When children started getting sick with a multisystem inflammatory syndrome (MIS-C) in the wake of COVID-19, physicians most often turned to two treatments: IV immunoglobulin (IVIG), because of MIS-C's similarities with Kawasaki disease, and steroids such as methylprednisolone because of its inflammatory features.

A new report from the CDC-funded Overcoming COVID-19 study, launched by Boston Children's Hospital in March 2020, concludes that when children treated for MIS-C are matched for initial illness severity, they do better when treated with IVIG and steroids together as initial therapy, compared with IVIG alone. Findings appear in today's New England Journal of Medicine.

The real-world study, involving 518 children and adolescents with MIS-C at 58 U.S. hospitals, found that early use of the combined treatment better protected patients' hearts and reduced their need for subsequent additional treatments.

"Until now, clinicians have been relying mainly on small studies in choosing treatments for MIS-C," says Boston Children's rheumatologist Mary Beth Son, MD, first author on the paper. "Our study found that MIS-C patients treated with IVIG and glucocorticoids at the outset had better short-term cardiovascular outcomes as compared with IVIG alone."

Study design

The study was not randomized, but to make the comparison as clean as possible, the investigators used two statistical techniques called propensity score matching and inverse probability weighting to analyze the groups. They matched the patients for initial illness severity, such as admission to the intensive care unit, and multiple other factors that might influence treatment decisions.

From their original cohort, the researchers were able to match 103 children and adolescents who initially received IVIG plus glucocorticoid and 103 who initially received IVIG alone. Patients overall were quite ill; about 68 percent of the matched patients were admitted to the ICU and more than 41 percent needed medication to maintain sufficient blood pressure. The analyses were led by CDC biostatistician Nancy Murray, MSc, Charles Rose, PhD, and CDC lead epidemiologist Manish Patel, MD.

"It's really hard to conduct a randomized trial, because MIS-C is a rare, sporadic post-infectious complication of SARS-CoV-2 infection," notes senior author Adrienne Randolph, MD, principal investigator of Overcoming COVID-19 and an ICU physician at Boston Children's. "Despite the limitations, our data are probably the best guide we have right now for how to treat patients either experiencing or at risk for severe cardiac complications."

The strength of the Overcoming COVID-19 registry is that it actively enrolled all eligible patients meeting the CDC case definition for MIS-C and rigorously and prospectively collected a large set of demographic, clinical, and treatment variables, including daily outcome measures throughout hospitalization. Investigators focused on potentially life-threatening complications, specifically shock and low cardiac function. To ensure high quality data, expert pediatric cardiologists were intensively involved, as were pediatric rheumatology, critical care, and infectious disease physicians.

Improved cardiovascular outcomes; less need for subsequent treatments

The patients' median age was 8.7 years. Those initially given the combined treatment were significantly less likely than those given IVIG alone to have cardiovascular dysfunction two or more days after initial treatment (17 vs. 31 percent). (Dysfunction was defined as a ventricular ejection fraction below 55 percent, or use of vasopressor drugs to boost blood pressure in patients with shock.)

Of the children receiving early IVIG plus steroids, 34 percent needed subsequent treatments for MIS-C, such as second doses of IVIG and biologic drugs like anakinra. In contrast, 70 percent of children given IVIG alone later received these additional treatments or received steroids.

There was no statistically significant difference in the percentage with persistent fever (31 vs. 40 percent, respectively). Long-term cardiovascular function was not assessed.

Although about a third of children in the cohort received biologics such as anakinra, infliximab, and tocilizumab, numbers were too small and the drugs' use too varied to do a rigorous comparison with other treatments.

The bottom line

"Our study illustrates that prompt, aggressive immunomodulatory treatment for severe MIS-C with IVIG and steroids is associated with a lower risk of new or persistent cardiovascular dysfunction," says Boston Children's cardiologist Jane Newburger, MD, MPH, a coinvestigator on the Overcoming COVID-19 studies and co-chair of the national NHLBI-sponsored MUSIC study, investigating long-term heart complications of MIS-C in children. 

"Until now, we've been managing patients without rigorous data to guide care," adds Son. "Our study demonstrates that for severely ill children treated for MIS-C, IVIG plus steroids rather than IVIG alone leads to better short-term cardiovascular outcomes."

The study was funded by the Centers for Disease Control and Prevention under a contract to Boston Children's Hospital.Learn more about COVID-19 and MIS-C research at Boston Children's.

About Boston Children's Hospital

Boston Children's Hospitalis ranked the #1 children's hospitalin the nation byU.S. News & World Report and is the primary pediatric teaching affiliate of Harvard Medical School. Home to the world's largest research enterprise based at a pediatric medical center, its discoveries have benefited both children and adults since 1869. Today, 3,000 researchers and scientific staff, including 9 members of the National Academy of Sciences, 23 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 415-bed comprehensive center for pediatric and adolescent health care.