The 114th edition of the Research Digest covers studies on potential treatments, biomarkers, and risk factors for long COVID and ME/CFS. Highlights include intravenous immunoglobulin as a possible therapy, biomarkers distinguishing long COVID patients with ME/CFS symptoms, a large paediatric study on risk factors and recovery, and a review of microRNAs in disease mechanisms. We also feature Australian research linking brain changes to cognitive symptoms, reinforcing the biological basis of these conditions.
Contributing Digesters: Jyothsna, Solène, Sarah, Shan and Simone.
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A review of intravenous immunoglobulin in the treatment of neuroimmune conditions, acute COVID-19 infection, and post-acute sequelae of COVID-19 syndrome
Authors: Morse AB, Motovilov K, Brode MW, Tee MF, Melamed E (University of Texas, USA)
Publication: Brain, Behavior, and Immunity
Link: https://www.sciencedirect.com/science/article/abs/pii/S0889159124006482
Easy Read Overview: Intravenous immunoglobulin (IVIG) is a treatment used for many diseases, especially those affecting the immune and nervous systems, like Guillain-Barré syndrome and myasthenia gravis. It has been studied for COVID-19, showing benefits in severe cases, by reducing inflammation and hospital stays, and it might also help with long COVID symptoms. Researchers believe IVIG could be useful for conditions like ME/CFS, but more studies are needed to confirm its effectiveness.
Intravenous immunoglobulin (IVIG) is a versatile therapy used to treat over 100 medical conditions, particularly neuroimmune disorders such as Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and myasthenia gravis. IVIG works by neutralising cytokines, modulating autoantibodies, and inhibiting the complement system.
The number of IVIG products approved by the US Food and Drug Administration (FDA) has increased from 9 in 2018 to 40 by 2024, targeting 31 different conditions like autoimmune neuropathies, and multiple sclerosis. Mostly, these formulations consist of standard polyclonal IgG for general applications, hyperimmune variants for specific diseases, and animal-derived products for targeted conditions.
During the COVID-19 pandemic, IVIG emerged as a potential therapy for addressing immune dysregulation and inflammation associated with COVID-19, as well as its long-term effects, known as post-acute sequelae of SARS-CoV-2 (PASC).
In acute COVID-19 cases, IVIG is used to address hypogammaglobulinemia, cytokine storms, and endothelial damage. Early administration in severe cases has shown benefits in reducing ICU stays, ventilator dependence, and mortality, while later use is less effective. Meta-analyses suggest IVIG helps critically ill patients, especially when given before disease progression. However, inconsistent findings highlight the need for optimised dosing and patient stratification, as IVIG’s efficacy may depend on its ability to reduce inflammation and modulate immune activity.
Emerging evidence suggests that IVIG may be an effective treatment for PASC, affecting 5–30% of COVID-19 survivors. Small studies have reported improvements in symptoms like fatigue, pain, and cognitive dysfunction. Ongoing clinical trials, including a phase II randomised controlled trial comparing IVIG to methylprednisolone, are exploring factors such as timing, dosing, and patient subgroups. As understanding of PASC and its pathophysiology grows, IVIG could significantly help manage long-term COVID-19 symptoms.
IVIG has shown positive results for some ME/CFS patients, especially those affected by an acute viral infection. There are similarities between ME/CFS and PASC, with around 50% of PASC patients meeting ME/CFS criteria, including post-exertional malaise. Both conditions may have an unclear autoimmune component.
Given that IVIG has been successful in treating autoimmune diseases like GBS, CIDP, and MMN, the authors propose that IVIG may also benefit PASC and ME/CFS. The authors conclude that, in light of the lack of evidence-based treatments for these conditions and the high prevalence of PASC, IVIG could be an important therapeutic option, pending further research.
Exploring the role of galectin-9 and artemin as biomarkers in long COVID with chronic fatigue syndrome: links to inflammation and cognitive function
Authors: Elahi S, Rezaeifar M, Osman M, Shahbaz S (University of Alberta, Canada)
Publication: Frontiers in immunology
Link: https://doi.org/10.3389/fimmu.2024.1443363
Easy Read Overview: The authors suggest that neurological symptoms in long COVID (LC) may be caused by inflammation and damage to the blood-brain barrier. They studied two blood markers, Gal-9 and ARTN, to see if they could help distinguish LC patients with ME/CFS symptoms from recovered COVID-19 patients, healthy individuals, and HIV patients. Their results showed that Gal-9 and ARTN levels were useful for identifying LC patients, with Gal-9 also linked to inflammation and cognitive problems, highlighting the need for further research.
These authors propose that neurological symptoms observed in long COVID (LC) are likely due to blood-brain barrier disruption and systemic inflammation. Previous research by these authors identified elevated galectin-9 (Gal-9) and artemin (ARTN) levels in LC patients with ME/CFS symptoms. The author’s goal was to assess plasma concentrations of Gal-9 and ARTN as biomarkers to differentiate LC patients with ME/CFS symptoms, SARS-Cov-2 recovered individuals and healthy controls. In addition, the authors compared these plasma concentrations with those of HIV patients.
The discovery cohort involved 44 LC patients and 24 SARS-Cov2-recovered individuals, all vaccine-naive and infected with the original Wuhan strain. The validating cohort involved 34 LC patients and 34 SARS-Cov-2-recovered individuals with vaccine coverage of 67.3% and 73.5%, respectively, and infected with the Delta and/or Omicron variants. The authors also involved 63 HIV patients for comparison with LC patients, as previous research showed elevated levels of Gal-9 in this population. Finally, 25 healthy individuals, serologically negative for HIV, hepatitis C virus, and hepatitis B viruses, were enrolled as controls.
Receiver operating characteristic (ROC) curve analysis identified relevant cut-off values for plasma Gal-9 and ARTN to differentiate LC patients, SARS-Cov2 recovered individuals, and controls in the discovery cohort. Plasma Gal-9 and ARTN were effective biomarkers with high sensitivity and specificity in differentiating groups in the validation cohort. The elevated plasma levels of Gal-9 positively correlated with sCD14, I-FABP, and LPS-binding protein in LC patients. These results suggest a complex interplay between immunity, compromised gastrointestinal integrity, and metabolic pathways in LC. Gal-9 levels also showed a positive correlation with cognitive failure scores, suggesting a role in cognitive impairment in LC patients with ME/CFS. In comparison with LC patients, HIV patients – who also displayed elevated Gal-9 plasma levels – presented significantly lower levels of ARTN.
The authors conclude that Gal-9 and/or ARTN may be sensitive biomarkers to identify and stratify LC patients with ME/CFS. The correlations between Gal-9, inflammatory markers, immune activation, and cognitive impairment provide valuable insights for future research. These findings highlight the need for longitudinal studies involving larger cohorts.
Characteristics and predictors of Long Covid in children: a 3-year prospective cohort study
Authors: Camporesi A, Morello R, La Rocca A, Zampino G, Vezzuli F, Munblit D … Buonsenso D (Gemelli University Hospital, Italy)
Publication: eClinical Medicine
Link: https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(24)00394-8/fulltext
Easy Read Overview: This study looked at long COVID in children and what factors might increase the risk of developing it. It found that older children, those with other health conditions, and those infected with early COVID-19 variants were more likely to have long COVID, while vaccines helped lower the risk. The study also showed that most children recovered over time, but more research is needed to improve treatment and prevention in the future.
This study sought to provide evidence of the characteristics and predictors of long COVID in children. It also aimed to establish the role vaccines might have in the prevention of the development of long COVID, as well as the risk of developing long COVID or autoimmune disease following reinfection with SARS-CoV-2 virus.
Participants were aged 0-18 years, had been infected with SARS-CoV-2, and were recruited from a paediatric post-COVID clinic in Rome. Participants were assessed at 3, 6, 12, 18, 24 and 36 months after their initial infection. 1319 participants were originally included in this study; however some were lost to follow-up. Vaccination status, demographic information, and detailed symptom logs were all collected, as well as newly acquired infections. Participants were also assessed for long COVID, as defined by the World Health Organization definition.
Statistically significant risk factors for developing long COVID included being over 12 years old, having co-morbidities, being infected with original variants, and female sex. At the 18-month follow-up, age over 12 years and infection with original and alpha variants remained statistically significant risk factors. Vaccinations were found to be associated with a lower risk of long COVID at time points 3, 6, and 12 months for older children, as well as a lower risk of reinfection with the SARS-CoV-2 virus. Infection with the original variant was associated with a higher risk of new-onset autoimmune disease. At the end of the study, the majority of participants were reported to have recovered, with only 11 participants continuing to meet the definition of long COVID. Only one participant was diagnosed with long COVID following re-infection.
The authors conclude that this study demonstrates the long-lasting impact of long COVID on children, as well as providing demographic and clinical predictors of long COVID development. Vaccines were associated with a lower risk of long COVID, and subsequent infections had minimal burden on most participants. These results highlight the need for further research into paediatric long COVID, to improve diagnosis and treatment, as well as inform prevention and management of future pandemics.
Identifying microRNAs possibly implicated in myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: a review
Authors: Tsamou M, Kremers FAC, Samaritakis KA, Roggen EL (ToxGenSolutions, The Netherlands)
Publication: International Journal of Molecular Sciences
Link: https://doi.org/10.3390/ijms25179551
Easy Read Overview: The authors reviewed studies on tiny molecules called microRNAs (miRNAs) that may play a role in illnesses like ME/CFS and fibromyalgia. They looked at 25 studies published after 2010 and grouped miRNAs based on the body processes they affect, such as immune function, pain, and energy production. Their goal was to show how certain miRNAs could help doctors better understand, diagnose, and treat these complex illnesses.
The authors conducted a literature review of studies into microRNAs (miRNAs) implicated in regulating purported pathophysiological mechanisms of ME/CFS and/or fibromyalgia. The scope of this review was limited to the 25 human studies published in English after 2010 that contained the keywords “miRNA”, “myalgic encephalomyelitis (ME)”, “chronic fatigue syndrome (CFS)”, and/or “fibromyalgia (FM)”.
miRNAs mentioned in two or more papers were noted and grouped according to the processes they regulate. The metabolic processes linked to the miRNAs included immunity and inflammation, central sensitisation or chronic widespread pain reception, reduction/oxidisation reactions and mitochondrial function, autophagy, vascular function, cell metabolism, hypothalamic-pituitary-adrenal (HPA) axis function, transient receptor potential (TRP) ion channels, and tryptophan metabolism.
The authors then broke these processes down further, using other current literature to list the specific mechanisms (such as dysfunctional CD8+ cytotoxic T cells affecting the immune system, and higher levels of arginine vasopressin causing sustained activation of the HPA axis) that have been found to be dysfunctional in ME/CFS and/or FM for each of these overarching processes. The miRNAs miR-29c, miR-99b, miR-128, miR-374b, and miR-766 were of particular interest for their roles in immune response, central sensitisation, oxidative stress, and mitochondrial dysfunction, as well as miR-23a, miR-103, miR-152, and miR-320 for their roles in the majority of processes involved in the pathophysiology of ME/CFS and/or FM.
The goal of this review was to consolidate data identifying aberrant miRNA as emerging biomarkers for ME/CFS and FM to bridge the gaps in the current understanding of complex, multisystemic illnesses. The authors hope that this approach could lead to earlier diagnosis and improved treatments.
Figure: Overview of miRNAs implicated in dysregulated processes manifesting myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and/or fibromyalgia (FM) that were reported at least two times in different research studies.
Long COVID patients show brain swelling linked to memory and concentration problems, study finds
Authors: Miles, J.
Publication: ABC News
Link: https://www.abc.net.au/news/2025-02-11/long-covid-brain-swelling-memory-problems-research-queensland/104917572
This article reported on the recent publication of a brain imaging study by Australian researchers at the National Centre for Neuroimmunology and Emerging Diseases (NCNED) which found that an area of the brain known as the hippocampus is larger in people with long COVID and ME/CFS than in healthy people. Hippocampus size was also found to be related to symptom severity in long COVID and ME/CFS.
The researchers suggest that the increased hippocampus size could result from the development of new cells as a way to compensate for cognitive difficulties associated with these conditions or possibly due to the ongoing presence of a virus. The researchers also claim that an enlarged hippocampus has not been observed in other conditions and may be unique to long COVID and ME/CFS.
Patients and clinicians report that this result validates that the condition is not psychological. The researchers are hopeful that this research could lead to better treatments.
