Pre-Pandemic Plasma IL-6 Levels are Positively Associated with Chronic Fatigue But Do Not Differentiate Those with COVID-19 Induced Fatigue

Background – Fatigue is a prominent symptom in the general population and may follow infection with a number of viruses including SARS-CoV2 causing COVID-19. Persistent or chronic fatigue lasting more than 3 months following COVID-19 infection is a major symptom of so-called long-COVID syndrome. The mechanisms underlying long-COVID fatigue are unknown. We hypothesized that the development of post-COVID chronic fatigue is driven by the pro-inflammatory immune status of an individual before COVID-19 infection.Methods – We tested this hypothesis by analysing pre-pandemic plasma levels of IL-6, one of the key cytokines in fatigue development, in n = 1274 community dwelling adult twins from TwinsUK. TwinsUK registry participants have been assessed longitudinally for persistent fatigue using selfcompleted questionnaire; and for COVID-19 infection by antigen and antibody testing.Findings – Persistent fatigue was a prevalent symptom among this population but the prevalence was found to be significantly higher in the COVID-19 antibody positive- compared to antibody negative twins (17% vs 11%, respectively; p = 0.001). The qualitative nature of persistent fatigue as determined by individual question responses was similar in those having had COVID-19 and those not having infection. Pre-pandemic plasma IL-6 levels were positively associated with chronic fatigue in COVID-19 negative, but not positive, individuals; while raised BMI was found associated with chronic fatigue in COVID-19 positive twins.Interpretation – This finding corroborates our hypothesis that pre-existing immune status provides the ground for chronic fatigue, but we found no evidence that this occurs specifically in COVID-19 infection.Funding Information: The study was supported by Kennedy Trust grant #KENN 19-20-10. JML is supported by the NIHR Birmingham Biomedical Research Centre, CMP by the South London and Maudsley NHS Foundation Trust & King’s College London Biomedical Research Centre. Mario Falchi is supported by MRC grant MR/T004142/1.Declaration of Interests: Authors declare no competing interestsEthics Approval Statement: Participants were selected from the UK Twin Registry (TwinsUK), an adult cohort which has been shown to be representative of the general population for lifestyle and health-related traits (14). Ethics permission was obtained and twins have provided fully informed consent; the Declaration of Helsinki is adhered to. The TwinsUK Study was approved by London-Westminster Research Ethics Committee (REC reference EC04/015), and Guy’s and St Thomas’ NHS Foundation Trust Research and Development (R&D). The TwinsUK BioBank was approved by the HRA - Liverpool East Research Ethics Committee (REC reference 19/NW/0187), IRAS ID 258513.