Researchers decipher MIS-C, the scary illness that followed COVID in some kids

It’s one of the enduring mysteries of the pandemic: What caused some children to develop a severe inflammatory syndrome weeks after a Covid infection?

The condition is called multi-system inflammatory syndrome in children, or MIS-C, and it is serious but rare. Early in the pandemic, kids began showing up in emergency departments with symptoms including persistent high fevers, vomiting, fatigue and heart inflammation. Some needed intensive care and ventilators.

"Very serious disease"

“They’d come to the ICU because they also got inflammation of their hearts, which meant their hearts weren't able to pump enough to get blood to all of the organs in their body and keep them alive. So it's really a very serious disease,” recalls Dr. Aaron Bodansky, an assistant professor of pediatrics at the University of California, San Francisco School of Medicine, who treated children with the condition.

At the time, Bodansky says, doctors couldn’t answer a pressing question for families: Why is this happening? He says they knew the syndrome had to be related to COVID, but they didn’t know how.

Now, researchers finally have discovered what led to many of these cases.

Out-of-control reaction

As Bodansky and his colleagues report in the journal Nature, many children who developed MIS-C had an out-of-control immune response to COVID as a result of mistaken identity. Basically, these children’s immune systems locked onto a part of the coronavirus that closely resembles a protein found in immune cells that are located throughout the body.

That caused the immune system to mistakenly target itself instead of the virus, says Joe DeRisi, president of Chan Zuckerberg Biohub San Francisco, and a senior author of the study. “And that causes inflammation, we believe, to spin out of control,” he says.

“Think of it like collateral damage or friendly fire,” DeRisi says.

The study drew on samples collected from patients with MIS-C through a national network of pediatric ICUs called Overcoming COVID-19. The researchers analyzed those samples using a sophisticated sequencing technology that allowed them to identify the targets of past immune responses. DeRisi says it essentially allowed them to ask, “What are your antibodies seeing in you?”

A particular protein

The analysis revealed that a third of the MIS-C cases had autoantibodies to a protein called SNX8, which is part of the body’s normal antiviral response and is found in immune cells all over the body, Bodanksy explains. A second analysis revealed that protein turned out to look a lot like a part of the coronavirus. In kids who developed MIS-C, their immune systems happened to latch onto that section of the coronavirus as a target, which led them to also produce autoantibodies that targeted SNX8.

A further analysis, conducted with collaborators at St. Jude Children’s Research Hospital, looked at the T-cells in kids who developed MIS-C. Killer T-cells normally attack invaders in the body. But the analysis revealed that, in children with MIS-C, their T-cells couldn’t tell the difference between the body’s own immune cells and the virus, DeRisi says.

At the height of the pandemic, only a small subset of children – about 1 out of every 2,000 – who got infected with COVID went on to develop MIS-C. Most recovered fully.

More rare today, but still happening

These days, the condition is even rarer. DeRisi says it now mostly occurs only in unvaccinated children.

But Bodanksy notes that some children still develop life-threatening immune responses after other infections. He hopes their work inspires other researchers to use novel tools to better understand those cases, too.

“We can, if we focus, find answers and understand specifically what is happening in these children, if we have the will to do it,” Bodanksy says.