ABSTRACT
Background: Systemic hyperinflammation is key to the pathogenesis of severe, acute COVID-19. However, few studies have analysed inflammatory profiles in adults with mild/moderate COVID-19, or in those with post-acute sequelae of COVID-19 (PASC). We aimed to i) describe trajectories of cytokines in a prospective cohort of adults with mild to severe COVID-19, compared to uninfected, healthy controls and ii) identify early (< 4 weeks after illness onset onset) predictors of ongoing PASC and inflammation at 6 months after illness onset. Method(s): RECoVERED is a prospective cohort of adults with laboratoryconfirmed SARS-CoV-2 infection between May 2020 and June 2021 in Amsterdam, the Netherlands. Serum was collected at weeks 4, 12 and 24. Participants completed monthly symptom questionnaires. PASC was defined as having at least one ongoing symptom that originated < 1 month of illness onset. Cytokine concentrations were analysed by human magnetic Luminex screening assay. We performed random forest regression to identify early predictors of PASC and raised CRP/IL-6 at 24 weeks, using Shapley additive explanation values as measures of importance for the different predictors. Result(s): Of 349 RECoVERED participants, 186 (53%) had >=2 serum samples and were included in current analyses. Of these, 101 (54%: 45/101 [45%] female, median age 55 years [IQR=45-64]) reported PASC at 12 weeks after illness onset, of whom none recovered by 24 weeks. We included 37 uninfected controls (17/37 [46%] female, median age 49 years [IQR=40-56]). At 4 weeks after illness onset, levels of IP10, IL10, IL17, IL1beta, IL6 and TNFalpha were significantly elevated among participants infected with SARS-CoV-2 compared to controls. Ongoing PASC was independently associated with raised CRP at 24 weeks. Early raised IL1beta and sCD14 levels and greater BMI at illness onset were the strongest predictors of PASC at 24 weeks. Those with higher early sCD14 or IL1beta and TNFalpha levels were also more likely to have persistently raised CRP and IL6, respectively, at 24 weeks (Fig.1). Conclusion(s): Differences in cytokine concentrations between individuals with COVID-19 and uninfected controls largely were greatest < 4 weeks after illness onset. In our study, ongoing PASC was associated with persistently elevated CRP at 24 weeks. Early immune dysregulation was, alongside BMI, an important determinant for persistent PASC. Further investigation of individuals with PASC and long-term aberrant cytokine levels may help improve our understanding of the condition. (Figure Presented).