Treatment of Multisystem Inflammatory Syndrome in Children

Patients

Figure 1. 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.

From June 20, 2020, to February 24, 2021, practitioners at 81 hospitals in 34 countries uploaded data for 651 patients with suspected MIS-C to the study database (Figs. S1, S2, and S3 in the Supplementary Appendix). Data for 37 patients were excluded owing to incomplete information or duplicate entries. Of the remaining 614 patients, 246 received primary treatment with IVIG alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone; another 22 patients received other immunomodulators, and 39 received no immunomodulatory therapy (Figure 1A). In the three primary treatment groups, 136 of 552 patients (25%) had received additional immunomodulators by day 2, and 238 patients (43%) received secondary agents at any time. The complex changes in treatments are shown in Figure 1B.

Clinical and Laboratory Measures

Table 1. Table 1. Demographic and Clinical Characteristics of the Patients on Admission.

Clinical and laboratory findings were similar among the treatment groups (Table 1 and Table S2). However, troponin levels and the percentage of patients who received inotropes on day 0 were higher in the group that received IVIG plus glucocorticoids (Figs. S4, S5, and S6). Of the 614 patients, 490 (80%) met the WHO criteria for MIS-C (Table S3). The most common criterion that was missing among the patients who did not meet the WHO criteria was evidence of SARS-CoV-2 exposure (Fig. S7). SARS-CoV-2 antibody measurements were not tested in 14% of the patients, and results were negative in 14%. Bacteria were cultured in blood samples obtained from 6 patients. The percentage of patients who met the American Heart Association (AHA) definition for Kawasaki’s disease¹⁸ was 37% in the overall population and 39% among those who met the WHO criteria for MIS-C (Table S4 and Fig. S8).

Primary Outcomes

Figure 2. 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.

A total of 50 of 553 patients (9%) received immunomodulators before transfer to the reporting hospital and were excluded from the weighted analyses. The receipt of inotropic support or mechanical ventilation on day 2 or later or death (the first primary outcome) occurred in 56 patients who received initial treatment with 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) (Figure 2). Unadjusted values are shown in Table S5.

In a subgroup analysis that included only the patients who met the WHO criteria for MIS-C, a first-primary-outcome event occurred in 40 patients who received initial treatment with IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.95; 95% CI, 0.37 to 2.45) and in 12 patients who received initial treatment with glucocorticoids alone (adjusted odds ratio, 0.30; 95% CI, 0.10 to 0.85). The results for the individual components of the composite outcome are shown in Figure 2 and Table S5.

A reduction in the score for disease severity on the ordinal scale by day 2 (the second primary outcome) occurred in 54 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 0.90; 95% CI, 0.48 to 1.69) and in 20 patients who received glucocorticoids alone (adjusted odds ratio, 0.93; 95% CI, 0.43 to 2.04). When WHO criteria for MIS-C were considered in a subgroup analysis, a second-primary-outcome event occurred in 52 patients who received IVIG plus glucocorticoids (adjusted odds ratio for the comparison with IVIG alone, 1.09; 95% CI, 0.53 to 2.23) and in 16 patients who received glucocorticoids alone (adjusted odds ratio, 1.95; 95% CI, 0.83 to 4.60).

The results for the two primary outcomes showed an acceptable degree of balance with respect to the covariates (Fig. S9). Analyses that were performed with the use of standardized weights did not change the interpretation of the primary outcomes.

Secondary Outcomes

Escalation of immunomodulatory treatment was less common among the patients who received IVIG plus glucocorticoids than among those who received IVIG alone (odds ratio, 0.18; 95% CI, 0.10 to 0.33). The comparison was inconclusive between the patients who received glucocorticoids alone and those who received IVIG alone (odds ratio, 1.31; 95% CI, 0.64 to 2.68) (Table S5; Table S1 shows additional details regarding treatment escalation according to group). No clear between-group differences were seen in blood markers, inotropic support, or mechanical ventilation between patients who had an escalation to other treatments by day 2 and those who continued to receive the initial treatment (Figs. S5 and S6B).

Left ventricular dysfunction was reported in 12% of the 538 patients who had undergone echocardiography starting on day 2, with no substantial differences among the treatment groups. Coronary-artery aneurysm was present on the latest echocardiogram at 2 days after the initiation of treatment or later in 6% of the 326 patients for whom data were available. The low numbers of coronary-artery aneurysms that were detected preclude statistical comparisons among the treatment groups, although among the patients with data, the incidence of coronary-artery aneurysm was not greater among those who did not receive any IVIG as part of primary treatment than among those who did receive IVIG (Table S6). Death was reported in 3 of 238 patients (1%) who received IVIG alone, in 5 of 192 patients (3%) who received IVIG plus glucocorticoids, and in 4 of 91 patients (4%) who received glucocorticoids alone; status with respect to death was not reported for 32 patients (Table S5).

In the analysis of the time until an improvement in disease severity on the ordinal scale, the average hazard ratio for the comparison with IVIG alone was 0.89 (95% CI, 0.67 to 1.19) for IVIG plus glucocorticoids and 1.03 (95% CI, 0.72 to 1.46) for glucocorticoids alone (Fig. S9 and Table S5C).

Drug complications were reported by clinicians in 16 of 411 patients (4%) who received glucocorticoids in any combination and in 9 of 408 (2%) who received IVIG in any combination. Glucocorticoid-related complications were predominantly hypertension and hyperglycemia (Table S7).

Effect of Immunomodulation on Blood Markers

Figure 3. 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.

Levels of C-reactive protein decreased more rapidly in patients who received immunomodulators than in those who did not receive such treatment (Figure 3A). Changes in levels of C-reactive protein, troponin, and ferritin followed a similar temporal decrease in the three groups (Figure 3B), although there was some variation in the rate of decline, which was most obvious in the patients who did not change treatment before day 3 (Figure 3C).

To investigate whether the inclusion of children with Kawasaki’s disease in the present study might have influenced treatment responses, we explored changes in blood markers separately in children with a likely diagnosis of Kawasaki’s disease and in those without such a diagnosis. Since Kawasaki’s disease generally is more frequent in children before the age of 6 years and MIS-C is generally reported in older children, we compared the patients who met the AHA criteria for Kawasaki’s disease and all those under the age of 6 years (whose illness may be described as Kawasaki’s disease–like) with the remaining patients with MIS-C. Among the children who received IVIG alone, the smoothed curves showed rates of decline in C-reactive protein levels among those younger than 6 years of age who met the AHA criteria for Kawasaki’s disease that were similar to the rates among the remaining children. However, among the children who received glucocorticoids with or without IVIG, there was a more rapid decline in the C-reactive protein level in the group of children who did not meet the AHA criteria for Kawasaki’s disease or were over 6 years of age (Fig. S10).