Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children

Abstract

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown.

Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C.

Design, setting, and participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021.

Exposures: IVIG and methylprednisolone vs IVIG alone.

Main outcomes and measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1.

Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]).

Conclusions and relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Figure 1.. Study Flowchart and Propensity Score Matching of Children With Suspected Multisystem Inflammatory Syndrome in Children (MIS-C)

COVID-19 indicates coronavirus disease 2019; IVIG indicates intravenous immunoglobulins; and WHO, World Health Organization. ^aThe reporting of all suspected MIS-C cases in France became mandatory since the first descriptions of this entity in April 2020. All French pediatric hospital centers were contacted by the French National Public Health Agency in April 2020 to electronically report any case of suspected MIS-C in French children.^{, b}Details of the characteristics of excluded patients are provided in eTable 2 in the Supplement. ^cMultisystemic WHO criteria (2 of the following): (1) rash or bilateral nonpurulent conjunctivitis or mucocutaneous inflammation signs (oral, hands, or feet); (2) hypotension or shock; (3) features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echocardiographic findings or elevated troponin/N-terminal pro–brain natriuretic peptide); (4) evidence of coagulopathy (by prothrombin time, partial thromboplastin time, elevated D-dimers); and (5) acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain). ^dDetails about the 5 patients are provided in eTable 3 in the Supplement. ^ePatients who received IVIG alone were then matched to those who received IVIG and methylprednisolone by their propensity score by using 1:2 nearest-neighbor matching, with a minimum caliper of 0.1. The following baseline characteristics were used to generate the propensity score: age, sex, comorbidities, hospital center, gastrointestinal symptoms, lower respiratory tract symptoms, neurological symptoms, positive severe acute respiratory syndrome coronavirus 2 antibody test result, initial acute left ventricular dysfunction, initial pediatric intensive care unit care, initial hemodynamic support, and intensity of inflammatory syndrome (C-reactive protein level > or ≤150 mg/L).

Figure 2.. Association Between First-line Therapy Group and Treatment Failure Depending on Age and Acute Left Ventricular Dysfunction

Shown are subgroup-specific odds ratios for all patients and those older or younger than 10 years of age and with or without acute left ventricular dysfunction (defined by left ventricular ejection fraction <55%) at baseline. Odds ratios are plotted as squares; the horizontal lines represent 95% CIs. All analyses displayed involved using the propensity score analysis with the inverse probability of treatment weighting approach. Age was transformed into a binary variable using the receiver operating characteristic curve to define the optimized cut-off value. The interaction test P value for age ≥ or <10 years was P = .78 and for presence or absence of initial acute left ventricular dysfunction was P = .74. IVIG indicates intravenous immunoglobulins.