From Pages to Practice

By Clement Lee, MD, MS

Published January 5, 2022


When it was initially described, multisystem inflammatory syndrome in children (MIS-C) bore a striking resemblance to Kawasaki disease, another pediatric inflammatory disease associated with mucocutaneous, dermatologic, and cardiac manifestations. With time, it became clear that despite some overlap, the two syndromes were distinct. Notably, MIS-C was more likely to affect older children and cause coagulopathy, respiratory failure, acute kidney injury, cytopenias, myocarditis with cardiogenic shock, and prominent gastrointestinal symptoms.

Despite striking differences and given many unknowns regarding disease pathogenesis, course, and prognosis, clinicians adapted Kawasaki disease therapeutics for MIS-C. As one might expect from a new and evolving disease entity, the applied therapies were highly variable, and many institutions developed their own protocols based on expert opinion in the absence of guidance of robust clinical trials. Italian rheumatologists, among the first worldwide to describe MIS-C, developed guidelines that involved intravenous immunoglobulin (IVIG) for mild cases and IVIG with glucocorticoids  for severe cases. The American College of Rheumatology (ACR) also released guidelines largely in agreement with the Italian ones.

In the July 1 issue of NEJM, two studies compared the management of MIS-C and reported different results. In a study conducted in the United States, upfront dual therapy with IVIG and glucocorticoids was associated with a lower rate of the composite endpoint (cardiovascular dysfunction) as well its individual components, left ventricular ejection fraction <55% and shock requiring vasopressors. In an international study; IVIG, glucocorticoids, or its combination fared similarly in the outcome of mechanical ventilation, vasopressor use, or death.

The contrasting outcomes of the two studies need to be interpreted with caution. The international study examined left ventricular ejection fraction as a secondary endpoint, but did not specify timing of echocardiography: Could combination treatment ameliorate late-occurring left ventricular dysfunction, not clearly measured in the international cohort? The unrandomized nature of the two studies also precludes conclusive statements about definitive effects in either case.

With many parts of the world waiting with bated breath to see how COVID dynamics shift in real time, the threat of many more MIS-C cases looms. As a pediatrician, my primary mission will be to encourage vaccination, which the CDC now recommends for children aged 12 years and older. However, the average age of MIS-C patients in the U.S. cohort was 8.7 years. With the real possibility of MIS-C becoming more common, the best data we have on hand thus far support upfront combination therapy with IVIG and glucocorticoids in children in the U.S. who develop MIS-C. 

The following NEJM Journal Watch summary provides more details of the two studies.


Initial Treatment of Multisystem Inflammatory Disease in Children

Deborah Lehman, MD, reviewing Son MBF et al. N Engl J Med 2021 Jul 1 McArdle AJ et al. N Engl J Med 2021 Jul 1

Shortly after the first descriptions of COVID-19 disease in children, a systemic and multisystem inflammatory condition (MIS-C; sometimes called pediatric inflammatory multisystem syndrome) was described (NEJM JW Pediatr Adolesc Aug 2020 and JAMA 2020; 324:259 and 294). Given the clinical similarities to Kawasaki disease, MIS-C was treated with immunomodulatory agents, including intravenous immunoglobulin (IVIG) and corticosteroids. Two studies have now retrospectively examined the effects of MIS-C treatments.

Son and colleagues analyzed data from 596 patients admitted with MIS-C to 58 U.S. hospitals submitted to a CDC surveillance registry between March and October 2020. Data included cardiovascular outcomes of 518 children who received various immunomodulatory treatments, including IVIG, glucocorticoids, and biologic agents. Of the 349 patients who received IVIG with or without glucocorticoids as initial therapy, 206 were included in a propensity-matched analysis. Those initially treated with both IVIG and glucocorticoids had a lower risk for subsequent overall cardiovascular dysfunction (left ventricular dysfunction and shock requiring vasopressor use) than those who initially received IVIG alone (17% vs. 31%). Length of intensive care unit stay did not differ significantly between the two groups (2 vs. 3 days, respectively).

McArdle and colleagues extracted information from an international database including 614 children with MIS-C registered between June 2020 and February 2021. They compared three initial therapeutic interventions — IVIG alone, IVIG plus glucocorticoids, and glucocorticoids alone — with respect to disease severity for the 2 days following initiation of therapy, including inotropic support, mechanical ventilation and death, as well as the need for additional therapy, and cardiodynamic outcomes. Other than a lower frequency of escalation of immunomodulatory therapy in the group receiving IVIG plus glucocorticoids, outcomes did not differ for children receiving various initial therapies for MIS-C.

Comment: Although children typically experience mild symptomatic infection with SARS-CoV-2, more than 4 million children in the U.S. have tested positive for COVID-19, accounting for up to 25% of reported cases, and as of this writing just over 324 children have died (American Academy of Pediatrics data). MIS-C is a devastating outcome of COVID-19; risk and outcomes are not predictable. These studies are a start to guiding clinicians toward the most effective initial therapy, but because neither is a randomized, controlled trial, treatment outcome is difficult to interpret. Clinicians are likely to treat more severely ill children with more aggressive and possibly combination therapy, making retrospective comparisons challenging. Further studies are needed to better establish treatment of this complex disease. Until then, aggressive initial therapy with an immunomodulatory agent or a combination of agents is certainly indicated. Of course, vaccination for all eligible children is the best intervention with the aim of avoiding infection altogether.

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Clement is a 2021–2022 NEJM Editorial Fellow.
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