Inflammatory profiles are associated with long COVID up to 6 months after illness onset: A prospective cohort study of patients with mild to critical COVID-19 7 209 INTRODUCTION Almost half of individuals[1] infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are estimated to experience symptoms related to “long COVID” or post-acute sequelae of COVID-19 (PASC). There are many uncertainties regarding the pathophysiological processes and predictors of PASC. Numerous studies have suggested that hyperinflammation observed during acute infection among individuals with severe COVID-19 [2-4] may persist among those with ongoing symptoms[5]. However, less is known about the role of aberrant cytokine levels in the pathogenesis of PASC in individuals with initially mild or moderate COVID-19. Observations to date have been largely inconclusive due to heterogeneity in research objectives, study design and population. Some studies aimed to outline immune disturbances in the first months after infection[6-8] in order to better understand COVID-19 immunopathology, whilst others specifically aimed to identify early inflammatory predictors for PASC that could be of clinical relevance [9-13]. In a prospective cohort of individuals with COVID-19, of whom 22% had been hospitalised, IL6 remained significantly raised among participants with PASC compared to those without PASC 90 days after infection[6]. A second study also observed elevated levels of IL6, as well as IL1 and TNF, around 10 months post symptom onset[14]. In a cohort of largely non-hospitalised patients, elevated TNFα at 4 and 8 months were strongest predictors of PASC overall, with no difference observed in IL6 between those with and without PASC[11]. Prospective data that aims to both outline longitudinal immune profiles among individuals with mild to critical COVID-19, and identify possible early markers of PASC, is needed to better understand previous findings. Using data from the RECoVERED cohort study in Amsterdam, the Netherlands, we aim to gain insight into longitudinal immune profiles among individuals with COVID-19 and PASC. A substantial proportion of study participants reported at least one persistent COVID-19 symptom 3 months or longer after initial illness onset[15]. In the current study, we evaluate the impact of SARS-CoV-2 infection on cytokine levels up to 6 months after illness onset, assess the association of PASC with specific inflammatory profiles, and evaluate possible early determinants of PASC.
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