Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2

Abstract

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Keywords: COVID-19; Cytokines.

Figure 1. Cytokine architecture associated with SARS–CoV-2 infections in children.

(A) Heatmap of the 5 most differentially present cytokines in the plasma of pediatric SARS–CoV-2 infections. Comparison of patients with and without coinfections for each of the 3 clinical phenotypes of pediatric SARS–CoV-2 infection (n = 20). Patient IDs are listed above each column for reference. (B) Cytokine profiles for each patient (n = 15) were treated as a 5-dimensional vector and converted into unit vectors by dividing each component by the root sum square of the vector. Box-and-whisker plot of each unit vector with median values of each for MIS-C versus severe COVID-19 presentations (line). Whiskers represent maximum and minimum and boxes represent the 25th to 75th percentiles. Differences between phenotypes or phenotype/cytokine interaction were not significant by 2-way ANOVA. (C) Vector magnitudes of each cytokine profile were computed as the root sum square with values plotted for severe COVID-19 and MIS-C phenotypes (n = 15). Bar represents the median of each group. Differences were not significant by Mann-Whitney U test. (D) The sum of the IL-10 and TNF-α concentrations were computed for each patient and plotted for severe COVID-19 and MIS-C phenotypes (n = 15). Bar represents the median of each group with P values computed by Mann-Whitney U test.

Figure 2. Viral Ct in pediatric SARS–CoV-2 infections.

(A) When available (n = 16), Cts for each patient are plotted. Bars represent mean values with P values computed using Dunn’s multiple comparisons test after Kruskal-Wallis testing. (B) Linear regression modelling of cycle time thresholds against IL-10 and TNF-α concentrations in plasma for all patients in the cohort (n = 16).

Figure 3. Soluble C5b-9 measurements in pediatric SARS–CoV-2 infections.

(A) Soluble C5b-9 was successfully measured in 19 patients. Data are plotted for each of the 3 phenotypes; bars represent the mean values of each group. P value computed using Dunn’s multiple comparisons test after Kruskal-Wallis testing. (B) Linear regression modelling of sC5b-9 against IL-6, IL-8, and TNF-α concentrations in plasma for all patients in the cohort. (C) Representative photomicrographs of red blood cells and neutrophils from patients in the cohort. From top to bottom: ×50 field showing burr cells and schistocytes; ×100 field showing the same; ×100 field showing toxic granulation. Thin arrow denotes a burr cell, black arrowhead denotes a schistocyte, white arrowhead denotes toxic granulation. (D) Number of patients with degree of burr cells, toxic granulation, and schistocytes for each clinical phenotype; n = 13 patients with smears available. Number of assessable patients for each group is displayed in the center of each circle. Severe COVID-19 was compared with MIS-C using χ² test for trend for burr cells; χ² statistic was impossible to compute for the dichotomous outcome of toxic granulation due to low n. There were no statistically significant differences in schistocytes across the cohort.