamate+glutamine negatively correlated with physical function. Phosphorylcholine and glycerophosphorylcholine positively correlated with cognitive impairment. In ME/CFS, glutamine, glutamate+glutamine, and creatine+phosphocreatine positively correlated with physical function; while creatine and creatine+phosphocreatine negatively correlated with cognitive impairment and unrefreshing sleep. Finally, inositol negatively correlated with pain.
long COVID and ME/CFS diseases share a very similar neurochemical signature, supporting the hypothesis of overlapping underlying pathologies in both diseases. Restoring the balance of glutamate and NAA may have therapeutic effects in both conditions.
In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS
Authors: Armstrong CW, Mensah FFK, Leandro MJ, Reddy V, Gooley PR, Berkovitz S, Cambridge G (University College London, UK)
Publication: Frontiers in Immunology
Link: https://doi.org/10.3389/fimmu.2023.1178882
ME/CFS is likely driven by alterations in the immune system and energy metabolism. The authors’ previous study, found increased glycoprotein CD24 expression in peripheral blood B cells of individuals with ME/CFS, along with an association between CD24 and energy metabolism. To further compare metabolic function following changes in B cell immunophenotype in both ME/CFS cells and healthy cells, this study examined the expression of cell cycle signalling enzymes (cell adhesion glycoprotein CD24; ATP and adenosine modulators CD39 and CD73; and NAD-degrading enzyme CD38) in response to stress stimulation and measured the mitochondrial mass (MM) over cell proliferation cycles.
Eight patients (6 female, 2 male) diagnosed with ME/CFS (Canadian Consensus Criteria), and 7 healthy controls (HC) were selected for this study. Whole blood samples were taken, from which peripheral blood mononuclear cells (PBMCs) were isolated and B cells were enriched. Isolated B cells were cultured in the presence and absence of ligand stimulation, with supernatants collected on days 1, 3, and 6 and analysed by NMR for metabolite consumption. MM and cell proliferation were confirmed by staining, and flow cytometry was used to identify immunophenotype markers, energy pathway markers, and cell proliferation.
Following stress stimulation, expression of CD24 should peak at day 1 and rapidly wane by day 3 as the cells enter proliferation cycles, as shown in the HC cells. This is not the case in ME/CFS cells, which exhibited a higher number of CD24-positive cells and continual expression of higher levels of CD24. CD24 is associated with increased AMPK phosphorylation, which is triggered in response to stress. The authors believe this indicates a slower turnover of cells in ME/CFS patients.
Ectoenzymes, such as CD39, CD73, and CD38, influence ATP and adenosine and regulate the cell cycle (proliferation, division, and death). The reduction in adenosine points to anti-inflammation pathways being activated, implicating immune stress. CD38-positive and CD73-positive B cells were more frequently expressed in ME/CFS vs HC cultures, and CD38 was significantly increased in ME/CFS cultures on days 1 and 3, the period of greatest proliferation. CD38 is significantly associated with B cell survival in ME/CFS. Mitochondria increase in number and/or volume during growth and division and periods of stress, as a method of cell protection. Both at baseline and throughout each cycle, B cells from ME/CFS patients exhibited significantly lower mitochondrial mass compared to cells from healthy controls (HC), indicating reduced reliance on mitochondria for energy production. B cells of ME/CFS patients were shown to consume greater amounts of glucose and essential amino acids and to produce more lactate, without a difference in B cell mass or quantity compared to HC. The authors surmise this indicates continual aerobic glycolysis in ME/CFS cells, preferential to using the mitochondria for oxidative phosphorylation, explaining the lower MM. They also believe the hypermetabolic state and the elevated amino acid consumption are necessary for these stressed ME/CFS cells to grow and survive.
Backing belief with better support for people with chronic fatigue
Authors:Minister for Health and Aged Care, Mark Butler
Link: https://emerge.org.au/news/media-release-backing-belief-with-better-support-for-people-with-chronic-fatigue/
Last week, the Minister for Health and Aged Care, Mark Butler, announced that the Albanese government would provide $1.1m to the National Health and Medical Research Council to develop much-needed ME/CFS clinical guidelines for Australia.
The Minister said, “I’d like to thank people with ME/CFS for their ceaseless campaign to be heard and believed in the face of, frankly, years of doubt and disregard. ME/CFS does not discriminate. It affects people of all ages, ethnicities, and socioeconomic backgrounds. The development of new Australian clinical guidelines will provide GPs and their patients with better diagnosis, treatment and care. The NHMRC will lead the development of these guidelines, in consultation with and for the benefit of the more than 250,000 people who suffer daily, often silently, with ME/CFS and related conditions.”
Read Emerge Australia’s response to the announcement: https://emerge.org.au/news/stop-press-update-me-cfs-clinical-guidelines/
Too many children with long COVID are suffering in silence. Their greatest challenge? The myth that the virus is 'harmless' for kids
Authors: Gleeson, H.
Publication: ABC News Link: https://www.abc.net.au/news/2024-06-16/children-with-long-covid-dismissed-doctors-myth-virus-harmless/103959078
While scientists try to unravel why some people don’t fully recover from COVID-19, the plight of young people living with the condition remains largely invisible, due to the myth that COVID-19 doesn’t affect children. Children with long COVID are struggling, with many being dismissed by doctors and teachers, and their parents feeling unheard or gaslit.
Dr David Putrino, Director of Rehabilitation Innovation at Mount Sinai Health System in New York, said that long COVID is “a lot more complicated and more brutal” for young people, and that “kids are having a harder time with it because people seem to be less understanding of it.”
For young people with long COVID, most people fail to understand how much is at stake. “They think it’s incredibly rare, or they don’t understand that just because you had one ‘nice’ bout of COVID doesn’t mean the next one isn’t going to do permanent damage,” says Katie, whose daughter lives with long COVID. “People just underestimate it; they assume it won’t happen to them and if it does, that someone will be there to help them.”
The article notes that many doctors dismiss long COVID as something they can do nothing about, and instead encourage patients to get back to being active as soon as possible. But Sydney GP Dr Mark Donohoe says, “That’s the advice that really exacerbates things.” Because if a child who suffers from post-exertional malaise (PEM) is pushed beyond their capacity, they can deteriorate rapidly.
While many people with long COVID meet the diagnostic criteria for ME/CFS, the article notes that “Australian guidelines seem to be stuck in the past”, continuing to promote graded exercise therapy, which is a “sure-fire way to provoke PEM”.
