#mis-c

Scientists have uncovered genetic variants that help to explain why some children with mild COVID-19 go on to develop a severe inflammatory condition weeks after their infection.

Throughout the COVID-19 pandemic, severe SARS-CoV-2 infections in children and infants were rare. But an estimated 1 in 10,000 children went on to develop multisystem inflammatory syndrome in children (MIS-C), presenting with a range of symptoms including rash, swelling and nausea and vomiting.

Now, an international team of researchers led by Imperial College London has identified a gene that may explain why some children were at greater risk of developing this rare condition. The study is published in the Journal of Experimental Medicine.

In an analysis including more than 150 cases of MIS-C from Europe and the United States, they found that rare variations of a gene that helps regulate the lining of the gut made children four-times more likely to develop systemic inflammation and an array of symptoms.

According to the researchers, understanding the genetic basis of MIS-C provides new insights into how the condition develops, who is at risk, and how patients and those with related conditions might be better treated.

Senior author Dr. Vanessa Sancho-Shimizu, from the Department of Infectious Disease at Imperial College London and The Francis Crick Institute, said, "MIS-C was a very worrying condition for children and their families as well as the clinical teams treating them. Thankfully, the majority of patients recovered, but the underlying mechanisms that drive this condition have been difficult to pin down.

"Working with colleagues around the world, we've been able to pinpoint rare genetic variants that we think are likely driving the systemic inflammation we've seen, making children more susceptible to MIS-C. We hope these findings will not only enable us to better understand the condition but to improve how we care for children with these types of conditions."

Genetic analysis During the COVID-19 pandemic, evidence suggested children were generally at very low risk of severe disease. But reports emerged of a new condition that affected a small proportion of children several weeks after their infection with SARS-CoV-2.

These children generally had mild or no symptoms at the time of their initial infection. But within six weeks they went on to develop a range of symptoms, including abdominal pains and vomiting, fever, rash and more. Clinicians initially reported the symptoms as resembling Kawasaki disease, but it was found to be a new condition call MIS-C .

In the latest analysis, 154 patients aged 0–19 with MIS-C were recruited in Europe and through a research center in the United States, with blood samples used to sequence patients' genomes. Researchers then developed a technique to search for genetic variants that might be associated with the condition.

Dr. Evangelos Bellos, first author of the paper and a Research Fellow in Imperial's Department of Infectious Disease, said, "Our new computational technique, which we call burdenMC, gives us the power to identify links between genes and diseases that were previously elusive. It is particularly useful for shedding light on small, diverse groups of patients with rare conditions such as MIS-C."

Using this approach, the researchers found that small changes in one gene, called BTNL8, were a common factor in children with the condition. Typically, this gene helps to regulate the immune cells in the gut lining, but in patients with MIS-C, rare variants of BTNL8 are believed to have made the gut more sensitive to the SARS-CoV-2 virus and increased inflammation throughout the body, leading to an array of symptoms.

The team worked with the Immunosurveillance Laboratory at the Crick, led by Professor Adrian Hayday, that first identified a function for BTNL8 in the human gut as a regulator of localized T-cells that seemed to contribute to maintaining gut barrier integrity.

Professor Adrian Hayday, Principal Group Leader at the Crick and Professor of Immunobiology at King's College London, said, "The discoveries implicating BTNL8 were wholly unexpected, and potentially offer entirely new insights into mechanisms that ordinarily prevent virus infections from leading to life-threatening disease."

Compared with matched healthy controls, patients with rare BTNL8 variants had a four-fold increase in the risk of developing MIS-C symptoms. The analysis also found that children with European and Hispanic ancestry were more likely to have the variants, and so were at greater risk of the condition.

The researchers say they are now working on understanding the exact mechanisms by which these rare variants promote MIS-C. They are also exploring if the gut also plays an important role in the development of other similar childhood inflammatory conditions like Kawasaki disease.

Stephanie Soucheray, MA

A new large study of children in California shows that unvaccinated kids are at a much higher risk of developing multisystem inflammatory syndrome in children (MIS-C) if they were unvaccinated with two doses of Pfizer's mRNA COVID vaccine before contracting COVID-19.

The protection was significant in all children ages 5 to 17 years, but most notable in children ages 12 to 17, where even one dose of vaccine offered strong protection against developing the severe condition.

MIS-C was first identified in the initial months of the pandemic. Clinically similar to Kawasaki disease or toxic shock syndrome, MIS-C occurs 2 to 8 weeks following COVID-19 infection in a small percentage of children.

"MIS-C is severe, with all children hospitalized, half requiring care in the intensive care unit, and 1–2 % dying," the authors wrote. "However, little is known about the effect of vaccination on the development of MIS-C, especially in the youngest children."

Adolescents most protected In the study, the authors looked at all MIS-C cases in California reported from January 2, 2021, to June 23, 2022. Vaccination history was linked to MIS-C cases.

A fully vaccinated MIS-C case was defined as a case occurring more than 14 days after the second dose of mRNA vaccine, the authors said.

In total, 133 children with MIS-C (60 aged 5 to 11 and 73 aged 12 to 17 ) were included in the study, though California officials noted another 5 cases of MIS-C in children who were partially vaccinated during the study's time frame.

In the 5- to 11-year-old age-group, 85% of those with MIS-C were unvaccinated, and the incidence rate ratio (IRR) of MIS-C in unvaccinated children was 3.3 (95% confidence interval [CI], 1.6 to 6.7) times higher than in fully vaccinated children.

Among 12- to 17-year-olds, 90% of those with MIS-C were unvaccinated, and the IRR of MIS-C in unvaccinated children was 22.9 times higher (95% CI, 10.5 to 49.8).

When partially vaccinated children—those who received one vaccine dose— were added to the analysis with fully vaccinated children, the IRR of MIS-C among unvaccinated children aged 5 to 11 years was 3.4 times higher (95% CI, 1.7 to 6.6), and in the older age-group it was 16.0 times higher (95% CI, 8.4 to 30.3).