Treatment of Multisystem Inflammatory Syndrome in Children

Abstract

Background: Evidence is urgently needed to support treatment decisions for children with multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2.

Methods: We performed an international observational cohort study of clinical and outcome data regarding suspected MIS-C that had been uploaded by physicians onto a Web-based database. We used inverse-probability weighting and generalized linear models to evaluate intravenous immune globulin (IVIG) as a reference, as compared with IVIG plus glucocorticoids and glucocorticoids alone. There were two primary outcomes: the first was a composite of inotropic support or mechanical ventilation by day 2 or later or death; the second was a reduction in disease severity on an ordinal scale by day 2. Secondary outcomes included treatment escalation and the time until a reduction in organ failure and inflammation.

Results: Data were available regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021; 490 met the World Health Organization criteria for MIS-C. Of the 614 children with suspected MIS-C, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; 22 children received other treatment combinations, including biologic agents, and 39 received no immunomodulatory therapy. Receipt of inotropic or ventilatory support or death occurred in 56 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.77; 95% confidence interval [CI], 0.33 to 1.82) and in 17 patients who received glucocorticoids alone (adjusted odds ratio, 0.54; 95% CI, 0.22 to 1.33). The adjusted odds ratios for a reduction in disease severity were similar in the two groups, as compared with IVIG alone (0.90 for IVIG plus glucocorticoids and 0.93 for glucocorticoids alone). The time until a reduction in disease severity was similar in the three groups.

Conclusions: We found no evidence that recovery from MIS-C differed after primary treatment with IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone, although significant differences may emerge as more data accrue. (Funded by the European Union's Horizon 2020 Program and others; BATS ISRCTN number, ISRCTN69546370.).

Figure 1. Study Enrollment and Treatments after Hospital Admission.

Panel A shows an overview of the total number of children with suspected multisystem inflammatory syndrome (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 who were enrolled in the study, according to treatment received. Patients who met the inclusion criteria were categorized according to enrollment in the three main treatment groups — intravenous immune globulin (IVIG) alone, IVIG plus glucocorticoids, and glucocorticoids alone — along with other immunomodulatory treatments (including anti–tumor necrosis factor, anti–interleukin-1, and anti–interleukin-6). Patients were further categorized according to whether they met the clinical criteria of the World Health Organization (WHO) for MIS-C. TSS denotes toxic shock syndrome. Panel B shows a Sankey diagram of treatments received by patients after hospital admission. Each vertical stack represents day 0 to 5 in the patient’s hospital admission. The arrows (gray bands) represent the movement of patients between treatment groups on subsequent days; the width of the arrows is proportional to the flow rate between days. Patients in the group that received glucocorticoids alone could have received either intravenous or oral formulations, and the continuation of glucocorticoid treatments on subsequent days at the same or lower dose did not constitute additional treatment. Other treatments — which included one or more other immunomodulatory therapies given alone or in combination with glucocorticoids, IVIG, or both — were anti–tumor necrosis factor, anti–interleukin-1, anti–interleukin-6, extracorporeal cytokine adsorber (CytoSorb), granulocyte colony-stimulating factor, colchicine, mesenchymal stem cells, and convalescent plasma.

Figure 2. Forest Plots for Primary, Secondary, and Subgroup Analyses.

Shown are outcomes for patients with suspected MIS-C who received IVIG plus glucocorticoids (Panel A) or glucocorticoids alone (Panel B) as compared with those who received IVIG alone (reference group, indicated by an odds ratio or average hazard ratio of 1.00). Odds ratios are shown for all comparisons except time-to-event analyses, for which average hazard ratios were calculated. Values to the right of the dashed vertical line indicate the superiority of IVIG alone, except for the second primary outcome (a reduction in disease severity on the ordinal scale by day 2, indicated by blue arrows), for which values to the left indicate the superiority of IVIG alone.

Figure 3. Changes in Levels of C-Reactive Protein, Troponin, and Ferritin, According to Type of Treatment and Timing.

Each of three key markers of inflammation (C-reactive protein, troponin, and ferritin) is plotted as a line and weighted by the covariate-balancing propensity score. The levels are shown as a percentage of each patient’s peak value. A generalized additive model was used to fit the curves. Panel A shows the fitted curves for the three measures in patients who received any immunomodulators, as compared with those who did not receive immunomodulators. Panel B shows the fitted curves for patients who received IVIG alone, IVIG plus glucocorticoids, and glucocorticoids alone as their primary treatment. Panel C shows the fitted curves for the three treatments combined in the patients whose primary treatment did not change between the day of admission (0) and day 3.