Welcome to the 109th edition of Emerge Australia’s Research Digest. This month, we summarise articles that delve into a deeper understanding of the pathophysiological of long COVID and its connection to ME/CFS, along with a report on the burden of long COVID in Western Australia.
Contributing Digesters: Jyothsna, Solène, Sarah, and Shan.
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Spontaneous, Persistent, T cell-dependent IFN-γ release in patients who progress to long COVID.
Authors: Krishna BA, Lim EY, Metaxaki M, Jackson S, Mactavous L, NIHR Bioresource, …. Wills MR (University of Cambridge,UK)
Publication: Science Advances
Link: https://www.science.org/doi/10.1126/sciadv.adi9379
Understanding the pathophysiological mechanisms and identifying biomarkers for long Covid is crucial. This study offers key insights, particularly highlighting interferon-gamma (IFN-γ) as a potential biomarker.
Researchers analysed cytokine secretion across three groups: 54 unexposed donors recruited before October 2019, 32 positive controls with confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, and 55 long COVID patients with persistent symptoms lasting at least five months. Participants recently treated with immunomodulatory drugs, anti-tumor necrosis factor (TNF) treatments, or cancer chemotherapy, as well as those reinfected during the study, were excluded to ensure clear group distinctions.
Results showed a significant increase in spontaneous IFN-γ production by cluster of differentiation 8 positive (CD8+) T cells in individuals with acute SARS-CoV-2 infection, which returned to normal in healthy individuals by 180 days. However, long COVID patients exhibited persistently elevated IFN-γ levels beyond 180 days, correlating with ongoing symptoms, particularly fatigue. Other cytokines, such as TNF-α, Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6), showed minor increases, while Interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) remained unchanged.
Analysis of immune cell sources identified CD8+ T cells as the primary producers of IFN-γ. Depletion assays confirmed that removing CD8+ cells significantly reduced IFN-γ production, emphasising their importance. Although cluster of differentiation 14 positive (CD14+) monocytes were not the primary source of IFN-γ, they were necessary for its production by facilitating antigen presentation.
Persistently high IFN-γ levels in long COVID patients were linked to ongoing symptoms, especially fatigue, suggesting IFN-γ as a biomarker for the disease. Monitoring IFN-γ levels could aid in diagnosing and tracking long COVID. Additionally, the correlation between symptom resolution and decreased IFN-γ levels post-vaccination suggests that vaccination might offer a therapeutic strategy. The study highlights the need for further research into cytokines, T-cell activation profiles, and the role of persistent viral or autoantigens in long COVID pathology.
Fecal microbiota transplantation for sleep disturbance in post-acute COVID-19 syndrome
Authors: Lau RI, Su Q, Ching JYL, Lui RN, Chan TT, Wong MTL, …, Ng SC (The Chinese University of Hong Kong, China)
Publication: Clinical Gastroenterology and Hepatology
Link: https://doi.org/10.1016/j.cgh.2024.06.004
Post-acute COVID-19 syndrome (PACS) is often associated with sleep disturbance. The gut microbiome has emerged as an essential regulator of sleep, and many studies report that it may play an important role in PACS. These authors performed a non-randomised, open-label prospective interventional study to assess the efficacy of faecal microbiota transplantation (FMT) in alleviating insomnia in patients with PACS.
Sixty patients with PACS who experienced insomnia (as defined by an Insomnia Severity Index (ISI) score above eight) were recruited from the Prince of Wales Hospital in Hong Kong. Thirty patients were assigned to the FMT group, while the remaining 30 served as controls. Faecal samples for the FMT were collected from two donors showing a high relative abundance in Gemmiger formicilis, as these bacteria are already known to be negatively associated with insomnia in PACS. Of the 30 patients in the FMT group, half received faecal samples from donor I, while the other half received samples from donor II. FMT was administered at baseline, as well as weeks two, four, and eight. The primary outcome was insomnia remission, as defined by an ISI score below eight. Secondary outcomes included change in sleep quality, daytime sleepiness, as well as levels of anxiety and fatigue. Faecal and blood samples were collected for microbiome profiling.
At week 12, a significantly higher proportion of PACS patients in the FMT group achieved insomnia remission. Overall, ISI scores were significantly lower in the FMT than control group. FMT was the only significant independent predictor of insomnia remission after a multivariable logistic regression analysis. At week 12, PACS patients in the FMT group also showed a significant improvement in sleep quality, improved daytime sleepiness, and improvement in anxiety level. No such changes were observed in the control group.
The cortisol concentration significantly decreased in the FMT group at week 12 compared to baseline. It was also significantly lower in the FMT group at week 12 compared to the control group. Comparison of patients’ faecal samples at baseline and week 12, and between FMT and control groups, showed that gut bacterial richness increased after FMT. Gemmiger formicilis and Coprococcus comes levels were significantly higher in the FMT group at week 12 compared with baseline.
FMT appears to be effective and safe in alleviating insomnia in PACS. However, as this study sample size was small with no randomisation or no treatment blinding, further clinical trials are needed to further assess FMT in the treatment of insomnia related to PACS.
Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome
Authors: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ … & Elahi S (University of Alberta, Canada)
Publication: Journal of Autoimmunity
Link: https://www.sciencedirect.com/science/article/pii/S089684112400101X
Many patients experience ongoing symptoms following acute SARS-CoV-2 infection, referred to as long COVID (LC). A subset of these patients experience the most debilitating of symptoms, fulfilling the diagnostic criteria for ME/CFS. This study aimed to examine the immunological changes associated with LC, recovery from acute COVID-19 (R), and ME/CFS.
199 participants were included in this study and were recruited in two cohorts. Cohort one (discovery cohort) included 44 LC, 24 R, and 30 acute COVID-19 patients (13 developed LC, and 17 recovered) and 33 healthy controls (HC). Cohort two (validating cohort) included 34 LC patients with ME/CFS (CCC), and 34 R. Study participants were age- and sex-matched. Samples from healthy controls were recruited before the COVID-19 pandemic and their samples had been frozen and stored. Patients were recruited from the University of Alberta Hospital. Cell cultures were performed on all participants.
The study found that ME/CFS patients had increased neutrophils and monocytes, but had decreased lymphocytes compared with the R group. Increased terminal effector T cells were also recorded in this group. The LC group was associated with increased levels of pro-inflammatory markers, and a variety of auto-antibodies. The authors found that the LC groups could be differentiated from R by elevated levels of CD4 terminal effector, artemin, CEC (immunosuppressive CD71+ erythroid cells), Galectin-9, CD8 terminal effector, and MCP1 along with lower levels of TGF-β and mucosal-associated invariant T (MAIT) cells.
The authors propose that these findings offer insights into the pathogenesis of long COVID with ME/CFS. Specifically, the results support the evidence of innate immune activation (helping to explain the increased numbers of females affected over men), hematopoietic dysregulation, T cell exhaustion, and chronic inflammation.
Long COVID in a highly vaccinated but largely unexposed Australian population following 2022 SARS-CoV-2 Omicron wave: a cross-sectional survey
Authors: Woldegiorgis M, Cadby G, Ngeh S, Korda RJ, Armstrong PK, Maticevic J,… Effler PV (Western Australia Department of Health, Australia)
Publication: The Medical Journal of Australia
Link: https://doi.org/10.5694/mja2.52256
In late February 2022, with more than 90% of its population vaccinated, Western Australia ended its strict lockdown and opened its borders, exposing its citizens to COVID-19 for the first time. Nearly all cases of COVID-19 at this period were caused by the Omicron variant. This provided a unique opportunity to observe the incidence and pathology of long COVID that was not obscured by prior COVID-19 infections. The authors aimed to discover the prevalence and impact of long COVID, in a vaccinated population where minimal extra variables would impact the findings.
Between mid-July and the beginning of August 2022, 70,876 adults reported positive tests for SARS-CoV-2 to the Western Australian Department of Health. Of these, 11,697 met the study criteria and completed a survey that asked about ongoing symptoms. The survey was constructed using the Symptom Burden Questionnaire for long COVID (SMQ-LC), as well as World Health Organization (WHO) and Centres for Disease Control & Prevention (CDC) resources.
Of those surveyed, 18.2% met the authors’ case definition of long COVID (reporting new or ongoing symptoms 90 days after a positive SARS-CoV-2 test). Those found to be at greater risk of long COVID were those aged 50-59 (aRR 1.6), female (aRR 1.5), had pre-existing health conditions (aRR 1.5), or had received two or fewer doses of the vaccine (aRR 1.4). Of those with long COVID, 90.4% experienced more than one lingering symptom, with as many as 70.6% reporting fatigue and 59.5% experiencing cognitive difficulties. 38.7% of those with long COVID experienced symptoms that caused them to use health services such as general practitioners (38.7%), emergency departments (3.9%), or hospital admission (1.6%). Regarding work and study, 15.2% needed to reduce their hours due to their health, and 2.7% had not been able to return at all. Those who had fewer doses of vaccine (aRR 2.0) or those who had pre-existing health conditions (aRR 1.3) were at greater risk of not being able to return to work.
This study found a higher incidence of long COVID compared to other large studies conducted worldwide, although the incidence was lower than a recent Queensland study. The burdens upon the health system and workforce system are comparable to other studies. The authors warn that differing accessibility and affordability of health care services, social welfare, and unemployment services throughout Australia and worldwide may prevent the findings from being universally applicable.
