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Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

In March 2020, Audrey Odom John was certain her teenage patient had a new disease. As chief of pediatric infectious diseases at the Children’s Hospital of Philadelphia (CHOP), John is accustomed to mystery cases and rare diagnoses. But within weeks, two more children were admitted with parallel symptoms: fever, rash, inflammation, and shock. Two of those first three patients had relatives who had recently tested positive for COVID-19, and just as John began to wonder about a connection, a late-April alert from the United Kingdom made the link explicit.

The notice described an uptick in cases that mirrored those at CHOP, with some affected children also testing positive for COVID-19. In the months since, John and pediatric specialists worldwide have raced to understand what’s now called multisystem inflammatory syndrome in children, or MIS-C. They’ve learned that—contrary to some early suspicions—it appears distinct from Kawasaki disease, a rare inflammatory reaction thought to strike young children after unknown infections.

They’ve also come to recognize its unique profile of immune system overactivity and have identified effective treatments. Now, they are hunting for clues to why it develops, 4 to 6 weeks after infection with the pandemic coronavirus, and how to spot it early.

Careful tracking of cases has shown that MIS-C is rare, though still frightening to parents: As of early March, the U.S. Centers for Disease Control and Prevention had logged more than 2600 MIS-C cases, including 33 deaths. But most youngsters recover after about a week in the hospital.

To explore its relation to COVID-19, researchers compared blood samples from 14 children with MIS-C against those of 16 children and more than 100 adults hospitalized for acute COVID-19. From an immune perspective, “There is a decent bit of overlap” in the different cohorts, says Laura Vella, a pediatric infectious disease physician at CHOP who led the work along with E. John Wherry at the University of Pennsylvania.

Both adults and children with acute COVID-19 had high levels of inflammation and immune activation, in which immune cells get revved up to target potential harms—but in MIS-C patients, the degree of activation sometimes exceeded that of the sickest adult patients, the researchers reported this month in Science Immunology. One subgroup of immune cells stood out: the so-called “vascular patrolling” T cells. Their high activation, suggesting they were targeting blood vessels, could explain the cardiac inflammation and aneurysms in some patients.

Vella and her colleagues also noted that despite the rampant inflammation in the MIS-C patients, it abated quickly with treatment. “They can turn this around with therapy,” Vella says, whereas people with COVID-19 experienced longer lasting inflammation.

The immunologic findings dovetail with what doctors have seen: Most children with MIS-C improve rapidly with therapies that suppress the immune system. U.S. MIS-C patients are routinely treated with intravenous immunoglobulin. But this treatment often isn’t available in underresourced countries. In September 2020, a large U.K. clinical trial called Recovery, which has been testing therapies on thousands of adults, began to recruit children for a study of other approaches. “Across the globe, people have adopted different strategies” for treating MIS-C, says Elizabeth Whittaker, a pediatric infectious disease specialist at Imperial College London, who’s involved in the trial. Trial leaders want to know whether children can be treated with steroids alone or even just supportive care, for example drugs to stabilize blood pressure.

Ironically, powerful treatments for MIS-C also make it harder to study: Blood samples to probe the immune system are often collected after therapy has started. Treatment “changes a tremendous number of cell types,” says Virginia Pascual, a pediatric rheumatologist and director of the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine. Her work is part of a large study called the Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM), which aims to decipher the causes and long-term outcomes of the syndrome.

Sponsored by the National Institutes of Health, PRISM has enrolled more than 100 patients since November, and hopes to include at least 250 overall. Over 1 year, researchers will repeatedly collect a raft of samples including blood, saliva, and urine from patients with symptoms of MIS-C or who have COVID-19. “All of our efforts … now are to try to capture these samples before [children] start to be treated with these very potent medications,” Pascual says. That’s not easy, says Steven Webber, pediatrician-in-chief at Vanderbilt University, who is leading the study. For parents whose child has fallen suddenly, critically, ill, “It’s hard to think straight,” he says. “And then someone comes along and says, ‘We would really love for you to be in this important study.’”

Theories for what’s driving MIS-C are emerging. Many children test negative for SARS-CoV-2 on a nasal swab, but the virus may hide elsewhere in the body; stool samples may provide clues. Some wonder whether antibodies produced after infection react to the body’s own tissues.

Pascual is exploring whether SARS-CoV-2 causes a subtle immune system abnormality, perhaps in immune system precursor cells, and subsequent exposure to another virus—a “second hit”—sends the immune system into overdrive. The good news, Pascual says, is “all these hypotheses are testable.”

Clarity could help physicians quickly diagnose MIS-C; right now, that requires sophisticated blood testing and specialists that not all health centers have access to. Early diagnosis and treatment could improve outcomes. Although most children have recovered, “I don’t think the low mortality is inherent to the disease,” Webber says.

A paper published last week in The Lancet Child & Adolescent Health identified factors linked to more severe disease in 1080 young people with MIS-C. High c-reactive protein, a marker of inflammation, increased risk, as did older age. Children who were Black were more likely to end up in the intensive care unit, and some 77% of children in the paper were Black or Hispanic—the groups hit hardest by COVID-19, John notes.

A deeper mystery to her is age. Teenagers can be severely affected by MIS-C, but people in their 20s almost never are, even though immunologically, the two groups are nearly identical. John wonders whether differences in hormones or exposure to other viruses might be at work.

Ultimately, she hopes ongoing studies will bring speedy, accurate diagnostics and more targeted treatment. “Our current approach is a hammer” to squash the entire immune system, she says, and it can have side effects like fluid buildup in the lungs. “There’s definitely room to take a precision immunology approach,” she says. One year after the mystery of MIS-C emerged, she’s eager for answers.