When an unusually severe wave of respiratory syncytial virus swept through hospitals in 2022, striking children far harder than the disease typically does, researchers at the University of Connecticut suspected something had changed in the virus itself. Steven Szczepanek, an associate professor in the Department of Pathobiology and Veterinary Science, and Dr. Ian Michelow, head of pediatric infectious diseases and immunology at Connecticut Children's, began investigating whether the virus had mutated—and their hunch proved correct.
RSV is ordinarily a childhood rite of passage: most children catch and recover from it by age three, with little fanfare. But 2022 was different. The early, severe outbreak overwhelmed hospitals across the region, suggesting that something about the virus had shifted. Szczepanek and Michelow knew that RSV, like many viruses, mutates readily because it lacks the cellular "proofreading" enzymes that protect human and animal DNA from copying errors during replication.
Working with Dr. Kevin Dieckhaus, head of infectious diseases at UConn Health, the team collected samples from both pediatric and adult patients during the end of the 2022–23 respiratory disease season. Then came the meticulous work of comparison: analyzing genetic sequences from children who experienced mild cases side by side with those who suffered severe illness. The pattern that emerged was striking. "There were 19 mutations that were consistently different between the kids that had mild disease and those that had severe disease," Szczepanek says. "It was the same mutations in the kids with severe disease that were different than those that had mild disease."
The implications became clearer when the researchers cultured these viral samples in the laboratory. The viruses carrying the mutations linked to severe illness replicated at rates that dwarfed the mild-case samples—between 10 and 100 times faster in the same span of time. This explosive replication rate, driven by mutations in genes controlling viral reproduction, proved telling. "Generally speaking, the faster virus replicates, the more virulent it is, because it can create more copies of itself in a given period of time," Szczepanek explains. "And the more copies of a virus you have in your body, generally speaking, the worse off you are."
These findings, published as a preprint on bioRxiv, offer a concrete step toward answering one of pediatric medicine's frustrating mysteries: why some children breeze through RSV with mild cold symptoms while others end up in intensive care. "We don't know why one child will have a mild cold, whereas another child may need to go to the ICU for care," Michelow says. "That's always been a challenge in the field, and if you can predict which children are going to get sicker, that's really important, because then you can offer greater supportive care up front."
Looking ahead, the researchers are exploring whether new RSV vaccines for pregnant mothers and newborns could inadvertently drive mutations—a trade-off worth understanding even as these vaccines protect infants. The team is also extending their work to adults over 65, who can face severe RSV complications, partnering with Hartford Hospital and St. Francis Health Center to examine patient records and uncover whether the same mutations that threaten children pose similar risks to older populations.