Learning in Real Time to Overcome COVID-19 and MIS-C

Learning in Real Time to Overcome COVID-19 and MIS-C 1024 491 Natalie Wilson
Illustrations of clock faces at different times and angles

When multisystem inflammatory syndrome in children (MIS-C) emerged in May 2020, the new condition made headlines. Although rare, MIS-C can appear in kids about a month after they’ve recovered from infections with SARS-CoV-2, the virus that causes COVID-19 — even if they haven’t felt sick at all.

“We don’t know why some children develop MIS-C,” says Mark W. Hall, MD, FCCM, chief and Development Board Endowed Chair of Critical Care Medicine at Nationwide Children’s Hospital. “The severity of a child’s initial COVID-19 disease does not appear to predict whether they will get MIS-C. In fact, some children who later develop MIS-C were asymptomatic and never knew they had COVID-19.”

Patients with MIS-C often develop fever, abdominal pain and lethargy. Most recover with treatment. For some, however, MIS-C is a serious and potentially deadly complication that causes the failure of blood vessels, the heart and other organs.

“MIS-C symptoms mimic the effects of an acute infection. After getting ‘turned on’ to protect the body during a COVID infection, the immune system becomes ‘confused’ and begins attacking blood vessels and the heart instead,” says Dr. Hall.

Now, new research from a network of more than 50 hospitals across the United States has begun uncovering evidence that will improve care for children with MIS-C and reduce its effects on their hearts.

We now believe that lower doses of glucocorticoids … can be an effective part of early, empiric treatment of children suspected of having MIS-C.

– Mark W. Hall, MD, FCCM

Black and White Image of Dr. Mark Hall


As a newly identified condition, MIS-C lacked clinical guidelines regarding its treatment. But patients with MIS-C arrived at hospitals needing help — and quickly.

Jeffrey Burns, MD, MPH, chief of the Division of Critical Care Medicine at Boston Children’s Hospital, began hosting weekly meetings, bringing together pediatric critical care experts from around the world, including Dr. Hall, along with cardiologists, hematologists, rheumatologists and more, to discuss new observations in real time and determine how to tackle COVID-19 and MIS-C.

“We were able to learn and adapt through remarkably fast global collaboration,” says Dr. Hall.

Through those initial grassroots efforts, plans of attack began to take shape. Dr. Hall and other physicians and researchers at Nationwide Children’s developed protocols for treating MIS-C locally, which recommended the use of intravenous immune globulin (IVIG) first, followed by glucocorticoids.

Once protocols were in place, clinical teams could observe these treatments working and share their insights with their peers. But in order to build evidence for their approach — and make tweaks to improve it — researchers needed to systematically collect and review larger amounts of data on patient outcomes.


A research effort led by Adrienne Randolph, MD, MSc, a leader in Critical Care Medicine at Boston Children’s Hospital and founder of the Pediatric Acute Lung Injury and Sepsis Investigator’s (PALISI) network, allowed Dr. Hall and other researchers to do just that. Funded by the Centers for Disease Control and driven by PALISI site data, “Overcoming COVID-19” has headed up efforts to track and study cases of MIS-C in children across the United States.

In a study published in The New England Journal of Medicine in July, Overcoming COVID-19 examined the cases of 518 critically ill patients who were diagnosed with MIS-C while admitted to one of 58 U.S. hospitals, including Nationwide Children’s, between March 15 and October 31, 2020.

The study found that early treatment with a low dose of glucocorticoids — an even lower dose than what’s used to treat asthma, for example — in addition to IVIG was associated with a lower risk of new or persistent cardiovascular dysfunction in MIS-C patients than treatment with IVIG alone.

The group’s investigators focused on differences in cardiovascular dysfunction in patients on or after “day 2,” with day 0 being the first day the patients received any immunomodulatory treatment after hospital admission, and day 2 being the second calendar day after day 0. Outcomes were measured on or after day 2 to allow time for a clinical response to the treatments. Researchers categorized patients according to which treatments they received on day 0 and at any time during their hospitalization.

Researchers used a propensity score-matched analysis and adjusted for baseline MIS-C severity and demo­graphic characteristics in order to compare children who had the most similar levels of illness at the time of presentation and best isolate the influence their treatments may have had on their outcomes.

“If you compared all patients with MIS-C, you might find worse outcomes in the patients who were treated most aggressively, but that could be because they were sicker to begin with, not because the treatments or doses they received were associated with worse outcomes,” says Dr. Hall, who is also the director of the Immune Surveillance Laboratory in the Center for Clinical and Translational Research in the Abigail Wexner Research Institute at Nationwide Children’s.

Even when accounting for other variables, the addition of glucocorticoids on day 0 was associated with better outcomes.


As a result of these findings, Dr. Hall says that he and others are modifying protocols for treating MIS-C to include the early use of real-time glucocorticoids.

“The symptoms of MIS-C look very much like what one sees in patients with overwhelming infection, or sepsis. We have historically limited the use of early, high-dose glucocorticoids in this patient population until we have ruled out the presence of sepsis, because high-dose glucocorticoids can worsen outcomes in septic children,” says Dr. Hall. “But we now believe that lower doses of glucocorticoids, which would likely be safer in septic children, can be an effective part of the early, empiric treatment of children suspected of having MIS-C.”

“This is great example of using existing networks, leveraging their infrastructure, gathering real-time data on responses to therapy in a national cohort of patients, and informing our practice,” he adds.

This article appears in the 2021 Fall/Winter print issue. Download the full issue.


Son MBF, Murray N, Friedman K, Young CC, Newhams MM, Feldstein LR, Loftis LL, Tarquinio KM, Singh AR, Heidemann SM, Soma VL, Riggs BJ, Fitzgerald JC, Kong M, Doymaz S, Giuliano JS Jr, Keenaghan MA, Hume JR, Hobbs CV, Schuster JE, Clouser KN, Hall MW, Smith LS, Horwitz SM, Schwartz SP, Irby K, Bradford TT, Maddux AB, Babbitt CJ, Rowan CM, McLaughlin GE, Yager PH, Maamari M, Mack EH, Carroll CL, Montgomery VL, Halasa NB, Cvijanovich NZ, Coates BM, Rose CE, Newburger JW, Patel MM, Randolph AG; Overcoming COVID-19 Investigators. Multisystem Inflammatory Syndrome in Children – Initial therapy and outcomes. The New England Journal of Medicine. 2021 Jul 1;385(1):23-34. Epub 2021 Jun 16.

Image credit: Nationwide Children’s

About the author

Marketing Strategist, Research Communications

Natalie is a passionate and enthusiastic writer working to highlight the groundbreaking research of the incredible faculty and staff across Nationwide Children's Hospital and the Abigail Wexner Research Institute. Her work at Nationwide Children's marries her past interests and experiences with her passion for helping children thrive and a long-held scientific curiosity that dates back to competing in the Jefferson Lab Science Bowl in middle school. Natalie holds a bachelor’s degree in sociology from Wake Forest University, as well as minors in women's, gender & sexuality studies and interdisciplinary writing. As an undergraduate student, Natalie studied writing and journalism, engaged with anthropological and sociological research with a focus on race and ethnic relations, served as executive editor for the student newspaper, the Old Gold & Black, and gained marketing experience as an intern for a nonprofit entrepreneurial incubator, Winston Starts, as well as by working for Wake Forest University School of Law Office of Communication and Public Relations and its Innocence and Justice Clinic.