The 126th edition of the Research Digest brings together clinical, biological, and lived-experience perspectives to strengthen our understanding of long COVID and its overlap with ME/CFS. The featured studies explore emerging diagnostic tools, long-term immune responses, and important biological differences between males and females, highlighting both progress and ongoing gaps. These insights are helping refine how we identify and characterise these conditions, while also pointing toward more personalised approaches to care. A powerful media perspective also reminds us of the significant real-world impact on individuals and families.
Contributing Digesters: Imogen, Jyothsna, Lauren, & Simone.
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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CLINICAL CARE
Putting the PASC score to the test: Clinical vs. statistical accuracy in long COVID diagnosis
Authors: Azola A, Dastgheyb RM, Easter R, Parker H, Della Penna C, Santiuste I, … Rubin LH ( Johns Hopkins School of Medicine, USA)
Publication: Journal of General Internal Medicine (November, 2025)
Link: https://link.springer.com/content/pdf/10.1007/s11606-025-10042-6.pdf
Easy Read Overview: This study tested a scoring tool made by the US National Institutes of Health to help identify long COVID. The tool uses 44 symptoms and correctly identified 80% of people with long COVID, though some cases were missed. A group of symptoms—loss of smell or taste, post-exertional malaise, and reduced sexual desire—was most helpful for spotting the condition.
This study evaluated the validity of the Post-Acute Sequelae of SARS-CoV-2 (PASC) scoring system for diagnosing long COVID (LC), developed by the US National Institutes of Health’s Researching COVID to Enhance Recovery (RECOVER) Initiative. The tool was designed to differentiate symptoms in people infected with SARS-CoV-2 from those who were not, 6 months or more after infection. It includes 44 symptoms. A score of 12 or higher indicates PASC+, while a lower score is classified as PASC– (intermediate).
The study included 130 patients clinically diagnosed with LC and recruited from specialised care clinics. All participants met the National Academy of Sciences, Engineering and Medicine (NASEM) definition of LC and reported at least one neuropsychiatric symptom (e.g., headache or brain fog). The mean age was 47.2 years, and 76% of participants were female. A demographically similar control group included 60 healthy participants.
The researchers found that the PASC scoring system correctly identified 80% of LC patients but produced 26 false negatives. No false positives occurred. Symptom patterns were then analysed and the researchers discovered that the combination of loss of smell/taste, post exertional malaise (PEM), and reduced sexual desire or capacity had the highest sensitivity for identifying LC.
These findings will likely help refine future diagnostic approaches. However, limitations include a small, predominantly white study group and a limited control group.
BIOLOGY
Robust antibody and T cell responses tracked longitudinally in patients with long COVID
Author: Metaxaki M, Ram R, Perera M, Wills M, Krishna BA, & Sithole N (University of Cambridge, UK)
Publication: Journal of General Virology (December 2025)
Link: https://doi.org/10.1099/jgv.0.002172
Easy Read Overview: This study followed people with long COVID for over three years to see how their immune systems changed. It found that their immune responses stayed stable or improved after vaccination and reinfection and were similar to people who recovered. Overall, there was no sign that long COVID caused the immune system to get weaker over time.
Although the molecular mechanism of long COVID remains unclear, research suggests several possible factors. These include persistent viral antigen, autoimmunity, ongoing inflammation, deactivation of herpes viruses, organ damage, and possible immunodeficiency.
To explore whether long COVID is associated with progressive dysfunction of the immune system, this study examined antibody and cellular immune responses over 40 months in a cohort of 129 long COVID patients recruited from a long COVID clinic. Of these, 33 attended at least one follow-up blood sample, and 13 completed four blood collections at 8.5, 19, 28, and 39 months post-infection. A control group of 13 individuals without persistent symptoms was included. During the study period, all the participants received the COVID-19 vaccine, and many experienced reinfections, particularly during the Omicron wave. Blood samples were analysed for antibody production, capacity to neutralise the virus, and SARS-CoV-2–specific T cell activity, as well as responses to other common viral antigens.
Results showed stable immune responses over time. Anti-spike antibody levels increased following vaccination, while anti-nucleocapsid antibodies rose after reinfection, reflecting antigenic exposure.
Serum neutralising capacity increased after vaccination or infection with SARS-CoV-2, and was similar in long COVID patients and recovered controls. Likewise, SARS-CoV-2 specific IL-2–producing T cells increased over time, suggesting boosting of the immune response from vaccination and reinfection, while the IFN-γ production remained relatively stable.
The cohort maintained a normal immune response to other common viruses, indicating intact antiviral immunity. Reinfection and improvement in long COVID symptoms were not associated with differences in antibody or T cell responses.
The authors concluded that long COVID patients do not exhibit progressive immune deficiency, with immune responses either remaining stable or increasing in response to vaccination and reinfection. Although fatigue was observed in some patients, most gradually improved. The authors suggest that future research should focus on including larger groups, a deeper analysis of additional immune cells and cytokines, improved T cell assays, and long-term monitoring beyond 40 months to detect rare or delayed immune dysfunction.
BIOLOGY
Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS
Authors: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S (University of Alberta, Canada)
Publication: Cell Reports Medicine (November, 2025)
Link: https://www.sciencedirect.com/science/article/pii/S2666379125005221
Easy Read Overview: This study looked at how long COVID with ME/CFS may affect males and females differently. It compared immune cells, hormones, and gene activity in people with long COVID and those who had recovered. Females showed more signs of ongoing inflammation, changes in immune cells, and different hormone levels than males. These differences may help explain why females often have more severe symptoms and suggest that treatments may need to be tailored by sex.
This study explored whether biological signatures – across immune cell profiles, hormone levels, and gene expression – differ between male and female long COVID patients with ME/CFS. Understanding these sex-specific differences may help explain why females often experience more severe symptoms and could inform tailored treatments.
The observational study included 78 long COVID patients meeting clinical criteria for ME/CFS (Canadian Consensus Criteria) and 62 matched recovered controls. All participants were at least 12 months post-acute infection. Immune cell subsets were quantified, plasma cytokines measured, hormone levels analysed, and transcriptomic (gene expression) data generated.
Female participants showed evidence of persistent immune activation, including increased neutrophils/monocytes, fewer regulatory T cells, and heightened pro-inflammatory cytokines compared with males. Females also exhibited markers of gut barrier dysfunction and elevated CD71+ erythroid cells, potentially contributing to fatigue and tissue stress. Hormone profiles differed by sex: females showing lower testosterone, and males showed reduced oestradiol. Transcriptomic analyses revealed neuroinflammatory gene expression signatures in females, which may underlie cognitive symptoms often reported in ME/CFS.
The findings suggest that ME/CFS following long COVID is not biologically uniform across sexes. Females appear to experience more pronounced immune and inflammatory dysregulation and distinct hormonal alterations, which may partly explain sex differences in symptom severity and presentation. These results underscore the potential value of sex-tailored diagnostic and therapeutic approaches in ME/CFS and long COVID, including consideration of hormonal modulation strategies.
MEDIA
Interview with Dr Emma Tippett for long COVID awareness week
Authors: McGuire, J
Publication: ABC Drive (NSW)
Link: https://www.abc.net.au/listen/programs/nsw-drive/drive/106430520
Dr Emma Tippett is Director of the Clinic 19 telehealth long COVID clinic. She describes the wide range of symptoms of long COVID, which is estimated to affect hundreds of thousands of people in Australia. She describes the devastating impact on people’s lives, especially young people who are unable to attend school and whose lives are changed forever as a result of the condition.
Interview starts at 41 mins and 20 seconds and runs for approximately 6 minutes.
