Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison

Abstract

Children and adolescents infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are predominantly asymptomatic or have mild symptoms compared with the more severe coronavirus disease 2019 (COVID-19) described in adults. However, SARS-CoV-2 is also associated with a widely reported but poorly understood paediatric systemic vasculitis. This multisystem inflammatory syndrome in children (MIS-C) has features that overlap with myocarditis, toxic-shock syndrome and Kawasaki disease. Current evidence indicates that MIS-C is the result of an exaggerated innate and adaptive immune response, characterized by a cytokine storm, and that it is triggered by prior SARS-CoV-2 exposure. Epidemiological, clinical and immunological differences classify MIS-C as being distinct from Kawasaki disease. Differences include the age range, and the geographical and ethnic distribution of patients. MIS-C is associated with prominent gastrointestinal and cardiovascular system involvement, admission to intensive care unit, neutrophilia, lymphopenia, high levels of IFNγ and low counts of naive CD4⁺ T cells, with a high proportion of activated memory T cells. Further investigation of MIS-C will continue to enhance our understanding of similar conditions associated with a cytokine storm.

Fig. 1. The temporal relationship between SARS-CoV-2 infection and development of MIS-C.

Evidence suggests that a relationship exists between the timing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and development of multisystem inflammatory syndrome in children (MIS-C). Cases of MIS-C tend to be seen 3–6 weeks after the peak of SARS-CoV-2 transmission in a community. Because of this time lag, MIS-C is associated with a strong anti-spike protein IgG response, but a weak IgM response. It should be noted that implication of SARS-CoV-2 as a triggering factor for the development of MIS-C has yet to be firmly established.

Fig. 2. Possible mechanisms implicated in aberrant activation of immune cells in MIS-C.

Clinical signs of multisystem inflammatory syndrome in children (MIS-C) mostly appear several weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MIS-C might be triggered by dysregulation of immune responses following viral infection. Aberrant activation of immune cells in patients with MIS-C could result from several factors. Infection with particular variants of SARS-CoV-2 might trigger hyperinflammatory responses. Genetic predisposition resulting from variants in the genes that encode pattern recognition receptors, Fcγ receptors and components of the signalling cascades of immune response, as well as mutations in genes such as SOCS1, which regulate inflammatory responses, could all contribute to enhancement of inflammatory responses to infection. Dysregulated activation of lymphocytes, with production of IgG corresponding to microbial pathogens or autoantigens, could cause immune-complex-mediated innate-cell activation by signalling via Fcγ receptors. Production of autoantibodies could also lead to complement activation and autoantibody-mediated endothelial damage. SARS-CoV-2 spike (S) protein might function as a superantigen, contributing to activation of T cells. SOCS1, suppressor of cytokine signalling 1; TLR, Toll-like receptor.

Fig. 3. Comparative incidence of clinical signs in MIS-C and Kawasaki disease.

Percentage incidence of particular symptoms in patients with multisystem inflammatory syndrome in children (MIS-C) or Kawasaki disease is shown, with the values derived from published reports^{,,,–,,,,–}. Although some clinical signs, such as fever and cervical lymphadenopathy are equally prevalent in both MIS-C and Kawasaki disease, the incidence of other symptoms, including shock, coronary artery involvement and gastrointestinal symptoms (vomiting, diarrhoea or abdominal pain), are characteristic of MIS-C. ^a‘Conjunctival injection’ refers to bilateral non-exudative conjunctivitis in Kawasaki disease. ^b‘Rash’ refers to polymorphous rash in Kawasaki disease. ^c‘Coronary artery dilation of aneurysm’ refers to incidence in untreated cases of Kawasaki disease.