Similarities and differences between the immunopathogenesis of COVID-19–related pediatric multisystem inflammatory syndrome and Kawasaki disease
Ana Esteve-Sole, Jordi Anton, Rosa Maria Pino-Ramirez, Judith Sanchez-Manubens, Victoria Fumadó, Claudia Fortuny, María Rios-Barnes, Joan Sanchez-de-Toledo, Mónica Girona-Alarcón, Juan Manuel Mosquera, Silvia Ricart, Cristian Launes, Mariona Fernández de Sevilla, Cristina Jou, Carmen Muñoz-Almagro, Eva González-Roca, Andrea Vergara, Jorge Carrillo, Manel Juan, Daniel Cuadras, Antoni Noguera-Julian, Iolanda Jordan, Laia Alsina
Ana Esteve-Sole, Jordi Anton, Rosa Maria Pino-Ramirez, Judith Sanchez-Manubens, Victoria Fumadó, Claudia Fortuny, María Rios-Barnes, Joan Sanchez-de-Toledo, Mónica Girona-Alarcón, Juan Manuel Mosquera, Silvia Ricart, Cristian Launes, Mariona Fernández de Sevilla, Cristina Jou, Carmen Muñoz-Almagro, Eva González-Roca, Andrea Vergara, Jorge Carrillo, Manel Juan, Daniel Cuadras, Antoni Noguera-Julian, Iolanda Jordan, Laia Alsina
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Research Article Immunology

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 (a) MIS-C and prepandemic KD cytokine profiles may be unique and justify the clinical differences observed, and (b) SARS-CoV-2–specific immune complexes (ICs) may explain the immunopathology of MIS-C. Seventy-four children were included: 14 with MIS-C, 9 patients positive for SARS-CoV-2 by PCR without MIS-C (COVID), 14 with prepandemic KD, and 37 healthy controls (HCs). Thirty-four circulating cytokines were quantified in pretreatment serum or plasma samples and the presence of circulating SARS-CoV-2 ICs was evaluated in MIS-C patients. Compared with HCs, the MIS-C and KD groups showed most cytokines to be significantly elevated, with IFN-γ–induced response markers (including IFN-γ, IL-18, and IP-10) and inflammatory monocyte activation markers (including MCP-1, IL-1α, and IL-1RA) being the main triggers of inflammation. In linear discriminant analysis, MIS-C and KD profiles overlapped; however, a subgroup of MIS-C patients (MIS-Cplus) differentiated from the remaining MIS-C patients in IFN-γ, IL-18, GM-CSF, RANTES, IP-10, IL-1α, and SDF-1 and incipient signs of macrophage activation syndrome. Circulating SARS-CoV-2 ICs were not detected in MIS-C patients. Our findings suggest a major role for IFN-γ in the pathogenesis of MIS-C, which may be relevant for therapeutic management.

Authors

Ana Esteve-Sole, Jordi Anton, Rosa Maria Pino-Ramirez, Judith Sanchez-Manubens, Victoria Fumadó, Claudia Fortuny, María Rios-Barnes, Joan Sanchez-de-Toledo, Mónica Girona-Alarcón, Juan Manuel Mosquera, Silvia Ricart, Cristian Launes, Mariona Fernández de Sevilla, Cristina Jou, Carmen Muñoz-Almagro, Eva González-Roca, Andrea Vergara, Jorge Carrillo, Manel Juan, Daniel Cuadras, Antoni Noguera-Julian, Iolanda Jordan, Laia Alsina

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Figure 2

Cytokine profile of the different groups.

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Cytokine profile of the different groups. Levels of 34 circulating cytok...
Levels of 34 circulating cytokines were evaluated in serum or plasma. (A) Principal component analysis: every data point represents one individual. (B) Total variance explained by principal component 1 (PC1) and PC2 and variables with higher scores. (C) Representation of canonical variants (Can1 and -2) of the linear discriminant analysis (LDA) built with the cytokines represented in B. (D) Representation of Can2 and Can3 of the LDA (HCs have been removed from the plot, not from the analysis). A “+” indicates subgroup of MIS-C patients differentiated from other MIS-C and KD patients (MIS-Cplus). Open symbols represent patients who previously received immunoglobulin treatment. (E) Heatmap representing the selected cytokines (represented in panel B). Every column represents a patient. An asterisk (*) identifies the cytokines with statically significant differences between KD+MIS-C and MIS-Cplus, and a “+” identifies cytokines with statically significant differences between MIS-C and MIS-Cplus and not with KD. Color gradient represents the z score. KD, pre–SARS-CoV-2 pandemic Kawasaki disease (n = 14); MIS-C, multisystem inflammatory syndrome in children (n = 13); COVID, pediatric patients with mild COVID-19 disease without MIS-C (n = 9); HC, healthy controls (n = 37 [53 samples]).