As students go back to school across the United States, the assumption that children and teens play little role in spreading Covid-19 is taking a beating. One Georgia school district quarantined more than 900 students and adults. At another in Mississippi, more than 100 students were sent home. One Indiana high school didn’t even make it through a full day—and on Monday, the entire University of North Carolina reversed course on in-person learning and went fully remote.
The clusters of illness and rolling stay-home orders represent a real-time experiment in how much young people pick up, shed, and suffer from the novel coronavirus. Adding to that picture: a still-mysterious illness that is sending a small subset of young Covid-19 patients into intensive care. New data from the Centers for Disease Control and Prevention, released this month, is beginning to sketch out how widespread the illness—dubbed “multisystem inflammatory syndrome in children” or MIS-C—has become in the US. And early research into it may help scientists understand the perplexing symptoms that Covid-19 causes in both adults and children—and may also be ringing an early warning bell on the challenges of achieving a coronavirus vaccine.
The possibility that a Covid-related syndrome was specifically affecting children was a diagnostic puzzle at first—even among the tightly knit networks of pediatric infectious disease medicine, in which children are sent to a small number of referral hospitals and everyone talks to everyone else. The first sign of something anomalous appeared in April, well into the pandemic, via a cluster of eight kids in southeast England who all came into clinics within 10 days with the same symptoms: rashes, bloodshot eyes, fevers that wouldn’t break, abdominal pain, and aching, swollen hands and feet. The kids, whose ages ranged from 4 to 14, went into shock, and several of them had to be put on ventilators. They developed problems with their hearts and circulatory systems, and one child died from a stroke.
“When these cases first started appearing, some people said, ‘No, this is just acute Covid’—which would be true in adults, that Covid can cause multi-organ dysfunction and inflammation,” says Adrienne Randolph, who is a professor at Harvard Medical School and a senior associate in pediatric critical care at Boston Children’s Hospital. “But the thing was, most of these kids had been fine; we might know they had been positive, from being in a home where everyone was tested, but they were not symptomatic. And then three weeks later, they were.”
The symptoms reminded pediatricians of Kawasaki disease, an illness in which the immune system revs up for no known reason and does long-term damage to arteries. Though Kawasaki disease has been studied since the 1960s, its cause hasn’t yet been identified—but is often assumed to be an infection that kicks off an immune reaction in children with some genetic vulnerability.
Staff at the pediatric intensive care unit where the British kids were treated would normally expect to see one or two Kawasaki-like cases in a week, instead of four times that many. It was reasonable to expect that the trigger might be the coronavirus that was circulating throughout the world at that point—and as it turned out, all of the kids possessed antibodies to Covid-19, and four had been exposed to positive family members.
Up to that point, Covid-19 was assumed to not affect children seriously, so the news that it might create a condition that could kill a child was dismaying. A ginned-up surveillance project linking the 23 pediatric intensive care units in the United Kingdom uncovered 78 cases there by the second week of May—so many that 21 of the 23 hospitals admitted kids with the condition, at one point 32 in a single week.
Other reports rolled in—a death in France, a cluster in Italy—and in the US, the CDC put together what had been observed of the unusual condition and asked physicians to report cases that matched to state health departments. Coming up with a case definition is a first step in conducting surveillance for what might be a new disease. With it, the CDC learned by mid-May of more than 100 US kids with the condition, three of whom had died.
On August 7, the agency updated those numbers. As of the end of July, 570 US kids had experienced that constellation of shock, heart problems, and gastrointestinal problems; had blood work that indicated inflammation was going on in their bodies; and were positive for Covid-19. Many of them were seriously ill: 364 needed to be treated in an ICU, and 10 died. In many of them, several organs—heart, lungs, kidneys and brain—were affected, which earned the disorder its agreed-on new “multisystem inflammatory syndrome in children” name. Almost one in five of the survivors was left with kidney damage or with weakened arteries and aneurysms for which they will need long-term drug treatment and monitoring.
Many of those cases came through a research network that Randolph supervises, the Overcoming Covid project, which collects case reports from 70 pediatric referral hospitals across the US and is collecting blood and respiratory samples from patients to get ready to launch clinical studies in children with acute Covid-19 and with MIS-C. The network published its first accounting in June, uncovering 186 child and teen patients in 26 states and confirming the novel syndrome was causing “serious and life-threatening illness,” including four deaths. “I think people are very cognizant of this now,” Randolph says. “They’re recognizing less severe cases as well, and defining that there is a spectrum of illness.”
It seems clear at this point that MIS-C is not Kawasaki: The children affected by the new syndrome are school-aged and teenagers, whereas Kawasaki occurs mostly in toddlers. And almost every child reported with MIS-C shows evidence of having had a novel coronavirus infection, whereas the underlying cause of Kawasaki is unknown. But the similarities between the two are enough to light up the science of both.
“If you frame the question as, ‘Are these two diseases the same?’ the answer to that is: clearly not,” says Jane Burns, a professor of pediatrics and director of the Kawasaki Disease Research Center at the University of California, San Diego. “If by the same you mean, ‘Are these immunologic responses in specifically genetically susceptible children, that happened as a result of an exposure that these children had, and then they make an unusual immune response to that exposure?’ Then yes, they’re exactly the same.”
That could be a critical insight, because it’s actually not uncommon for children to have inflammatory responses to an infection, and for physicians to never figure out just what the cause was. Still, it could take a while for researchers to gather enough data to understand the immune processes that create MIS-C, even with the help of networks such as Randolph’s.
“Learning what a genetic predisposition might be requires tons of samples, because it’s unlikely to be due to a single rare mutation,” says Burns, who has seen 10 MIS-C patients in her center. As with Kawasaki disease, she said, “It’s likely to be a complex pathway” that allows for a range of responses, from very mild disease to the most serious versions that put children into ICUs.
Finding a genetic link will be challenging because, viewed simply by the numbers, MIS-C is rare, occurring in only about two children out of 100,000. Researchers worry, though, that it is not as unusual as those numbers make it seem, because the MIS-C case definition that causes a child to be counted requires proof of either infection or exposure—and as has been observed many times since the pandemic started, children can carry the virus without symptoms, so their cases are not consistently recognized or recorded.
That means the cohort of children who are at risk of developing the condition could be much larger than believed. Since its complications can include circulatory system damage that requires long-term monitoring, MIS-C is becoming a research priority. On the day the CDC released its updated numbers, officials at the National Institutes of Health announced they would fund a crash research program aimed at understanding what the trigger of MIS-C might be—whether that’s the coronavirus itself, a genetic quirk in some kids, co-infection with another virus, or some unknown environmental factor.
The project, which is based at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), is called the Predicting Viral-Associated Inflammatory Disease Severity in Children with Laboratory Diagnostics and Artificial Intelligence, which the institute has shrunk down to the acronym PreVAIL kIds. It plans to give up to $5 million in total, distributed to six teams over four years, to deploy AI and machine learning to identify genes or aspects of the immune system that could help explain, and also predict, the range of kids’ reactions.
“This is the beginning step to developing treatments, identifying these biomarkers and biosignatures,” says Bill Kapogiannis, a physician in the NICHD’s maternal and pediatric infectious disease branch. “We can treat stuff now, but it’s sort of shooting in the dark, because we don’t know exactly what we are trying to target. This is a stepping stone to developing treatments that are tailored.”
There’s another reason why MIS-C is becoming a research priority. The kids who have fallen ill with it developed its range of symptoms not immediately when they were infected, but two to four weeks afterward. That means it represents not a response to the initial infection, but a reaction by the immune system at some point after infection has resolved. This could be a red flag for any hoped-for Covid-19 vaccine: Since vaccines will try to provoke an immune response similar to what happens in infection, will they set up recipients for a post-infectious after-effect resembling MIS-C as well?
The immunologic phenomenon that could cause this is called “antibody-dependent enhancement,” or ADE. It’s a bizarre trick of the immune system that can happen at any age, in which previous exposure to a virus doesn’t protect someone against infection, but instead makes them more vulnerable. It’s a known complication of a few viral infections such as dengue, and a few immunizations against viruses, such as the vaccine for respiratory syncytial virus (RSV), a common and sometimes dangerous childhood lung infection.
Researchers are aware of the risk; several journals already have published articles asking whether ADE could be caused by a Covid-19 vaccine. The NICHD project hopes the research it intends to fund will further illuminate the risks; its Request for Applications names ADE as a potential consequence of vaccine deployment. “We hope this work will contribute to the body of knowledge that can help develop vaccines, particularly vaccines as we use them in children, because the immune system is a little bit different in children than it is in adults,” Kapogiannis says.
As far as anyone can tell, MIS-C by itself doesn’t represent ADE. But the fact that the syndrome arises as a delayed aftermath of infection indicates the immune processes causing it could take a while to develop. This could mean that an adverse reaction to a vaccine—if one even occurred—might be a slow-brewing thing too.
That could make kids, once thought to be safe from Covid-19, into canaries in the pandemic’s coal mine—early indicators of yet another uncertainty in the larger puzzle of the disease.
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