Prognostic Value of Baseline Serum Pro-Inflammatory Cytokines in Severe Multisystem Inflammatory Syndrome in Children

<b>Background:</b> Severe clinical manifestations of multisystem inflammatory syndrome in children (MIS-C) are associated with the dysregulation of immune response following SARS-CoV-2 infection. Therefore, we analyzed the levels of 10 selected cytokines at admission to estimate disease severity and to predict the length of hospitalization. In remission samples, these mediators were followed after intravenous immunoglobulin (IVIG) treatment before discharge. <b>Methods:</b> Thirty-five MIS-C patients at the age of 8.4 ± 4.1 years and 11 clinical controls were included. Acute MIS-C patients were divided into two severity subgroups based on their clinical score determined by the WHO criteria. Serum concentrations of IFN-γ, IL-1α, IL-1RA, IL-8, IL-10, IL-17A, IL-18, IP-10, MCP-1, and TNF-α were measured by MILLIPLEX^® Human Cytokine/Chemokine panel, while ACE2 activity was determined by a fluorescent kinetic assay. These results were correlated with routinely determined laboratory parameters and clinical characteristics. <b>Results:</b> MIS-C patients demonstrated significantly elevated baseline levels of most of these cytokines compared to controls. Even higher concentrations of IL-18, TNF-α and ferritin with reduced lymphocyte count were found in severe subjects with elevated clinical scores of 4-5 compared to moderate cases with a clinical score of 1-3. Furthermore, the development of cardiovascular dysfunction and prolonged hospitalization (≥8 days) were related to augmented ACE2 and IL-6 levels. IL-18, IL-1RA, IL-10 and TNF-α were diminished in response to IVIG treatment in remission samples. Finally, pre-treatment IL-18 (≥516.8 pg/mL) and TNF-α (≥74.2 pg/mL) effectively differentiated disease severity in MIS-C with AUC values of 0.770 and 0.750, respectively. <b>Conclusions:</b> IL-18 and TNF-α have a prognostic value in disease severity at admission and are capable of monitoring the efficacy of IVIG treatment in MIS-C.