Background
SARS-CoV-2 infections in children are generally mild or asymptomatic. A significant concern is the post-infectious immune response, particularly multisystem inflammatory syndrome in children (MIS-C). This is a severe complication usually developing 4-6 weeks after infection, likely triggered by a hyperinflammatory response to SARS-CoV-2. This study analyzed the inflammatory profile in children with acute MIS-C, convalescent COVID-19 children without MIS-C, and acute Kawasaki disease (KD), aiming to differentiate these conditions and understand the immune responses involved.
Methods
Serum was collected from Convalescent Control COVID-19 (17 participants, 4-6 weeks post-infection), MIS-C (22 patients, including follow-ups at 2 months [n=11] and 18 months [n=15]), and KD (10 acute pre-pandemic patients) and assayed for 92 inflammatory markers using the Olink Target 96 Inflammation panel. Data normalization and statistical analyses, including random forest, PCA, and unsupervised clustering, were performed using R v4.3.
Results
The MIS-C and Control COVID-19 groups were balanced by age (median 7.8 and 9.8 years) and gender (females 45.5% and 47%). KD patients had a median age of 3.2, with 30% female. We identified eighteen key cytokines and chemokines differentiating MIS-C from Control COVID-19 , including increased levels of IL-6, IL-10, IL-18, IL-18R, TNF, CXCL9, CXCL10, CXCL11, PD-L1, MCP-3, CDCP1, CCL3, and CD40 and decreased levels of TRANCE, TWEAK, SCF, and NT.3 in acute MIS-C. These markers were consistent across sex, but better classified males (100%) than females (89%). Our cohort had 50% of severe MIS-C cases, and 81.8% of these were males. Six markers (high IL-2, IL-33, and low CD8A, TNFRSF9, CD244, SCF) were linked to severe MIS-C cases. Over time, longitudinal analysis showed inflammatory markers normalazing post-treatment, reaching levels comparable to the Control COVID-19 group. Finally, MIS-C was also distinguished from KD by lower levels of TNFRSF9, TWEAK, and TRAIL.
Conclusions
This study offers critical insights into the inflammatory mechanisms of MIS-C, distinguishing it from convalescent COVID-19 and KD, indicating a distinct hyperinflammatory response. Identifying cytokines that predict MIS-C severity or differentiate MIS-C from KD are crucial for improving early diagnosis and treatment. Longitudinal analysis show fast normalization (2 months) of the inflammatory profile post-treatment, suggesting immunological recovery.
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