Clues About MIS-C and COVID-19 in Kids

The U.S. fell short of its goal of giving at least one dose of the COVID-19 vaccine to 70 percent of adults by July 4, but not by much. About two-thirds of everyone above the age of 18 had gotten a shot when the holiday arrived, with coverage among seniors surpassing even that benchmark. That leaves kids—mostly unvaccinated—as the Americans most exposed to the pandemic this summer, while the Delta variant spreads. It’s said that COVID-19 may soon be a disease of the young. If that’s what’s coming, then its effects on children must be better understood.

This month, The New England Journal of Medicine published new treatment guidelines for the occasionally fatal, COVID-related condition known as multisystem inflammatory syndrome in children (MIS-C). When kids first started showing signs of MIS-C in early 2020—rash or conjunctivitis; low blood pressure; diarrhea or vomiting; etc.—doctors guessed it was an inflammatory disease that occurs most often in toddlers called Kawasaki disease. Now most experts believe it’s a separate condition, affecting kids at an average age of 8. No more than a few hundred children in the U.S. have died from COVID-19 during the pandemic—compared with more than half a million deaths overall—but more than 4,000 have developed MIS-C, and we still don’t have foolproof ways to cure it. But a handful of scientists think they’ve found important clues about what drives MIS-C. The disease, they say, may have something to do with a dangerous condition most commonly associated with tampon use.

That condition, called toxic shock syndrome, was also quite mysterious when it first appeared, in a group of kids in the late 1970s. Within a few years, it was clear that women who used high-absorbency tampons were also falling ill, with symptoms very much like those now seen in MIS-C: They had kidney failure, diarrhea, and skin rashes; a few went into shock and died. (Indeed, one of the early sufferers, like the early MIS-C patients, was initially and incorrectly thought to have Kawasaki disease.) Doctors soon realized that the tampon-induced sickness was caused by a buildup of toxins from certain strains of Staphylococcus or Streptococcus bacteria. In people who do not yet have immunity to those strains, the toxins somehow bypass the immune system’s usual processes for developing a targeted response to a pathogen. That sets off a widespread, confused, nonspecific immune reaction.

The toxins that caused the immune system to run amok were called “superantigens” in 1989. (More than two dozen types have now been discovered in tampon-related bacteria, rabies, Ebola, and other pathogens.) What makes them “super” is their ability to short-circuit T-cell receptors. Under normal circumstances, a foreign substance provokes an immune reaction when a piece of it, called an antigen, binds to the nook in the middle of a T-cell receptor. That prompts the body to make antibodies tailored to the antigen’s specific shape. But superantigens manage to grab on and connect to the T cells outside the nook. That still triggers an immune response, but it isn’t one that’s custom-made for the infection. “What does a superantigen do? It comes on from the side,” says Moshe Arditi, a pediatric-infectious-disease doctor at Cedars-Sinai Medical Center, in L.A. “That’s why it’s able to bind to many, many, many, many cells—20 to 30 percent of your T cells that suddenly could be bound by the superantigen and—boom—activated like crazy.”

Arditi has been studying Kawasaki disease for years, but when cases of MIS-C began to be described last year, he suspected they had more in common with toxic shock syndrome. So Arditi reached out to the computational biologist Ivet Bahar, of the University of Pittsburgh School of Medicine, among other scientists, to help investigate. Bahar’s lab found a resemblance between the SARS-CoV-2 spike protein, which allows the pandemic virus to infect human cells, and the Staphylococcus superantigen toxin. The results appeared in September in the Proceedings of the National Academy of Sciences. “This level of similarity, both in sequence and structure with the bacterial toxin, tells us for sure that this segment of spike has the same behavior,” Bahar told me.

Still, the scientists continued to gather evidence in support of this idea. In spring, Arditi, Bahar, and other colleagues reported that children with MIS-C, like people with toxic shock syndrome, have increased numbers of T cells with a receptor that binds to superantigens. Around the same time, scientists in France reached a similar conclusion, likening the unusual T-cell pattern in MIS-C to that of toxic shock syndrome.

If it’s true that a protein from the virus that causes COVID-19 is a superantigen, then you might expect to see something akin to toxic shock syndrome among a larger segment of those who are infected, as opposed to just in kids. In fact, there is an adult version of MIS-C, known as MIS-A (the incidence of this condition is not known, however). It’s also possible that long COVID in adults, as well as other suspected autoimmune features of the disease, is related to superantigens, says Michel Goldman, an immunologist at the French-speaking Free University of Brussels.

However, not every MIS-C researcher is convinced that the spike protein itself causes a superantigen-like illness. “I don’t buy that it’s driven by SARS-CoV-2 directly,” says Carrie Lucas, an immunologist at the Yale University School of Medicine who has studied the pediatric disease. Lucas notes that toxic shock syndrome tends to come on in a matter of days following a bacterial infection, whereas MIS-C often manifests several weeks after a child has contracted the coronavirus. Also, affected children usually show only mild symptoms during their initial encounter with the pathogen. To Lucas, those two factors suggest that another mechanism is in play. Perhaps the body creates a molecule in response to the coronavirus infection, and this molecule, in turn, behaves as a superantigen.

Another unusual finding about MIS-C could explain its delayed onset, though. Lael Yonker, a pediatric pulmonologist at Massachusetts General Hospital, and her collaborators found some evidence suggesting—but not definitively proving—that the condition originates, weeks after infection, in a child’s gut. It’s been well established that the coronavirus, or at least bits of it, can be detected for some time post-exposure in people’s stool samples. But samples from kids with MIS-C also show elevated levels of a protein called zonulin, which is normally found in the gut lining and makes the intestine more permeable when it’s released. If children with MIS-C have leaky guts, that could explain their prolonged gastrointestinal symptoms. It might also tell us why infected kids who develop MIS-C (as opposed to infected kids who don’t) end up with spike protein from the coronavirus circulating in their blood.

Yonker and her colleagues wanted to see if they could prevent this damage to the gut, so they tried giving a toddler with MIS-C an experimental medicine for celiac disease that goes after zonulin. “He was very ill,” Yonker says. “He was being treated with the standard treatments like steroids and his symptoms kept coming back.” The toddler got better: Spike levels in his blood dropped by 90 percent and his fever lessened. One case can’t demonstrate a connection between the drug and the response, so the scientists are now launching a formal study of the celiac drug, called larazotide, for MIS-C.

Meanwhile, Arditi and his colleagues have reported that, in laboratory testing, a monoclonal antibody drug developed as a potential (but still experimental) treatment for patients with toxic shock syndrome also attached to the suspected superantigen portion of SARS-CoV-2 and blocked the virus from infecting cells. The team has patented the new use of the experimental toxic-shock drug for COVID-19 and is waiting to see if there is interest from industry in moving it forward in development.

The approval of those drugs for COVID-19, or MIS-C patients specifically, is a very distant prospect. For now, the fact that SARS-CoV-2 might function as a superantigen in children (as well as some adults) underscores a risk that may be growing. Youngsters who are not yet immunized against COVID-19 would be the most important beneficiaries of a better understanding of this link. “The global sweep of newer, more infectious, variants means we need to remain vigilant,” says Diana Berrent, the founder of the patient advocacy group Survivor Corps. “With no child under 12 vaccinated, and the general trend towards abandonment of masking, testing, and isolation, we are putting our children in an unnecessarily vulnerable position.”

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