Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children

Abstract

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Keywords: COVID-19; Clinical practice; Immunology.

Figure 1. Comparison of clinical features and laboratory parameters in patients with MIS-C versus those with KD.

MIS-C n = 28; KD n = 40. (A) Histogram display of age range of MIS-C and KD patients. Comparisons of (B) prevalence of individual KD features (*P < 0.01; **P < 0.001; ***P < 0.0001, Fisher’s exact test), (C) the number of KD diagnostic feature (P < 0.0001, χ² test), (D) prevalence of coronary abnormalities (P > 0.05, χ² test), and (E) ejection fraction as an index of left ventricular function (by percentage and by Z score) in the MIS-C and KD groups. (F) Comparison of key laboratory parameters including white blood cell count (WBC), hemoglobin, absolute neutrophil count (ANC), absolute lymphocyte count (ALC), platelet count, aspartate transaminase (AST), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Median with interquartile range and P value by Mann-Whitney U test are displayed for each plot. Gray shading indicates the normal range for laboratory parameters.

Figure 2. Immunologic profile of patients with MIS-C and comparison with MAS.

(A) Quantitation of lymphocyte populations, (B) baseline immunoglobulin levels, (C) serum cytokine levels in MIS-C patients (n = 15–22 for each panel). (D–G) Comparison of (D) soluble IL2 receptor levels, (E) ferritin, (F) IL-18, and (G) CXCL9 levels in MIS-C with a cohort of patients with MAS associated with systemic JIA or infection. Median with interquartile range and P value by Mann-Whitney U are displayed for each plot. Gray shading indicates the normal range for laboratory parameters.