Study in JAMA reports interim findings from CDC-funded Overcoming COVID-19 Public Health Surveillance Registry; other studies ongoing

Multisystem inflammatory syndrome in children (MIS-C) was first formally recognized in May 2020 as a post-infectious syndrome in children exposed to the SARS-CoV-2 coronavirus. In today’s JAMA, a study led by Boston Children’s Hospital refines the medical understanding of MIS-C and helps distinguish this rare condition from severe, acute COVID-19 in children, with which it shares some features.

The findings are the second report from the national Overcoming COVID-19 study, led by Boston Children’s across 66 pediatric centers in 31 U.S. states and funded by the Centers for Disease Control and Prevention. The first report, in The New England Journal of Medicine in June 2020, described findings in 186 children with MIS-C. This new report reviews the cases of 539 children under age 21 who met the CDC’s current definition of MIS-C, comparing them to 577 children with severe, acute COVID-19.

“This is the largest study we know of to describe severe COVID-19 versus MIS-C in kids,” says Adrienne Randolph, MD, MSc, a critical care physician at Boston Children’s and corresponding author on the paper. “Our findings highlight that there’s a lot of overlap between the two conditions, but also point to differences that could affect treatment.”

MIS-C versus severe COVID-19

The current CDC criteria are meant to capture as many MIS-C cases as possible: age under 21, fever lasting at least 24 hours, laboratory evidence of inflammation, dysfunction of two or more organ systems, and either a positive result on viral antigen, PCR, or antibody testing or a known exposure to the virus.

“Our study shows that this broad definition of MIS-C includes some patients who are possibly critically ill from acute COVID-19,” says Randolph.

The children studied were hospitalized from March 15–October 31, 2020, at 66 U.S. hospitals in 31 states. Among the findings that emerged:

• Children age 6-12 were at most risk for having MIS-C rather than severe COVID-19. “This is not an age group that is usually at high risk for infections,” Randolph notes. “We need to understand this better.”
• Black children were more likely to have MIS-C than severe COVID-19 when compared to white children, another finding the team would like to explore further. “While both Black and Hispanic populations are at high risk of getting infected with SARS-CoV-2, we found that Black children may be at higher risk of MIS-C,” Randolph says.
• While 62 percent of children with severe COVID-19 had at least one underlying condition, 69 percent of children with MIS-C had no underlying conditions.
• Lab tests showed more extreme inflammation in the MIS-C group.
• Gastrointestinal symptoms such as diarrhea and abdominal pain were common in children presenting with MIS-C or COVID-19 (90 vs. 58 percent, respectively) but mucocutaneous symptoms such as rash, inflamed mucosa of the mouth, conjunctivitis, or redness or swelling of the hands or feet were more common in those with MIS-C (67 vs. 10 percent).
• Children with MIS-C were more likely than those with severe COVID-19 to be diagnosed with severe cardiovascular problems such as left ventricular dysfunction or coronary artery aneurysms (67 vs. 12 percent). Most of these problems resolved within 30 days, although the investigators note the need for continued monitoring. “Many with acute COVID did not have echocardiograms, so we can’t assume they were disease free,” Randolph notes.
• Severe respiratory symptoms developed in 80 percent of both groups. However, only 24 percent of children with MIS-C had respiratory symptoms in the absence of cardiovascular involvement, compared with 71 percent of the acute COVID-19 group.

“Overall, our observations show that MIS-C and severe COVID-19 in children fall on a continuum, but there are some features that are more strongly associated with MIS-C,” says Randolph. “Our data may help consensus bodies like the CDC and World Health Organization refine their definitions and guidelines.”

Implications for care

The more detailed information in the new report could help doctors better distinguish between MIS-C and severe COVID-19 and choose the most appropriate treatments, the researchers say.

For example, IV immunoglobulin, which is in short supply, is commonly used in MIS-C but may not be appropriate for acute COVID-19, Randolph notes. Similarly, while monoclonal antibodies and the antiviral drug remdesivir might be helpful in children with acute COVID-19, they are not appropriate in MIS-C, in which there is no longer an active viral infection to combat.

Future research directions

In addition to Overcoming COVID-19, Boston Children’s is leading and participating in many other multicenter studies to better understand the complications of acute COVID-19 and MIS-C.

• In Boston Children’s Heart Center, Jane Newburger MD, is co-leading the MUSIC study, investigating long-term heart complications of MIS-C in children.
• Sitaram Emani, MD, of the Heart Center and Riten Kumar, MD, MSc, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center each have studies of thrombotic events and predictors of blood clotting in children with SARS-CoV-2.
• In the Rheumatology Program, MaryBeth Son, MD, is reviewing treatments used for MIS-C and their effects on children’s outcomes.
• Tina Young Poussaint, MD (neuroradiology), and Kerri LaRovere, MD (neurology), will soon publish a report on neurologic complications of MIS-C and COVID-19.
• Janet Chou, MD, of immunology, and Catherine Brownstein, PhD, and Alan Beggs, PhD, of the Manton Center for Orphan Disease Research, are leading studies of immune responses and genetic factors that increase susceptibility to COVID-19 and MIS-C.

The study was funded by the CDC under a contract to Boston Children’s Hospital. Leora Feldstein, PhD, and Mark Tenforde, MD, of the CDC’s COVID-19 Response Team and Kevin Friedman, MD, of Boston Children’s were co-first authors on the paper. Randolph, Manish Patel, MD, of the CDC’s COVID-19 Response Team, and Newburger were co-senior authors.