Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may result in the multisystem inflammatory syndrome in children (MIS-C). The clinical presentation of MIS-C includes fever, severe illness, and the involvement of two or more organ systems, in combination with laboratory evidence of inflammation and laboratory or epidemiologic evidence of SARS-CoV-2 infection. Some features of MIS-C resemble Kawasaki Disease, toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome. The relationship of MIS-C to SARS-CoV-2 infection suggests that the pathogenesis involves post-infectious immune dysregulation. Patients with MIS-C should ideally be managed in a pediatric intensive care environment since rapid clinical deterioration may occur. Specific immunomodulatory therapy depends on the clinical presentation. The relationship between the immune response to SARS-CoV-2 vaccines in development and MIS-C requires further study.

Keywords: COVID-19; Kawasaki Disease; SARS-CoV-2; hemophagocytic lymphohistiocytosis; macrophage activation syndrome; multisystem inflammatory syndrome in children (MIS-C); toxic shock syndrome.

Figure 1

Infographic showing CDC criteria for the diagnosis of MIS-C. A combination of fever, evidence of inflammation, involvement of at least two organ systems, and prior evidence of SARS-CoV-2 infection are required to establish the diagnosis.

Figure 2

Pathogenesis of MIS-C. Early infection (phase I) with SARS-CoV-2 is likely to be asymptomatic or mildly symptomatic in children. The pulmonary phase (phase II) is severe in adults but is mild or absent in many children. The early infection appears to trigger macrophage activation followed by the stimulation of T-helper cells. This in turn leads to cytokine release, the stimulation of macrophages, neutrophils, and monocytes, along with B-cell and plasma cell activation with the production of antibodies leading to a hyperimmune response (stage III). This immune dysregulation is associated with the inflammatory syndrome in affected children. Direct infection with SARS-CoV-2 is less likely to play a role in MIS-C. ACE2—angiotensin converting enzyme 2 receptors; TNF-β—tumor necrosis factor β; IL—interleukins.