The 123rd edition of the Research Digest highlights advances across theory, care, treatment and biology in long COVID and ME/CFS. A new model suggests that chronic inflammation, immune dysregulation and autonomic imbalance together underpin the complexity of Long COVID. A qualitative study reveals that incorporating lived-experience experts can enhance clinicians’ understanding of PAIS and enhance care. Early trial findings indicate that pyridostigmine may help improve strength and orthostatic symptoms in ME/CFS. New biological data also reveal heightened innate immune activation and metabolic dysfunction linked to PEM.
Contributing Digesters: Jyothsna, Lauren, Imogen and Shan.
In response to helpful feedback from our community, we now include a short word before each article to indicate what the article is about. We hope this addition – along with the Easy Read Overview and audio summary – makes it even easier for our readers to keep to date with the latest ME/CFS and long COVID research.
Please note: The Research Digest shares current scientific findings for awareness and discussion. It is not a substitute for medical advice or treatment guidance, as much of the research featured is in its early stages and requires further confirmation.
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THEORY
A multidimensional immunological perspective on long COVID
Authors: Giunta S, Giuliani A, Sabbatinelli J , Olivieri F (Universit`a Politecnica delle Marche, Italy)
Publication: Cytokine and Growth Factor Reviews (August 2025)
Link: https://doi.org/10.1016/j.cytogfr.2025.07.001
Easy Read Overview: These authors suggest that changes in both the immune system and the nervous system work together to keep symptoms going in people who develop long COVID after an initial COVID-19 infection. Overactive immune cells can cause damage that leads to tiredness, pain and other long-lasting symptoms, while problems in the autonomic nervous system can affect heart rate, blood pressure and thinking. The authors believe that certain tests, such as checking immune markers or heart rate changes, may help diagnose Long COVID earlier and guide better treatment.
Long COVID, like other post-acute infection syndromes, is thought to involve several mechanisms, including immune dysregulation, chronic inflammation and autonomic dysfunction. These authors propose a framework that integrates neuroimmune dysregulation, innate immune dysfunction and autoantibody-mediated mechanisms to explain the persistence and heterogeneity of long COVID.
SARS-CoV-2 infection triggers acute inflammation via viral entry through ACE2 receptors and the transmembrane protease TMPRSS2-mediated mechanisms, causing systemic immune activation and endothelial injury. In some individuals, especially older adults or those with metabolic or immunogenetic vulnerabilities, immune dysregulation persists, leading to chronic inflammation, microvascular dysfunction, and impaired immune resolution. This can lead to autoantibody production, T cell exhaustion, and neuroimmune imbalance.
Innate immune cells, particularly neutrophils and macrophages, are central to long COVID pathogenesis. Neutrophils release extracellular traps (NETs), which, if dysregulated, can drive tissue damage and autoimmunity. Macrophages contribute to chronic inflammation through cytokine production and antigen presentation, with aging-associated “inflammaging” amplifying these effects. Persistent activation of inflammasomes, complement dysregulation, and trained immunity further lead to sustained low-grade inflammation and breakdown of the body’s immune tolerance.
Autonomic nervous system (ANS) dysfunction is another feature and driver of long COVID. Sympathetic nervous system overactivation leads to neuroimmune dysregulation, promoting fatigue, orthostatic intolerance, and cognitive defects. Autoantibodies targeting ANS receptors may also enhance this. The complicated web of chronic inflammation, autoimmunity, and ANS imbalance makes long COVID a dyshomeostasis syndrome, with inflammaging acting as an amplifier, particularly in older adults and women.
The authors believe that biomarkers such as cytokine profiles, phenotyping immune cells, epigenetic clocks, and heart rate variability can aid early diagnosis, help sort people by their level of risk, and offer personalized interventions. They conclude that it can also provide insight into broader mechanisms of post-infectious and age-related chronic diseases.
CLINICAL CARE
Assessing the influence of lived-experience experts on healthcare providers in a virtual community of practice: a qualitative study
Author: Weaver SS, Carry M, Bertolli J, Godino J, Struminger B, Taren D, … Ramers CB (Laura Rodriguez Research Institute, USA)
Publication: Frontiers in Health Services (June 2025)
Link: https://www.frontiersin.org/journals/health-services/articles/10.3389/frhs.2025.1562651/full
Easy Read Overview: This study looked at whether including people with lived experience in an online learning group could help doctors better understand conditions like long COVID and ME/CFS. The researchers reviewed webinar sessions and interviewed patients to see how doctors were using what they learned. Patients said their doctors listened more, showed more empathy and gave advice that better matched their real needs. The study suggests that involving lived-experience experts may improve care and reduce stigma.
This qualitative evaluation investigates how embedding lived-experience experts (LEEs) in a virtual community of practice shapes healthcare providers’ approach to complex, often misunderstood conditions such as long-COVID, ME/CFS and other post-acute infection syndromes (PAIS). By blending patients’ voices with professional discourse, the study aimed to illuminate whether this model could help reduce stigma, improve empathy, and change care practices.
Over an 18-month period, the project collected transcripts from regular webinar sessions (January 2022 – March 2024) in which LEEs – people living with Long-COVID, ME/CFS or PAIS, or caregivers – shared educational input to clinicians. In parallel, 22 patients receiving care from participating providers were interviewed using semi-structured methods to explore how they perceived those providers’ adoption of LEE-driven recommendations. Transcripts were thematically analysed via content analysis.
Key themes emerged around validating illness experience, shifting clinician beliefs about symptoms beyond psychological attribution, fostering empathetic communication, improving navigation of referrals, recognising fluctuating disability and encouraging patient self-management. Patients reported feeling heard, better understood and more confident in advocating for themselves. Many recounted that providers gradually incorporated LEE messages, especially around pacing and acknowledging disability, into interactions. Notably, participants described how integration of lived experience helped bridge the gap between biomedical uncertainty and human suffering in PAIS settings.
The authors argue that this model offers a promising way to reduce the “invisibility” of these syndromes. Involving LEEs as co-educators can shift provider attitudes, heighten validation of symptoms, and encourage more responsive care, especially in the context of long-COVID and ME/CFS. Future research should examine the longitudinal effects on clinician behaviour and explore how such models could scale across health systems to better address the needs of patients with PAIS.
CLINICAL TRIAL
Pyridostigmine improves hand grip strength in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Schlömer E, Stein E, Kedor C, Rust R, Brock A, Wittke K, … Kim L (Charité-Universitätsmedizin Berlin, Germany)
Publication: Frontiers in Neuroscience (September 2025)
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12441162/pdf/fnins-19-1637838.pdf
Easy Read Overview: The study looked at whether a medicine called pyridostigmine (PS) (Mestinon) could help people with ME/CFS who have weak muscles and trouble standing. Twenty patients did hand grip strength tests and standing tests with and without the medicine. Their grip strength dropped after an hour without PS, but it doubled after taking PS, and their heart rate increase while standing improved. The authors say more research is needed because the study was small and had no control group.
This paper explored whether low acetylcholine activity contributes to the reduced exercise capacity, muscle strength, and orthostatic intolerance seen in ME/CFS patients. The body requires acetylcholine for muscle activity, muscle activity control and cardiovascular adaptations such as standing up. Pyridostigmine (PS), also known as Mestinon, is a drug that inhibits the enzyme that breaks down acetylcholine. PS has been used off label for ME/CFS patients, specifically those with orthostatic intolerance to mitigate symptoms.
The study included 20 post-infection ME/CFS patients (7 men, 13 women) diagnosed using the Canadian Consensus Criteria. Muscle fatigue was assessed using hand grip strength (HGS) test with all patients recording values below the manufacturer’s cutoff.
During the first visit, baseline HGS values were obtained using a dynamometer. Participants held the dynamometer in their dominant hand and exerted maximum force for a 3 second period with 5-second rests. This was repeated 10 times, and the highest value over each 3 second period was recorded in kgs. This process was then repeated 60 minutes later and followed by a passive stand test that 7 participants declined. During the second visit, patients repeated the initial HGS protocol. After the first set of 10, 30
milligrams of PS was administered. HGS was retested after one hour, again followed by a passive stand test.
The researchers found that HGS fell after an hour without PS but doubled after PS administration. Heart rate rise whilst standing also dropped from 17 BPM to 13 BPM with PS. This indicates that PS could have significant benefits for ME/CFS patients with orthostatic intolerance, muscle weakness and impaired exercise capacity.
The authors acknowledge the limitations of the small sample size and the lack of a control group. They recommend further study of PS to validate these findings in a larger, controlled trial, and to better understand its effects on symptoms and function, as well as possible side effects.
BIOLOGY
Heightened innate immunity may trigger chronic inflammation, fatigue and post-exertional malaise
Authors: Che X, Ranjan A, Guo C, Zhang K, Goldsmith R, Levine S, … Lipkin WI (Columbia University, USA)
Publication: npj Metabolic Health and Disease (September, 2025)
Link: https://doi.org/10.1038/s44324-025-00079-w
Easy Read Overview: This study looked at how the immune system and metabolism of people with ME/CFS react to signals that mimic germs, both before and after exercise. The researchers found that ME/CFS patients had stronger and more unusual immune responses than healthy people, especially in younger women. They also showed signs of problems with energy production, inflammation and how their bodies process fats and amino acids after exercise. The authors say these results highlight serious immune and metabolic problems in ME/CFS and point to possible areas for future treatments.
The similarity with long-COVID, ME/CFS and other post-infectious syndromes suggests that a generic response to multiple microbial triggers, rather than a specific pathogen, may be responsible for these conditions. This study examines the effects of microbial mimics on immune and metabolic function before and after exercise, with the aim of better understanding the pathophysiology of post-exertional malaise (PEM).
This study consisted of 56 ME/CFS participants (Fukuda & Canadian Consensus Criteria) and 52 healthy controls (HC) from which 47 case-control matched pairs were made. Blood samples were taken before and after exercise and analysed for inflammatory markers when exposed to the superantigens: lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C); and to the mimics of infectious agents: Staphylococcus aureus enterotoxin type B (SEB) and heat-killed Candida albicans (HKCA). These samples underwent proteomic and metabolic analyses. Clinical symptoms were monitored via self-reported questionnaires before exercise, and 24 hours and 48 hours post exercise.
Cytokine response was significantly altered in ME/CFS in response to SEB and HKCA both before and after exercise, particularly in females under 45 years old. Female subjects experienced glutathione depletion, whilst male subjects displayed peroxisome dysfunction. ME/CFS participants demonstrated a lower threshold for immune activation after exposure to microbial components.
Proteomics analysis showed altered immune activation and cell-adhesion proteins, evidence of extended complement activation and overactive calcium signalling, increased levels of oxidative stress proteins; reduced neuron-related proteins and markers of gastrointestinal barrier dysfunction. In combination, these point to systemic inflammation, barrier disruption, and extensive immune dysregulation.
After exercise, ME/CFS participants displayed several indicators of metabolic dysfunction. Increased citrate, elevated growth differentiation factor 15 and unchanged phosphate levels suggest mitochondrial stress and reduced mitochondrial activity. Increased tri- and diglycerides and reduced levels of carnitines post-exercise suggest abnormal metabolism of lipids, while altered tryptophan metabolism indicated a shift to a pathway linked with neuroinflammation. Levels of propionic acid (PPA) and endogenous retrovirus group V member 1 (ERVV1) were elevated post-exercise, both of which have been associated with inflammation and neurological dysfunction.
The authors conclude that these results support the need for further research into the role of innate immunity in ME/CFS, and suggests some targets for clinical trials.