Courtesy of Sarah Eisenberg

Although risk for hospitalization and death due to COVID-19 increases with age, children seem to be susceptible to a rare but serious condition called multisystem inflammatory syndrome, or MIS-C, which typically manifests a few weeks after infection with COVID-19.

Scientists and physicians have struggled to understand what causes MIS-C, as well as why it affects children but not adults. In a quest for answers to the many questions surrounding this syndrome, along with collaborators at clinical centers including the Yale New Haven Hospital and the Yale School of Medicine, associate professor of immunology Carrie Lucas, clinical fellow and pediatric intensivist Nina Brodsky and PhD candidate Anjali Ramaswamy GRD ’24 immunologically profiled the disease. Though they were not pursuing specific hypotheses to begin with, their findings provide evidence for unique immune cell signatures while pointing to a number of future directions for further studies on MIS-C.

“The challenge is really trying to separate what is cause of this inflammatory condition, and what is consequence,” Lucas said. “In the end, we’re just looking at a picture of what the immune cells look like. Is that picture sort of painted early on and that’s causing this immune disease, or is what we’re picturing happening after the inflammation itself caused changes?”

Part of what is so difficult about unraveling medical mysteries such as MIS-C, Lucas described, is finding where to start. While their goal was to develop a better understanding of the condition, the absence of a specific hypothesis to pursue and the fact that they had limited samples, which had to be collected from sick children, motivated her team to try to retrieve as much information as possible. Their goal was to let “the patients teach us what’s going on with their immune system,” Lucas said.

To Lucas, the most puzzling aspect of MIS-C is the time delay between when children have COVID-19 and when they develop the inflammatory condition.

“These kids often have asymptomatic or very mild SARS-CoV-2 infection, many of them didn’t know they even had the infection, until about a month later, when they show up with this abdominal pain, diarrhea, fever and they get diagnosed with MIS-C,” Lucas said. “What is happening in this four-week period to cause these kids who were fine when they had the viral infection, and fine shortly thereafter, but then acutely sort of fall off a cliff?”

In an effort to understand this and other questions, methods including single-cell RNA sequencing were used, which help scientists understand which genes are being expressed by cells, and serum proteomic analysis, which allows for proteins in a sample to be identified and quantified. The data that resulted “inundated” the team with information, Lucas said.

The patterns they uncovered included signs of potential autoreactivity — these children’s cells could be attacking their own tissue, seeding an autoinflammatory nightmare. Looking at antibody-secreting cells, the team found that a type of immune cell called plasmablast, which later develops into immune cells that produce antibodies, were expanding in the blood. Lucas explained that while this sort of response is usually expected during infection, in this case, it was observed weeks later, during acute illness with MIS-C.

To Ramaswamy, one of the most interesting results of their study, which was consistent with recent research in MIS-C, was a notable T-cell response to an unclear stimulus. She and Lucas hypothesized that this could have something to do with a superantigen response — a reaction of the immune system to bacterial toxins that could be present somewhere in the body, such as the gut microbiome.

Ramaswamy explained that superantigens can bind to TCR sequences, which are the receptors located on the surface of T cells. According to Lucas, these TCR sequences have a V-beta chain, which is a structure that allows these immune cells to recognize disease-causing agents. The fact that the T cells that are responding in bulk have this chain could mean that they are reacting to a supposed superantigen.

“My favorite hypothesis is that the antibodies we see in this expansion of plasmablasts may actually be secondary to tissue damage,” Lucas said. “Because the kids are so inflamed, their tissues get damaged and now more of their self-tissue is accessible to the immune system and we get this burst of autoreactivity, so that leaves open the question of what caused the tissue damage to begin with.”

Brodsky, who has been working on the frontlines as an intensivist since the beginning of the pandemic, explained how she cared for children and young adults at the Yale New Haven Children’s Hospital who presented with the typical respiratory symptoms of COVID, but also those with MIS-C.

According to Brodksy, YNHCH saw a peak of MIS-C cases around May of last year and continued to contend with trickles of it following the big waves of adult COVID-19. 

“When you do see a child with MIS-C, they often present critically ill,” Brodsky said. “This post-infectious syndrome really sets off a shock state.”

Comparisons have often been drawn between Kawasakii’s disease, which is also an inflammatory disease, and MIS-C. Though both diseases affect children, Brodsky explained, Kawasaki tends to present in those younger than five while MIS-C has been observed in school-aged children and teenagers. 

Ramaswamy pointed out that a unique aspect of the pandemic is that many people are falling ill in a synchronized fashion. Because of the nature of COVID-19 and how it spreads, the progression of the disease in different patients has, in many ways, become temporally synchronized. This phenomenon could help scientists understand how this disease progresses over time, she said.

“When something comes along like this it changes your perspective a little bit on what those questions are and how far we need to go in terms of our fundamental understanding,” Ramaswamy said. “It just goes to show how much we know, but also how little we know immunologically. The fact that MIS-C is puzzling means that there is important immunology left to be uncovered.” 

While immunological studies have been fundamental in answering perplexing questions that COVID-19 has raised, the coronavirus itself has also been laying bare how much remains to be understood when it comes to the human immune system, Ramaswamy explained.

Another area of interest is the demographic pattern of MIS-C. According to the CDC, as of March, 63 percent of all children who had MIS-C in the United States had been either Black, Latino or Hispanic. A study from the end of last year by Yale assistant professor of pediatrics Carlos Oliveira found 3 out of 4 children hospitalized with either acute COVID-19 or MIS-C in eight hospitals in the tristate area were Black or Hispanic.

Lucas, Ramaswamy and Brodsky emphasized that researchers are interested in understanding why it seems like MIS-C is impacting children from these groups more dramatically. From exploring whether this is due mostly to social determinants of health, or whether there could be a biological signature to explain this discrepancy, scientists need to unpack the reason why they seem to be more affected. 

The CDC reports that there have been 3,185 pediatric cases and 36 deaths of MIS-C in the United States since the beginning of the pandemic.

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