Source: Son MBF, Murray N, Friedman K, et al Multisystem inflammatory syndrome in children—initial therapy and outcomes. N Engl J Med. 2021;385(1):23-34; doi:10.1056/NEJMoa2102605Investigators from multiple institutions conducted a retrospective study to evaluate the effectiveness of initial immunomodulatory treatments of children with multisystem inflammatory syndrome (MIS-C). For the study, they abstracted data from the Overcoming COVID-19 surveillance registry, which includes data on children diagnosed with MIS-C at participating US hospitals. At each participating site, demographic data and information on underlying conditions, signs and symptoms at presentation, clinical course, laboratory and medications, and outcomes were entered into a central database on patients meeting CDC criteria for MIS-C (serious illness leading to hospitalization in patients <21 years old, fever, laboratory evidence of inflammation, multisystem organ involvement, and evidence of SARS-CoV-2 infection).For the study, the investigators focused their analyses on patients whose initial immunomodulatory treatment was either intravenous immunoglobulin (IVIG) alone or IVIG plus glucocorticoids (initial day of treatment designated as Day 0). The primary study outcome was evidence of left ventricular dysfunction, defined as left ventricular ejection fraction <55%, echocardiogram, or shock treated with vasopressors, documented anytime between Day 2 of treatment until discharge. Secondary outcomes included recurrent fever (after Day 2), use of other therapies (second dose of IVIG, glucocorticoids in those in the IVIG alone group, or biologics), and length of ICU stay. Multiple baseline variables were combined to develop a propensity score on study patients, then those treated with IVIG plus glucocorticoids were propensity score matched 1:1 with those receiving IVIG alone and the outcomes assessed with regression analyses.A total of 518 patients with MIS-C received an immunomodulatory treatment. The median age of these children was 8.7 years, 58% were male, 75% were previously healthy, and 9 died. The most common initial treatments (on Day 0) were IVIG alone in 192 (37%) and IVIG plus glucocorticoids in 157 (30%); 34 patients received a biologic on Day 0 and were excluded from the analysis. Outcomes were compared in 206 patients (103 treated with IVIG plus glucocorticoids and 103 who received IVIG alone on Day 0) who could be propensity score 1:1 matched. Among these children, those receiving IVIG plus glucocorticoids had significantly less left ventricular dysfunction than those receiving IVIG alone (17% and 31%, respectively; risk ratio [RR], 0.56; 95% CI, 0.34, 0.94). Among those treated with IVIG plus glucocorticoids, 34% received adjunctive therapies vs 70% of those initially treated with IVIG alone (RR, 0.49; 95% CI, 0.36, 0.65). There were no significant differences between groups for rate of recurrent fever or length of ICU stay.The authors conclude that among patients with MIS-C, initial treatment with IVIG plus glucocorticoids was associated with a lower risk of left ventricular dysfunction than treatment with IVIG alone.Dr Bratton has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.MIS-C is a rare complication of COVID-19 in children and teenagers with some similarities to Kawasaki Disease (KD) (See AAP Grand Rounds. 2020;44[3]:30.)1, but it typically occurs in older children.2 Because children and teenagers may have asymptomatic infections, the rate of MIS-C is difficult to ascertain accurately. Two prospective observational studies of MIS-C were published in the same journal edition.2,3 The authors of the current study included only patients from the US who met CDC criteria for MIS-C, while McArdle et al, authors of the second report, included children from 32 countries who met the slightly different WHO criteria.4 The current investigators reported that treatment with IVIG and glucocorticoids was associated with lower risk of left ventricular dysfunction. McArdle et al, however, did not find additional benefit in patients treated with IVIG and glucocorticoids compared to IVIG alone. Why these different findings? First, the description of MIS-C has evolved, and coronavirus variants have emerged. The 2 groups of investigators examined somewhat different time periods. Likewise, differing criteria for study selection may impact the findings, and these reports are observational and at risk for bias if treatment selection and these or other factors are associated with myocardial dysfunction. Disease presentation and response to therapy also may differ in US patients due to genetic differences. In summary, the rate of MIS-C may be changing with the development of new virus strains; refinement of criteria for disease diagnosis and therapy also likely will change.Among US children and adolescents with MIS-C, IVIG plus glucocorticoids appear to be associated with a lower risk of cardiovascular dysfunction than IVIG alone. The long-term health of MIS-C affected children remains to be ascertained.Of note, the safety and efficacy of targeted biologic agents (eg, infliximab) in addition to or instead of IVIG and glucocorticoids were not evaluated in either of the 2 New England Journal of Medicine studies.2,3