On a late October morning in southern Wyoming, 12-year-old Madilyn Dayton woke up feeling sick. The normally energetic child assumed she was coming down with a common cold, but in short order her symptoms got worse.
“I had a really bad headache and just body aches all over,” said Madilyn, who goes by “Maddie.” “Two to three days later I couldn’t walk, and I wouldn’t eat. Then, I started getting rashes all over my body.” But she said things got worse. “I woke up and I couldn’t move at all. My head, I couldn’t move it from side to side. I was stuck.”
“She just progressed so fast,” said Marilyn Dayton, Maddie’s mom.
Frantic and scared, Dayton rushed Maddie to the hospital, where her daughter ended up in intensive care. By morning, Maddie had become one of the children in the United States diagnosed with a rare condition—discovered only in April—called multisystem inflammatory syndrome in children (MIS-C).
An overreactive immune response to the novel coronavirus (COVID-19), MIS-C appears two to four weeks after a child or teen, typically younger than 15, is infected with SARS-CoV-2, the virus that causes COVID-19. What happens next is much like the body’s immune “alarm” turning on to fight infection and not being able to switch off. Fever, shock, and multi-organ inflammation often set in. And while most children survive, they usually require medications and therapies, such as antibodies, steroids, blood thinners, medications that affect the immune system, and sometimes even devices to support breathing and heart function to support them until the infection passes. Although pediatric cases of COVID-19 represent 11% of COVID-19 cases in the United States, MIS-C is rare. So far 2 in 100,000 children—or less than .01% of the population—have been affected by MIS-C.
The Daytons, who shared their experience at a virtual news conference hosted by Primary Children’s Hospital in Salt Lake City, said they were bewildered by the MIS-C diagnosis, which followed Maddie’s positive COVID-19 antibody test. Nobody in their family had been sick in the previous six weeks or had shown symptoms for COVID-19. “We live in a little, tiny town in Southwest Wyoming,” Dayton said. “I thought we were social distancing by default just because we don’t have a lot of people in our community.”
Researchers are just as curious about the condition, which is why children like Maddie who have been diagnosed with MIS-C are being invited to join a five-year longitudinal study to help doctors better understand it. The observational “Long-TerM OUtcomes after the Multisystem Inflammatory Syndrome In Children (MUSIC)” study will enroll up to 600 patients over the next two years at more than 29 medical centers by using the platform of the Pediatric Heart Network, a pediatric research consortium created and funded by the National Heart, Lung, and Blood Institute (NHLBI).
Study participants will have the option to share medical data collected at the onset of their symptoms, when they are discharged from the hospital, during follow-up visits, and then annually. The study, supported by the National Institutes of Health (NIH) and NHLBI, aims to quickly characterize MIS-C.
In the United States, doctors diagnose MIS-C after a patient has had a fever that lasts for at least a day, shows clinical markers of inflammation, and has been hospitalized for severe illness involving multiple organs or systems, including the heart, lungs, blood, kidneys, or brain. The patient must have had COVID-19. Hospitals can confirm this by testing for SARS-CoV-2, SARS-CoV-2 antibodies, or by determining if a patient had been exposed to someone with COVID-19 in the past month. Other MIS-C symptoms may include a rash, headache, dizziness, shortness of breath, and gastrointestinal distress, such as vomiting, diarrhea, or stomach pain. Most patients require intensive care and stay in the hospital for 5-8 days, which matches Maddie’s experience.
Maddie spent six days in the hospital, including four days in intensive care. To recover, she is taking smaller doses of steroids, which balance her immune response, and aspirin, which reduces the risk of blood clots in her coronary arteries. She’s also taking a 3- to 6-month break from playing basketball and doing strenuous exercises.
“She’s never had any health problems,” Dayton said about her daughter, a multi-sport athlete, but they are proceeding with caution. A distinctive feature of the MUSIC study will be researchers’ ability to follow immediate and long-term outcomes related to the patients’ cardiovascular health and overall health and well-being.
This is important, because cardiovascular issues, including complications like impaired heart function, swelling of the coronary arteries, and changes in heart rhythm, occur in about 80% of those affected by MIS-C, said Jane Newburger, M.D., M.P.H., a national MUSIC study co-chair and pediatric cardiologist at Boston Children’s Hospital. “Although we understand that these problems occur after a child or teen first becomes sick,” she said, “we have very little data about the long-term effects of MIS-C on the heart and a child’s general health. The MUSIC study will close that knowledge gap.”
When patients are diagnosed with MIS-C, they are screened for a variety of conditions, including heart abnormalities, such as decreased heart function (meaning how the heart squeezes), enlargement of the coronary arteries (the blood vessels that bring oxygenated blood to the heart), and heart rhythm problems. Early detection and treatment are critical to reduce the likelihood of long-term complications to the body’s organs. After diagnosis, children with MIS-C are carefully monitored with serial diagnostic tests to assess the heart’s structure and function, as well as with blood work to measure the degree of inflammation, tendency to form blood clots, and heart muscle strain or damage.
The care of children with MIS-C often involves a multidisciplinary team of pediatric subspecialists. In addition to cardiologists, subspecialists in rheumatology, infectious diseases, hematology, gastroenterology, and other areas work together to monitor the health of a child’s organs and systems. The MUSIC study will track the well-being of children who have had MIS-C, including all of the body’s organ systems, for up to five years.
Understanding why Maddie had myalgia, or all-over muscle pain, for example, and examining any long-term symptoms, helps researchers create “deep phenotypes,” or pooled patient characteristics, that match MIS-C immune profiles. Machine learning models may transfer this knowledge into algorithms to help physicians quickly diagnose and treat MIS-C in emergency-room settings. Study participants will have a chance to share genetic samples to support existing and future MIS-C research.
“There are no known risk factors at this point that would make some kids with COVID-19 develop MIS-C and others not,” says Dongngan Truong, M.D., M.S., a national MUSIC study co-chair with Newburger and a pediatric cardiologist at Primary Children’s Hospital. “That’s where research studies like MUSIC are going to play an important role.”
MIS-C, like COVID-19, has disproportionally affected Hispanic and African-American children and teens. By integrating sociodemographic variables into the study, including age, race, health insurance status, income, and location, the researchers will analyze potential MIS-C determinants and risk factors.
MUSIC data will be integrated into BioData Catalyst, a cloud-based system developed by NHLBI that enables scientists to access heart, lung, blood, and sleep research. For example, Kawasaki disease, an acute illness that affects infants and younger children, has benefitted from genomic research, and scientists are currently studying molecular and biological differences between Kawasaki disease and MIS-C. The two conditions can look very similar at presentation and sometimes are hard to distinguish based on physical examination alone.
The MUSIC study, which allows physician-scientists to use critical data from hundreds of patients, should go a long way toward helping us understand this new disease, said Gail Pearson, M.D., Sc.D., a pediatric cardiologist helping to guide the research and the associate director of the Division of Cardiovascular Sciences at the NHLBI. “We can now study MIS-C on a molecular, genomic, and clinical level and feel confident that what we discover will lead to treatment guidelines for this rare condition.”
“The impacts of COVID-19 have been devastating,” Pearson added. “But researchers have never been better positioned to use new technology, scientific insight, and partnerships to help minimize them. The MUSIC study is especially exciting because it holds many of the keys to unlocking the mysteries of this new disease, which should help ensure that children with MIS-C can go on to live healthy lives.”
Learn about additional COVID-19 research at www.NIH.gov/Coronavirus.