A research team has discovered important clues that could help explain why some children with respiratory syncytial virus (RSV) infections get mild cases while others get more severe disease and require hospitalization. Their new research was published in the April 22 issue of Science Translational Medicine.
The results identify some surprising features in the immune response to RSV and could inform the development of a historically elusive vaccine for the disease. Although more work is needed, the authors speculate their discoveries might help researchers answer how other viral infections such as COVID-19 affect older children differently than adults and children under one year of age.
RSV is one of the most frequent infections in children, prompting more than 2.1 million medical visits among children younger than five years old, according to the Centers for Disease Control and Prevention. Although symptoms are usually mild, RSV still represents the most frequent cause of hospitalization in newborns in developed countries, causing over 57,000 hospitalizations among children younger than five years annually.
The virus also poses a substantial problem for older adults. The CDC estimates that RSV results in 177,000 hospitalizations and 14,000 deaths among adults over 65 each year.
Despite the massive health burden of RSV, scientists still don't fully understand why some children get mild infections while others get severe cases. Most children with RSV who end up in the hospital don't have preexisting conditions, according to the study, suggesting there may be other variables at play.
Previous studies have hinted that factors ranging from age to the amount of virus in the body can influence the severity of infections, according to the study. Researchers also suspect that more severe cases are tied to abnormal responses from the immune system, but they haven't defined exactly what these responses are and why they occur.
The development of safe and effective vaccines for RSV has been seriously held back by the lack of biological markers for severe cases, according to Asuncion Mejias, principal investigator at The Research Institute at Nationwide Children's Hospital in Columbus, OH and senior author of the new study.
"Defining the differences in immune responses and viral replication between these two groups of patients is critical to understand the mechanisms of protection against this virus and should help when designing protective vaccines," she said.
To investigate, Santtu Heinonen, a researcher at The Research Institute at Nationwide Children's Hospital in Columbus, Ohio, and colleagues studied the composition of immune cells and the activity of immune-related genes in blood samples from a group of 190 young children, including 125 children with RSV infections and 65 healthy children.
Surprisingly, the authors saw that children who developed mild cases actually had higher amounts of virus compared with children who required hospitalization. In the mild cases, children were more likely to also be infected with rhinovirus — which causes the common cold — or another respiratory virus.
The research team probed further and determined there were specific patterns in the innate immune response — one of the two major defensive components of the immune system — that correlated with mild symptoms.
The children with mild cases displayed higher activity of genes involved in the production of interferons — molecules that are important in the innate immune response — but had less expression of inflammatory genes. In contrast, the hospitalized children showed an uncontrolled inflammatory response, and displayed poorer activation of immune cells called monocytes, according to Mejias.
The authors say their findings support a key role for innate immunity in determining the severity of RSV infections. They add their results could help the design of clinical studies to evaluate new vaccines and antivirals against RSV, which has no curative treatments and no effective vaccine.
"These findings are important for designing groups of patients in the context of clinical trials studying antiviral agents for RSV and other respiratory viral infections in children," said Mejias.
Although the study looked specifically at RSV infections, Mejias is convinced that her team's work could offer a template to understand how the immune system interacts with other respiratory infections such as COVID-19.
As the COVID-19 pandemic continues to evolve, scientists have observed that children tend to show milder symptoms than adults and seem to be at lower risk of severe infections. Researchers still don't understand why this is, and it's also mysterious why many infants and children under the age of five seem to be more vulnerable to the new virus than children over five.
"Understanding how SARS-CoV-2 activates or suppresses the immune response in children of different ages will help to uncover the immune mechanisms associated with protection against severe COVID-19 in children," said Mejias. "Those findings could be relevant as surrogates of the immune response that a protective and safe COVID-19 vaccine should induce."