The Underlying Immunological Mechanisms of Multisystem Inflammatory Syndrome in Children

Several inflammatory conditions and sequelae have been associated with SARS-CoV-2 infection and COVID-19, from cytokine release syndrome (Jose, Manuel 2020), to Kawasaki disease (Jones et al. 2020), and immune thrombocytopenic purpura (see updates for 6/8/2020). Though distinct in etiology and presentation, these complications have in many cases warranted hospitalization and treatment apart from treatment for COVID-19. Another of these inflammatory conditions observed in the wake of COVID-19 is multisystem inflammatory syndrome, particularly in children (MIS-C). Given the severity of MIS-C, it is imperative to determine its physiological mechanisms, and how these may differ from Kawasaki or any of the other COVID-19-associated inflammatory conditions. Consiglio et al. assayed immune cells, cytokines, and autoantibodies in children with Kawasaki disease, children infected with SARS-CoV-2, children with MIS-C, and healthy controls to elucidate the similarities and differences between these clinically relevant pathologies for the development of optimal treatment regimens for each.

Children with MIS-C presented with significantly lower white blood cell counts than those with Kawasaki disease and healthy controls, though their counts were comparable to children with mild COVID-19. Additionally, MIS-C patients had higher levels of C-reactive protein (CRP) and ferritin, as well as lower platelet counts, than children with Kawasaki disease and COVID-19. Specifically, patients with MIS-C had inflammatory responses characterized by low expression of the interleukins (ILs) 8 and 7, which are pro-inflammatory cytokines involved with T cell activation and differentiation. More significantly, IL-17A and the plasma protein DCBLD2 were lower in MIS-C patients than Kawasaki disease patients, which indicated an underlying difference in immunopathology of the two conditions. The secretion of DCBLD2 suggests pronounced arterial damage in Kawasaki disease. In terms of lymphocyte expression, children with MIS-C had both significantly reduced levels of T follicular helper cells and higher levels of terminally differentiated CD4+ T cells – characterized by CD57 expression – compared to those with Kawasaki disease and healthy controls.

This paper goes into further detail describing the nuances of MIS-C, COVID-19, and Kawasaki disease as well as their overlap, and makes the case for a more specific and mindful approach to the treatment of MIS-C. Though largely a diagnosis of exclusion, MIS-C presents with serious complications  if not recognized early and not treated effectively. The idea of COVID-19 being a mild disease in children has now been challenged by these reports of severe MIS-C and Kawasaki disease, conditions that – at their worst – can result in organ failure and death. The role of the immune system and inflammatory responses in these diseases suggests lots of potential targets for therapies, especially those aimed at reducing inflammation in COVID-19. The authors acknowledge the limited sample size of their study and suggest that future work focused on obtaining more extensive control pairs pre- and post-treatment would be important. However, the data presented in this paper are significant, and designate MIS-C as a COVID-19-associated disease worthy of attention and follow-up