For months now during the COVID-19 pandemic, doctors have observed a rare but consistent scenario in a small number of kids: It starts with a SARS-CoV-2 infection, which can be mild, even asymptomatic. But weeks after the children seem to have fully recovered, they suddenly come down with symptoms that may include fever, vomiting, diarrhea, and severe abdominal pain.
“They had the infection, they got through it. And then all of a sudden . . . they can have this collapse in their bodies a few weeks later,” says Alvaro Moreira, a neonatologist at the University of Texas Health San Antonio who recently coauthored a review on the condition, known as multisystem inflammatory syndrome in children (MIS-C).
MIS-C is rare, and not all children who become severely ill or die from COVID-19 develop it. According to the Centers for Disease Control and Prevention (CDC), fewer than 1,000 cases of MIS-C have been reported so far in the US, the country hardest-hit by the COVID-19 pandemic, with 19 deaths. Early reports of cases of MIS-C pointed to similarities between it and Kawasaki disease, a rare condition linked to viral infections that involves inflammation in the blood vessels. But there were notable differences observed between the two, such as the fact that Kawasaki mainly affects children under five, while even teenagers have come down with MIS-C. A study published earlier this month in Cell examines the similarities and differences between MIS-C and Kawasaki, as well as immune responses to COVID-19 in children and adults, to find unique features of the new condition and clues to the immune missteps that bring it about.
“I think that everyone has been waiting for something like this,” says Moreira of the work, which he was not involved in. “This one is the first study that I’ve really seen that is looking at pathways, signaling mechanisms. . . . It’s still premature, but it will start to tell us a little bit more about what is happening at the molecular level.”
The study team had been investigating Kawasaki disease before the pandemic, and had collected blood samples from 28 children with the condition between 2017 and 2019. They compared levels of white blood cells and proteins in those samples with those of 12 healthy children, 13 with MIS-C, and 41 with COVID-19 who did not develop MIS-C, along with 17 adults with severe COVID-19.
“One of the first things that happened when these kids [with MIS-C] started coming into the hospital was that people said, ‘Well, maybe we should treat them the same way as we treat adults with severe disease,’” says coauthor Petter Brodin, a pediatric immunologist at the Karolinska Institute and the Karolinska University Hospital in Sweden. But the study found that the inflammatory response in MIS-C is “completely different,” he adds, indicating that it should probably be treated differently. Specifically, the severe adult COVID-19 patients and MIS-C cases had much different blood levels of the cytokines used to guide the immune response, particularly interleukin (IL)-8 and IL-7—both of which are associated with, among other things, the number of infection-fighting immune cells available in the blood. Levels of both of those cytokines were higher in adults with COVID-19 than in either Kawasaki or MIS-C patients.
Brodin and his coauthors found more overlap in the profiles of MIS-C and Kawasaki disease than they did with MIS-C and severe COVID-19 in adults. MIS-C and Kawasaki both had lower overall numbers of T cells compared with healthy children. Both conditions also involved the presence of antibodies to some of the body’s own proteins, known as autoantibodies, Brodin notes. “Some of them overlapped between MIS-C and Kawasaki, and some were unique to MIS-C, and we didn’t see them in any of the other groups,” he says, which “suggests that there’s a pathological process induced by [SARS-CoV-2] that is unique to this particular virus.”
One possible explanation, he says, has to do with a phenomenon other studies have observed: that SARS-CoV-2 tamps down an early, innate immune defense cells mount to viral infections, known as the interferon response. That could lead to a scenario where, in the later adaptive immune response, T cells and antibody-producing B cells “potentially then have a less-focused response and more of a wide response that might cross react and lead to autoimmunity,” he says, adding that this has yet to be proven.
Another hypothesis, put forward in a study published yesterday in PNAS, is that a unique part of SARS-CoV-2’s spike protein acts as a so-called superantigen that causes an excessive adaptive immune response. Brodin says the idea is “interesting,” but adds that in his opinion, “the evidence in the paper are not strong enough to conclude that this is the principal mechanism” in causing MIS-C.
The finding from Brodin’s Cell study that there are clear differences between the proteins found in the blood of Kawasaki and MIS-C patients jibes with what Betsy Herold, a pediatric infectious disease physician and virologist at Albert Einstein College of Medicine and Montefiore Health System, has seen in the clinic, she says. (Herold was not involved in the Cell study.) That finding, she says, “is very important, because I think there’s a lot of confusion out there [about], is this Kawasaki? And I think the answer is no, it has some overlap with Kawasaki, but it’s not the same thing.”
Herold, along with her spouse Kevan Herold, an immunobiologist at Yale University, recently led their own study that touched on MIS-C, although its primary aim was to ferret out differences in the immune responses to SARS-CoV-2 between children and adults. In that study, the cytokine responses of infected children who later went on to develop MIS-C matched those of kids who did not, leading Betsy Herold to think that both groups of patients do indeed mount an effective innate response initially. “We postulate that [the MIS-C patients] made a good innate response and that they protected their lungs from disease, and then . . . a few weeks later, when their antibody responses start kicking in, there’s something else that’s perhaps a little bit dysregulated,” she says. But, notes Kevan Herold, “I think we still don’t have a completely clear answer” on what it is that causes some children to develop MIS-C after a SARS-CoV-2 infection, while most don’t.
The good news, says Moreira, is that “even though we still don’t completely understand a lot of the mechanistic drivers of the disease, [MIS-C patients] are responding to common therapies that we use for Kawasaki disease.” These include intravenous immunoglobulin and steroids. “So they work, but I think we would feel more comfortable if we knew how, exactly, they work.”
C.R. Consiglio et al., “The immunology of multisystem inflammatory syndrome in children with COVID-19,” Cell, doi:https://doi.org/10.1016/j.cell.2020.09.016, 2020.
C.A Pierce et al., “Immune responses to SARS-CoV-2 infection in hospitalized pediatric and adult patients,” Sci Transl Med, doi:10.1126/scitranslmed.abd5487, 2020.