Researchers Continue to Find Clues About MIS-C

[Originally published: May 15, 2020. Updated: July 14, 2021.]

As the country continues to reopen and kids return to pre-pandemic activities, researchers are still trying to understand a rare, but serious, inflammatory syndrome in children that is linked to COVID-19 infection. 

Known as multisystem inflammatory syndrome in children (MIS-C), the median age for the condition is 9, and half of children with it have been between ages 5 and 13, according to CDC data. 

Researchers believe that MIS-C, which can cause dangerous levels of inflammation throughout the entire body, occurs as a response to COVID-19 infection (including asymptomatic cases), but many questions remain. 

A Yale-led study published in the journal Immunity in May offers a few theories on why some children develop MIS-C and others don’t. Carrie Lucas, PhD, an assistant professor of immunobiology at Yale School of Medicine, is the corresponding author of the study, which tested blood of children with MIS-C, adults with severe COVID symptoms, and healthy children and adults. 

The study found that children with MIS-C had high levels of alarmins. Alarmins are molecules within cells that are part of the innate immune system, which reacts swiftly to infections. Prior research has suggested that a child’s innate immune response is stronger than an adult’s, which could explain why children’s COVID-19 symptoms in general are milder. 

“Coupled with high alarmins were specific expansion of adaptive immune cells [T cells and plasmablasts] with signatures consistent with strong activation and potential self reactivity,” says Lucas. 

Children with MIS-C also were found to have an elevated amount of specific adaptive immune responses, which fight off certain pathogens (such as SARS-CoV2, the virus that causes COVID-19). But instead of being protective, the immune reaction in these children seems to attack various host tissues, which may be a sign of autoimmune disease. 

MIS-C came on the radar in April 2020 when physicians in Europe and the U.S. began to report a small but growing number of children with inflammation in multiple organs. Many of these children had tested positive for COVID-19 or had a confirmed case previously. While doctors have since learned more about the syndrome, much is still unknown. 

“It appears to occur in children after they have gotten better from COVID and it has a lot of similarities to other diseases we see in pediatrics, including Kawasaki disease and toxic shock syndrome,” says Marietta Vázquez, MD, a Yale Medicine pediatric infectious disease specialist. “This is not a cause for panic, but a message to be vigilant. If you have a child with a high fever for no other apparent reason, and other symptoms such as red eyes, belly pain, a prickly heat rash all over the body, muscle aches, vomiting, or diarrhea, call your pediatrician. It is also important to note that we have taken care of many children of all ages with MIS-C, and they all have done very well after the disease.” 

Clifford Bogue, MD, chair of Yale Medicine Pediatrics and chief medical officer of Yale New Haven Children’s Hospital, adds that early treatment is important.

“Based on our experience with this and other conditions in which there is a severe inflammatory response that could lead to organ injury or failure, we want to identify and treat patients as soon as we can,” Dr. Bogue says. “Parents should be aware of symptoms of this syndrome, even if there is no history of COVID—because many kids have COVID with no symptoms. This can also appear weeks after a COVID infection.” 

To treat MIS-C, Dr. Bogue says Yale doctors have been using high-dose steroids, intravenous immunoglobin (blood plasma that contains antibodies), and a biologic medication commonly used for rheumatoid arthritis and other inflammatory diseases. “The therapies are all geared toward tamping down the body’s inflammatory response,” Dr. Bogue explains.

Controlling the inflammatory reaction is vital, Dr. Vázquez says, because as patients get sicker, their hearts begin to race and blood pressure decreases, which can lead the body to go into shock—a potentially fatal condition if not treated quickly. 

Fortunately, Dr. Bogue says, physicians now have a heightened suspicion to look for the syndrome. “We have put together a team of infectious disease specialists, rheumatologists, cardiologists, and critical care doctors who are aggressive about treating this and will be following up with patients,” he adds. 

As of late June, the CDC says there have been 4,196 reported cases of MIS-C, and 37 deaths. 

Not only is MIS-C extremely rare, COVID-19 remains uncommon in children. In the U.S., 14% of confirmed coronavirus cases (more than 3.9 million) have been in children under age 18.  

For the most part, the common presentation of COVID-19 as a respiratory disease has been less severe in children, Dr. Vázquez says. 

“We don’t know why children get less severe disease with COVID, but it probably is because they are younger and healthier. With other respiratory infections, like pneumonia and influenza, it is mostly the elderly who get very sick,” she says. “And now when we look at this syndrome, it is thought to occur as a child’s body is making protective antibodies against COVID. Children’s immune systems are very robust and they respond and make a lot of antibodies, so maybe that is why we see this antibody-linked manifestation.” 

Beth Emerson, MD, medical director of YNHCH Emergency Department, says that parents should not be afraid to bring their children in for medical care if they suspect MIS-C.

“The main thing for parents to know is that this inflammatory syndrome is different from a COVID respiratory infection, and it has been seen mostly after a known or suspected infection,” she says. “Families with concerns should contact their pediatrician. If they are worried that the child is having trouble breathing, is sleepier than usual, is having severe pain, or there are other concerns that the family does not think should wait, our emergency departments are ready to provide care.”

Click here to learn more about Yale’s research efforts and response to COVID-19.