Reference: JAMA. 2021 Feb 1
Identifying the best treatment approach to a relatively rare yet severe illness like multisystem inflammatory syndrome in children (MIS-C) represents a challenge for clinicians and researchers. The WHO defined the condition early in the pandemic to include a COVID diagnosis with fever for > 3 days, elevated serum inflammatory markers, and problems in at least two of the following systems: cardiac, skin, gastrointestinal, coagulation, or blood pressure maintenance. Although there are similarities to Kawasaki and other inflammatory conditions of childhood, the unique features of MIS-C may have implications for management.
Researchers in France conducted a retrospective cohort study of children with MIS-C found through a national surveillance system between April and October 2020. Hospitals reported demographics, clinical findings, treatments, and hospital course characteristics. The study included 106 children with confirmed MIS-C, of whom 34 received IVIG plus methylprednisolone and 72 received IV immunoglobulin (IVIG) alone. Prior to first-line therapy, children receiving additional methylprednisolone were older (median 9 vs. 8.1 years), more likely to require PICU care (91% vs. 58%), and had more comorbidities such as obesity or asthma. Researchers used propensity matching to adjust for baseline differences, ultimately matching 32 children in the methylprednisolone group to 64 in the IVIG-alone group. Compared to IVIG alone, adding methylprednisolone was associated with a lower rate of treatment failure (9% vs. 38%, odds ratio [OR] 0.25, 95% CI 0.09-0.7), defined as persistent fever 48 hours after treatment or recrudescence within 7 days. Six different sensitivity analyses found a similar reduced risk of treatment failure in children who received methylprednisolone. IVIG plus methylprednisolone was associated with a shorter duration of PICU-level care (4 vs. 6 days, difference -2.4 days, 95% CI -4 to -0.7 days) and lower rate of administration of second-line therapy (9% vs. 31%, OR 0.19, 95% CI 0.06-0.61).
This study provides modest evidence of benefit for adding methylprednisolone to IVIG for children with MIS-C. The causal inferences we hope to assume from observational data in this study and many others like it, however, rely on the ability of propensity matching to approximate the benefits of randomization by adjusting for baseline differences. The IVIG plus methylprednisolone group appeared much sicker at baseline (prior PICU care 91% vs. 58%) and adjustment for this degree of confounding with propensity scoring can only carry us so far. Still, the group with greater illness severity had significant improvement in their fever curve. Fever duration and recrudescence have been weakly associated with persistent coronary anomalies in children with Kawasaki disease; experts have extrapolated this information to make recommendations for MIS-C. Without statistical adjustments for secondary analyses, the more meaningful endpoints such as duration of PICU stay must be considered hypothesis-generating rather than conclusive.
For more information, see the topic COVID-19 and Pediatric Patients in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Assistant Professor at Cone Health Family Medicine Residency. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School, Dan Randall, MD, Deputy Editor for Internal Medicine at DynaMed, and Katharine DeGeorge, MD, MS, Associate Professor of Family Medicine at the University of Virginia and Clinical Editor at DynaMed.