Welcome to the 115th edition of Emerge Australia’s Research Digest. This edition explores post-acute sequelae of COVID-19 (PASC) mechanisms, with magnetic resonance imaging (MRI) and cognitive studies revealing lasting brain alterations and impairments. Comparative studies of ME/CFS with PASC highlight both shared and distinct dysfunctions. Beyond research, the lived experiences of Australians with long COVID emphasise the urgent need for recognition, research, and support.
Contributing Digesters: Jyothsna, Solène, Shan and Simone.
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Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19(PASC)
Authors: Adhikari A, Maddumage J, Eriksson EM, Annesley SJ, Lawson VA, Bryant VL, Gras S (La Trobe University, Australia)
Publication: Medical Journal of Australia
Link: https://doi.org/10.5694/mja2.52456
Easy Read Overview: Long COVID, or PASC, affects many people worldwide, including 5–10% of COVID-19 cases in Australia. It causes problems in the immune system, ongoing inflammation, and damage to the brain, gut, and energy-producing cells. Scientists need more research to understand these effects, track symptoms, and find possible treatments.
The global prevalence of long COVID ranges from 9% to 81%. In Australia, 5–10% of 11.8 million confirmed cases experience post-acute sequelae of COVID-19 (PASC), with 14.2% in Victoria. Despite these statistics, PASC’s mechanisms remain complex and not fully understood. This review analyses nearly 100 global studies (2020–2023) on symptoms, diagnostics, and pathophysiology of PASC, while identifying critical research gaps.
PASC results from multiple biological mechanisms, with immune dysregulation being a major factor. Persistent inflammation affects multiple organs, including the central nervous system (CNS). The SARS-CoV-2 virus can infect brain cells, which could lead to neuronal and glial cell fusion. Even without direct invasion, prolonged cytokine activity, microglial activation, and reduced neurogenesis contribute to neurological symptoms. Central nervous system-targeting autoantibodies suggest an autoimmune component to the neurological disruption.
The gut microbiome is also highly vulnerable due to the abundance of ACE2 receptors, making the intestine a SARS-CoV-2 viral reservoir. This can disrupt the gut barrier, cause mucosal inflammation, and lead to a leaky gut. These changes drive fatigue, metabolic issues, and cardiovascular dysfunction. PASC is associated with type 2 diabetes and inflammatory bowel disease. The virus may also impair mitochondrial function, as seen in ME/CFS, potentially linked to Epstein–Barr virus (EBV) reactivation.
Persistent activation of primary immune cells like neutrophils and monocytes is found in PASC. Continued activation of adaptive immune cells, T- and B-cells drives prolonged inflammation. Type I/III interferons, exhausted T-cells, and viral reactivation (Epstein–Barr virus, Cytomegalovirus) suggest ongoing immune dysregulation. THe SARS-CoV-2 virus may trigger autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus (SLE), particularly in genetically predisposed individuals.
Based on analysis by the authors, further research is needed to clarify neurological dysfunction, gut dysbiosis, immune dysregulation, and autoimmunity. Additionally, extended studies should track symptom persistence, risk factors, and potential treatments.
Figure: Proposed mechanisms for post-acute sequelae of coronavirus disease 2019 (PASC) pathogenesis: (A) SARS-CoV-2 triggers microglia and astrocytes to generate neuroinflammation; (B) Potential damaged gut/intestinal barrier leads to an inflamed gut blood axis; (C) The hyperactivation of circulatory neutrophils and monocytes promotes the damage of endothelial linings within blood vessels by direct infection, which can lead to microclots; (D) Immune dysregulation with hyperinflammation and production of autoantibodies by B cell.; (E) Autoantibodies produced by aberrant B cells potentially predispose individuals to early onset of diabetes; (F) Autoantibodies dampen the early innate immune response against infection, providing opportunities to latent/opportunistic infections
Cognitive impact and brain structural changes in long COVID patients: a cross-sectional MRI study two years post infection in a cohort from Argentina
Authors: Cataldo SA, Micciulli A, Margulis L, Cibeyra M, Defeo S, Horovitz SG,…, Belzunce MA. (Centro Universitario de Imágenes Médicas, Argentina)
Publication: BioMed Central Neurology
Link: https://doi.org/10.1186/s12883-024-03959-8
Easy Read Overview: People with Long COVID (LC) still experience memory problems, fatigue, brain fog, and muscle weakness more than two years after infection. MRI scans showed that LC patients had smaller brain areas linked to memory and thinking, similar to changes seen in Alzheimer’s disease. While some cognitive tests did not show major differences, researchers believe more studies are needed to fully understand LC’s long-term effects on the brain and find treatments.
Long COVID (LC) patients report experiencing cognitive symptoms and exhibit measurable cognitive impairment, as assessed with cognitive tests. Previous neuroimaging studies have identified structural alterations in brain regions linked to cognitive functions; however, these studies focused on patients within months after their initial infection. In this work, the authors assess: (1) the long-term cognitive effects of LC, (2) the structural changes of the brain, and (3) the quality of life of LC patients more than two years post-infection.
This cross-sectional study involved a cohort of 109 LC patients (72.5% women) and 28 healthy controls (70.4% women) from Argentina. All participants completed structured questionnaires to evaluate the persistence of their LC symptoms. They also performed a cognitive assessment and a brain magnetic resonance imaging (MRI) scan. The differences between LC patients and controls were assessed and the relationships between reported symptoms, cognitive test scores, and brain morphologic measures evaluated.
The LC group reported persistent memory problems, including fatigue, brain fog, attention problems, and muscle weakness. The standardised scales identified statistically significant higher levels of fatigue and lower quality of life in the LC group compared with the controls; however, no significant differences in sleep quality were found.
The LC group had lower performance on the Trail Making Test Parts A compared to the control group. The other cognitive assessments found no difference in performance and net scores between the two groups, suggesting that these tests may not be sensitive enough to detect subtle impairments.
The MRI scans showed a statistically significant reduction in the volume of the right cerebellum in the LC group. Given the cerebellum’s role in working memory and executive functions, the authors’ suggest that these findings may explain some of the cognitive symptoms in LC. The MRI analysis also revealed a statistically significant reduction in the cortical thickness of several brain regions, which are similar to those observed in Alzheimer’s disease, suggesting that LC may increase the risk of neurodegenerative diseases.
Finally, no significant relationship was identified between brain regions atrophy, cognitive test scores, and symptom scores.
This study showed persistent structural brain changes two years after symptom onset in LC, despite most cognitive tests not revealing significant differences between the groups. The authors conclude that further research is essential to understand the impact of LC on cognition and develop effective therapeutic strategies.
Stroop task and practice effects demonstrate cognitive dysfunction in long COVID and myalgic encephalomyelitis / chronic fatigue syndrome
Authors: Baraniuk JN, Thapaliya K, Inderyas M, Shan ZY, Barnden LR (Griffith University, Australia)
Publication: Scientific Reports
Link: https://doi.org/10.1038/s41598-024-75651-3
Easy Read Overview: The Stroop task tests attention and thinking skills by asking people to match the colour of a word’s ink with its meaning. This study used the Stroop task and brain scans (fMRI) to compare thinking abilities in people with ME/CFS, long COVID, and healthy individuals. The results showed that ME/CFS and long COVID participants had slower reaction times than healthy people, with long COVID participants struggling the most at first but improving more with practice.
The Stroop task measures a range of executive and attention functions. The task requires participants to determine if the colour of ink used to write a word matches the presentation of a word colour (eg: the word “red” written in red ink is considered congruent, whereas the word “red” written in green ink is incongruent). The Stroop task was used to examine cognitive function in ME/CFS and long COVID participants.
This study was conducted in two cohorts. The 2016 cohort, consisted of 42 participants with ME/CFS (24 who met the Fukuda criteria, and 18 who met the International Consensus Criteria (ICC)) and 27 healthy controls (HC). The 2023 cohort consisted of 31 participants with ME/CFS (ICC), 19 participants with long COVID (LC) who met the WHO working case definition and 16 healthy controls (HC). Each participant underwent functional magnetic resonance imaging (fMRI) before sitting the Stroop task.
The Stroop task included a string of three basic stimuli (see Figure below): congruent (C – the colour used to present the upper word matched the meaning of the lower word), incongruent (I – the colour used to present the upper word did not match the meaning of the lower word) or neutral (N – the upper word was XXXX, but the participant still needed to determine if the colour used matched the meaning of the lower word). Participants viewed and responded to 120 stimuli over 900 seconds.
Figure: The three types of stimuli: Congruent (C), Incongruent (I), and Neutral (N).
Overall, participants with ME/CFS and long COVID had significantly slower reaction times than healthy controls. In the first half of each test, LC participants had a longer reaction time than ME/CFS participants, who in turn had a longer reaction time than HC. However, by the second half of each test, LC and ME/CFS reaction times were equal and slightly improved. These results suggest cognitive dysfunction in the patient groups which improved but could not be overcome with practice.
The LC group began with the largest cognitive deficit, with a capacity to significantly improve adaptation and processing, whilst the ME/CFS group had more moderate cognitive deficits with less improvement with practice and adaptation. The authors conclude that there may be differing dysfunction at play between the disease groups and that the initial difference between the LC and ME/CFS groups may reflect the ME/CFS group’s adaptations due to their longer disease duration. The authors believe further insights may be gained by examining fMRI conducted over the process of Stroop testing, particularly the comparison of the first and second halves of the test, where learning and practising change cognitive methods and improve reaction time.
The world has largely moved on from COVID-19. Meet the people who can't
Authors: Bahr J
Publication: SBS News
Link: https://www.sbs.com.au/news/article/the-world-has-largely-moved-on-from-covid-19-meet-the-people-who-cant/3hdyntaf6
Australians with long COVID are feeling forgotten as the world moves on from the pandemic. Anne Wilson, Emerge Australia CEO, said “[People’s] lives have been completely disrupted because they can’t work, they have no income, their family life has been affected, their ability to function in every possible way has been impacted.”
Plum Stone, who contracted COVID-19 in March 2020, was reinfected in November 2022, and has never recovered said, “These are symptoms I’m going to be living with forever.”
Anne said she believes Long COVID and related conditions have not been taken as seriously as other illnesses.
“These are invisible disabilities and the people are invisible. They’re invisible to society, they’re invisible to their doctors, and they’ve been very invisible to government.”
