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BACKGROUND: COVID-19 disease severity and need for intensive care has been associated with profound immune disturbances in which interleukin 6 (IL-6) is central. IL-6 signals through two pathways: classical IL-6 signalling with C-reactive protein (CRP) as a product is pivotal in the acute immune response against pathogens while IL-6 trans-signalling is involved in prolonged inflammation. We measured biomarkers of the IL-6 classical and trans-signalling pathways in patients with moderate or severe COVID-19 in the first wave of the COVID-19 pandemic. METHOD: In a longitudinal cohort study including patients admitted to Danderyd hospital, Stockholm, Sweden, with COVID-19 (n = 112), plasma IL-6 mirroring activity in both pathways, CRP as marker of classical signalling and the soluble IL-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) as markers of trans-signalling were analysed at baseline. Potential differences in biomarker levels between groups of moderate and severe COVID-19 defined by care level, level of respiratory support and one-month mortality was analysed, as was correlations between biomarkers. In addition, levels 4 months after hospital admission were compared to those at baseline. RESULTS: Levels of IL-6 and CRP were increased in severe COVID-19 whereas IL-6 trans-signalling markers (sIL-6R, sgp130) did not differ between the groups. CRP correlated positively with IL-6 in all patients while correlation with IL-6 could not be demonstrated for sIL-6R and sgp130 in either group. Levels of IL-6, CRP and sIL-6R were significantly decreased after 4 months whereas sgp130 levels increased. CONCLUSION: Classical signalling is the dominating IL-6 pathway in moderate-severe COVID-19.
Ziegler et al. (2022) studied this question.