A hyperactive immune response in children, associated with COVID-19, is the subject of clinical trials.
Marija Stepanovic / iStock
By Jennifer Couzin-Frankel
ScienceCOVID-19 reports are supported by the Heising-Simons Foundation.
In March 2020, Audrey Odom John was sure that his teenage patient had a new illness. As head of pediatric infectious diseases at the Children’s Hospital of Philadelphia (CHOP), John is used to mysterious cases and rare diagnoses. But within weeks, two more children were admitted with parallel symptoms: fever, rash, inflammation and shock. Two of the first three patients had relatives who had recently tested positive for COVID-19, and as soon as John started wondering about a connection, a UK alert in late April made the link explicit.
The warning described an increase in CHOP-like cases, with some affected children also testing positive for COVID-19. In the months that followed, John and pediatric specialists around the world rushed to understand what is now called multisystemic inflammatory syndrome in children, or MIS-C. They learned that – contrary to some initial suspicions – it looks different from Kawasaki disease, a rare inflammatory reaction that is believed to strike young children after unknown infections.
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They also recognized their unique immune system hyperactivity profile and identified effective treatments. Now, they are looking for clues as to why it develops, 4 to 6 weeks after pandemic coronavirus infection, and how to identify it early.
Careful case tracking has shown that MIS-C is rare, though still scary for parents: in early March, the United States Centers for Disease Control and Prevention recorded more than 2,600 cases of MIS-C, including 33 deaths. But most young people recover after about a week in the hospital.
To explore their relationship with COVID-19, the researchers compared blood samples from 14 children with MIS-C with those from 16 children and more than 100 adults hospitalized for acute COVID-19. From an immunological perspective, “there is a little decent overlap” in the different cohorts, says Laura Vella, a CHOP pediatric infectious doctor who led the work together with E. John Wherry at the University of Pennsylvania.
Adults and children with acute COVID-19 had high levels of inflammation and immune activation, in which immune cells are accelerated to reach potential damage, but in patients with MIS-C, the degree of activation sometimes exceeded that of older adult patients. sick, the researchers reported this month in Scientific Immunology. A subset of immune system cells stood out: the so-called “vascular patrol” T cells. Their high activation, suggesting that they targeted blood vessels, could explain cardiac inflammation and aneurysms in some patients.
Vella and his colleagues also noted that, despite the rampant inflammation in patients with MIS-C, it decreased rapidly with treatment. “They can reverse this with therapy,” says Vella, while people with COVID-19 experienced more lasting inflammation.
The immunological findings correspond to what doctors have observed: most children with MIS-C get better quickly with therapies that suppress the immune system. US MIS-C patients are routinely treated with intravenous immunoglobulin. But such treatment is generally not available in resource-poor countries. In September 2020, a large clinical trial in the UK called Recovery, which tested therapies on thousands of adults, started recruiting children for a study of other approaches. “Around the world, people have adopted different strategies” for the treatment of MIS-C, says Elizabeth Whittaker, a specialist in pediatric infectious diseases at Imperial College London, who is involved in the study. The test leaders want to know if children can be treated with steroids alone or only with supportive care, for example, drugs to stabilize blood pressure.
Ironically, powerful treatments for MIS-C also make the study more difficult: blood samples to probe the immune system are often collected after starting therapy. The treatment “changes a large number of cell types,” says Virginia Pascual, a pediatric rheumatologist and director of the Gale and Ira Drukier Institute for Child Health at Weill Cornell Medicine. His work is part of a large study called Pediatric Research Immune Network on SARS-CoV-2 and MIS-C (PRISM), which aims to decipher the causes and long-term results of the syndrome.
Sponsored by the National Institutes of Health, PRISM has enrolled more than 100 patients since November and expects to include at least 250 in total. Over the course of 1 year, researchers will repeatedly collect a series of samples, including blood, saliva and urine from patients with symptoms of MIS-C or who have COVID-19. “All of our efforts … are now to try to capture these samples before [children] start being treated with these very potent drugs, ”says Pascual. This is not easy, says Steven Webber, chief pediatrician at Vanderbilt University, who is leading the study. For parents whose child fell suddenly, seriously, ill, “it is difficult to think straight,” he says. “And then somebody comes up and says, ‘We would love for you to participate in this important study.'”
Theories are emerging about what drives MIS-C. Many children test negative for SARS-CoV-2 on a nasal swab, but the virus can hide in other parts of the body; stool samples can provide clues. Some wonder if the antibodies produced after infection react to the body’s own tissues.
Pascual is exploring whether SARS-CoV-2 causes a subtle abnormality of the immune system, perhaps in the precursor cells of the immune system, and the subsequent exposure to another virus – a “second hit” – causes the immune system to over-function. The good news, says Pascual, is that “all of these hypotheses are testable”.
Clarity can help doctors quickly diagnose MIS-C; this now requires sophisticated blood tests and specialists to which not all health centers have access. Early diagnosis and treatment can improve results. Although most children have recovered, “I don’t think that low mortality is inherent to the disease,” says Webber.
An article published last week in The Lancet Child & Adolescent Health identified factors linked to more serious illnesses in 1080 young people with MIS-C. The elevated c-reactive protein, a marker of inflammation, increased the risk, as did advanced age. Black children were more likely to end up in the intensive care unit, and about 77% of children in the newspaper were black or Hispanic – the groups most affected by COVID-19, notes John.
A deeper mystery for her is age. Teenagers can be severely affected by MIS-C, but people in their 20s are almost never, although immunologically the two groups are almost identical. John wonders whether differences in hormones or exposure to other viruses may be at work.
Ultimately, she hopes that ongoing studies will bring rapid and accurate diagnoses and more targeted treatment. “Our current approach is a hammer” to crush the entire immune system, she says, and it can have side effects like fluid buildup in the lungs. “There is definitely room for a precision immunology approach,” she says. A year after the MIS-C mystery emerges, she is eager for answers.