COVID-19 is frequently asymptomatic in children and, if symptoms arise, they are typically mild. However, one complication that can arise from a SARS-CoV-2 infection is Multisystem Inflammatory Syndrome in Children (MIS-C). Little is known about MIS-C, which presents 4–6 weeks after infection with a high fever, organ dysfunction, and inflammation. Now, a team of researchers has mapped the immune response in children affected by MIS-C. The findings reveal that, although MIS-C shares some features with Kawasaki disease, the inflammatory response differs from that in Kawasaki disease and severe acute COVID-19.

“Our results show that MIS-C is truly a distinct inflammatory condition from Kawasaki disease, despite having some shared features,” said Petter Brodin, MD, PhD, pediatrician and researcher at the department of women’s and children’s health, Karolinska Institutet. “The hyperinflammation and cytokine storm detected in children with MIS-C is also different from that seen in adult patients with severe, acute COVID-19, which we recently described in another publication.”

The study is published in the journal Cell in the paper titled, “The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19.”

Researchers compared blood samples from 13 MIS-C-patients treated at Karolinska University Hospital in Stockholm, Sweden, and Bambino Gesù Children’s Hospital in Rome, Italy, with samples from 28 Kawasaki disease patients collected from 2017 to 2018, prior to COVID-19. The analyses also included samples from children with mild COVID-19.

When comparing MIS-C to these other inflammatory states, the study observed differential frequency of specific immune cell populations, inflammatory cytokines, and chemokines in the blood. More specifically, the authors write that the “inflammatory response in MIS-C differs from the cytokine storm of severe acute COVID-19, shares several features with Kawasaki disease, but also differs from this condition with respect to T-cell subsets, IL-17A, and biomarkers associated with arterial damage.”

Unlike children with Kawasaki disease and children with mild COVID-19, children who developed MIS-C were lacking IgG-antibodies to common cold coronaviruses. The researchers also found several autoantibodies that target the body’s own proteins and that may contribute to the pathogenesis of MIS-C. These data, the authors noted, suggest “possible targets of autoimmune attack.” The hypothesis that autoantibodies contribute to the pathology in MIS-C is supported, the authors write, “by the efficacy of intravenous immunoglobulin in MIS-C, a common approach to activate inhibitory Fc-receptors and prevent membrane-attack complexes by complement factors and thereby mitigating autoantibody-mediated pathology.”

The researchers are now investigating the genetic risk factors for developing MIS-C after SARS-CoV-2 infection. The authors noted that treatments of MIS-C have, for the most part, followed protocols used in atypical Kawasaki disease “given the overlap in presentation between these groups of patients.” Their data, they suggested, “present a more complex picture with both shared features and stark differences that should influence treatment strategies for these conditions.”

“There is an urgent need to better understand why a small minority of children infected with SARS-CoV-2 develop MIS-C, and we are adding a piece to the puzzle,” said Brodin. “Better knowledge of the pathogenesis is important for development of optimal treatments that can dampen the cytokine storm and hopefully save lives, as well as for vaccine development to avoid MIS-C caused by vaccination.”

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