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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.

SUBMITTER: Esteve-Sole A

PROVIDER: S-EPMC7954607 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a potentially life-threatening hyperinflammatory syndrome that occurs after primary SARS-CoV-2 infection. The pathogenesis of MIS-C remains undefined, and whether specific inflammatory biomarker patterns can distinguish MIS-C from other hyperinflammatory syndromes, including Kawasaki disease and macrophage activation syndrome (MAS), is unknown. Therefore, we aimed to investigate whether inflammatory biomarkers could be used to distinguish between these conditions.MethodsWe studied a prospective cohort of patients with MIS-C and Kawasaki disease and an established cohort of patients with new-onset systemic juvenile idiopathic arthritis (JIA) and MAS associated with systemic JIA (JIA-MAS), diagnosed according to established guidelines. The study was done at Cincinnati Children's Hospital Medical Center (Cincinnati, OH, USA). Clinical and laboratory features as well as S100A8/A9, S100A12, interleukin (IL)-18, chemokine (C-X-C motif) ligand 9 (CXCL9), and IL-6 concentrations were assessed by ELISA and compared using parametric and non-parametric tests and receiver operating characteristic curve analysis.FindingsBetween April 30, 2019, and Dec 14, 2020, we enrolled 19 patients with MIS-C (median age 9·0 years [IQR 4·5-15·0]; eight [42%] girls and 11 [58%] boys) and nine patients with Kawasaki disease (median age 2·0 years [2·0-4·0]); seven [78%] girls and two [22%] boys). Patients with MIS-C and Kawasaki disease had similar S100 proteins and IL-18 concentrations but patients with MIS-C were distinguished by significantly higher median concentrations of the IFNγ-induced CXCL9 (1730 pg/mL [IQR 604-6300] vs 278 pg/mL [54-477]; p=0·038). Stratifying patients with MIS-C by CXCL9 concentrations (high vs low) revealed differential severity of clinical and laboratory presentation. Compared with patients with MIS-C and low CXCL9 concentrations, more patients with high CXCL9 concentrations had acute kidney injury (six [60%] of ten vs none [0%] of five), altered mental status (four [40%] of ten vs none [0%] of five), shock (nine [90%] of ten vs two [40%] of five), and myocardial dysfunction (five [50%] of ten vs one [20%] of five); these patients also had higher concentrations of systemic inflammatory markers and increased severity of cytopenia and coagulopathy. By contrast, patients with MIS-C and low CXCL9 concentrations resembled patients with Kawasaki disease, including the frequency of coronary involvement. Elevated concentrations of S100A8/A9, S100A12, and IL-18 were also useful in distinguishing systemic JIA from Kawasaki disease with high sensitivity and specificity.InterpretationOur findings show MIS-C is distinguishable from Kawasaki disease primarily by elevated CXCL9 concentrations. The stratification of patients with MIS-C by high or low CXCL9 concentrations provides support for MAS-like pathophysiology in patients with severe MIS-C, suggesting new approaches for diagnosis and management.FundingCincinnati Children's Research Foundation, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, the Deutsche Forschungsgemeinschaft, and The Jellin Family Foundation.

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

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