Similarities and differences between the immunopathogenesis of COVID-19–related pediatric multisystem inflammatory syndrome and Kawasaki disease

Abstract

Multisystem inflammatory syndrome associated with the SARS-CoV-2 pandemic has recently been described in children (MIS-C), partially overlapping with Kawasaki disease (KD). We hypothesized that: 1) MIS-C and pre-pandemic KD cytokine profiles may be unique and justify the clinical differences observed; 2) SARS-CoV-2-specific immune complexes (IC) may explain the immunopathology of MIS-C. Seventy-four children were included: 14 MIS-C; 9 patients with positive SARS-CoV-2-PCR without MIS-C (COVID); 14 pre-pandemic KD and 37 healthy controls (HC). Thirty-four circulating cytokines were quantified in pre-treatment serum or plasma samples and the presence of circulating SARS-CoV-2 IC was evaluated in MIS-C patients.Compared to HC, MIS-C and KD groups showed most cytokines to be significantly elevated, with IFN-γ-induced response markers (including IFN-γ, IL-18, IP-10) and inflammatory monocytes activation markers (including MCP-1, IL-1α, IL-1RA) being the main triggers of inflammation. With linear discriminant analysis, MIS-C and KD profiles overlapped; however, a subgroup of MIS-C patients (MIS-C plus ) differentiated from the remaining MIS-C patients in IFNγ, IL-18, GM-CSF, RANTES, IP-10, IL-1α and SDF-1 and incipient signs of macrophagic activation syndrome. Circulating SARS-CoV-2-IC were not detected in MIS-C patients. Our findings suggest a major role of IFN-γ in the pathogenesis of MIS-C, which may be relevant for therapeutic management.

Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: a cohort study

“…We found that patients with MIS-C showed a modest elevation in S100 proteins and IL-18, reflecting activation of innate immune effectors. This finding was in line with previous work showing elevated IL-18 concentrations in patients with MIS-C, and upregulation of S100A8/A9 and S100A12 genes in neutrophils and monocytes in six patients with MIS-C. 27 , 28 , 29 Although MIS-C and Kawasaki disease had similar S100 and IL-18 elevations, these disease entities could be distinguished by markedly higher CXCL9 elevations in patients with MIS-C, comparable to those seen in patients with systemic JIA-MAS.…”

“…By contrast, Lee and colleagues found lower CXCL9 concentrations in patients with MIS-C than those with MAS associated with infection or systemic JIA, but they only examined concentrations in three patients with MIS-C. 3 Other reports have found that MIS-C and Kawasaki disease have similar IFNγ cytokine profiles and that CXCL10 concentrations were higher in patients with Kawasaki disease than in those with MIS-C, but comparison to patients with MAS was not done in either of these reports. 9 , 29 …”

“…This hypothesis aligns with observations from Esteve-Sole and colleagues, who define two subclasses of MIS-C: one more closely related to Kawasaki disease and the other defined by marked IFNγ overproduction. 29 Carter and colleagues similarly proposed that pronounced increase of IFNγ, and less so IL-1β, in Kawasaki disease represents a distinction from MIS-C pathology. 11 Our results describing the clinical spectrum of MIS-C are also similar to a large study that did a latent class analysis based on clinical characteristics and manifestation to identify three clinical spectrums in the patients with MIS-C reported to the Centers for Disease Control and Prevention.…”

A Monocyte/Dendritic Cell Molecular Signature of SARS-CoV-2 Related Multisystem Inflammatory Syndrome in Children (MIS-C) with Severe Myocarditis

“…In the postacute patients, elevated levels of plasma IFN-, IFN2, IL-10, IL-15, and, to a lesser extent, TNF-, were found, as previously described in other cohorts (Brodsky et al, 2020;Carter et al, 2020;Consiglio et al, 2020;Esteve-Sole et al, 2021;Gruber et al, 2020). These findings are typical of an ongoing anti-viral immune response, not directly related to SARS-CoV-2 infection.…”

SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?

“…KD patients have high frequencies of T helper type 17 cells in the bloodstream, consistent with their high plasma IL-17A concentrations (Jia et al, 2010). This T helper type 17 cell response may, therefore, be a key feature distinguishing between KD and MIS-C hyperinflammation in untreated patients (Consiglio et al, 2020), although other studies have reported high plasma IL-17A levels in MIS-C patients too (Esteve-Sole et al, 2021;Gruber et al, 2020;Lee et al, 2020). The autoantibody profiling of serum from untreated children with MIS-C and KD has revealed many candidate targets, some of which differ between MIS-C and KD.…”