Children's Hospital Colorado

A Protocol for Multisystem Inflammatory Syndrome in Children (MIS-C)

Heart | October 15, 2020

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Multisystem inflammatory syndrome in children, or MIS-C, is associated with COVID-19 but has a clinical presentation similar to that of Kawasaki disease, with symptoms like high fever and high inflammatory markers.

“There are important laboratory and clinical differences that put MIS-C patients at risk for requiring admission to the intensive care unit,” says Children’s Hospital Colorado critical care fellow Christina Osborne, MD. 

In addition to being a critical care fellow, Dr. Osborne recently completed a pediatric infectious disease fellowship — coincidentally studying coronavirus prior to the global pandemic. Given her interest in both infectious disease and pediatric critical care, she offered to oversee the creation of a protocol at Children’s Colorado to help rule out or rule in patients with suspected MIS-C, allowing for early recognition. The design and implementation of the protocol was collaborative and multidisciplinary, with input from infectious disease, hospital medicine, critical care, cardiology, rheumatology and emergency medicine.

Like in most hospitals across the country, the protocol combines recommendations from the Centers for Disease Control and Prevention, World Health Organization and European Centre for Disease Prevention and Control. But there are several intentional differences. 

A comprehensive echo is essential

“When a patient has MIS-C, the body starts to respond in a typical way, developing anti-inflammatory cells to eradicate the coronavirus,” says Children’s Colorado pediatric cardiologist Pei-Ni Jone, MD. “But then the immune system goes hyperactive and a cytokine storm develops in which the immune cells starts to harm the normal cells in addition to the virus. So these patients get sicker and faster than those with Kawasaki disease.” 

Heart inflammation will often cause damage to the heart cells. And that sets off a marker called troponin, which can be elevated in patients with MIS-C. Additional tests reveal these patients have low lymphocyte counts, meaning that these cells are fighting the virus and depleting the lymphocytes. That’s what makes MIS-C a totally different entity from Kawasaki disease.

Those characteristics trigger steps in the protocol including a comprehensive echocardiogram with coronary imaging and a function assessment of the heart. It’s one of the most important steps the multidisciplinary team wrote, says Dr. Jone, and something that’s unique to Children’s Colorado. 

“It’s very sophisticated imaging. These are 1- or 2-millimeter measurements,” she says. “If you wait to do that kind of assessment until the next day, you’re likely already too late. We need to know immediately if the coronary is dilated so we can be very aggressive with treatment.” 

IVIG therapy

IVIG therapy, or intravenous immunoglobulin therapy, is an anti-inflammatory medication that gives a patient the antibodies they need to fight an infection. It’s often used in patients with Kawasaki disease who, because of coronary artery dilation, are at increased risk of clotting and heart attack. MIS-C is the same in that respect, so delaying IVIG is dangerous. Depending on symptoms, coronary involvement and their severity, the multidisciplinary team may combine IVIG with a chimeric monoclonal antibody drug called infliximab. 

They then monitor the patient throughout recovery, repeating labs and other steps in the protocol as necessary.

Information sharing and research

Since May, the protocol has helped the multidisciplinary team successfully treat more than 45 patients who’ve been diagnosed with MIS-C. They continue to adjust the pathway for efficiency, removing excess labs as they learn more. The comprehensive protocol is so effective, in fact, that institutions across the country have asked for it, and Children’s Colorado readily provides the information.

Boston Children’s Hospital also took note of the protocol and asked Children’s Colorado to join a study called Long-Term Outcomes after the Multisystem Inflammatory Syndrome in Children that looks at heart function and long-term outcomes of MIS-C patients. Children’s Colorado is also participating in several other research initiatives related to MIS-C and COVID-19. One is with Rady Children’s Hospital called Characterization of Multisystem Inflammatory Syndrome in Children (CHARMS) and its relationship to Kawasaki disease. That study will compare blood work in KD and MIS-C patients for biomarker differences. The other is a multicenter study funded by the National Institutes of Health called Overcoming COVID-19.

Additionally, Dr. Jone is in the process of writing a guideline paper for the American Heart Association on COVID-19 and the cardiovascular complications in pediatric congenital heart disease patients. She and the paper’s other authors hope to publish in the next three months.

“We are fortunate to have such a robust group of providers that have studied Kawasaki disease and management for quite some time, and I think that gave us an advantage in responding to this newly emerging disease,” says Dr. Osborne.

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