UB Study Shows Pretreatment Drug for RSV-Related Wheezing also is Effective After Symptoms Set In

BUFFALO, N.Y. -- Infectious disease specialists at the University at Buffalo have demonstrated a potentially effective treatment to prevent the frequently life-threatening complications that can develop in infants from infection with respiratory syncytial virus (RSV), a significant cause of infant deaths around the world.

Using mice as an animal model, the researchers showed that treatment with the drug zileuton after RSV infection had taken hold reduced the production of proinflammatory compounds called cysteinyl leukotrienes (LT), known to promote the airway congestion and constriction that causes wheezing.

The results were the first to show that inhibition of LT release with zileuton also reversed the rapid respirations occurring in mice with RSV infection.

Results of the study were presented May 4 at the Pediatric Academic Societies meeting in Seattle.

"RSV is the most common cause of hospitalization in infants and children," said Robert C. Welliver, M.D., professor of pediatrics in UB's School of Medicine and Biomedical Sciences, and lead author on the study.

"Two to three percent of all infants in the U.S. are hospitalized each year for this infection, and it is a significant cause of infant mortality worldwide," he said. "From a humanitarian and financial standpoint, the cost is huge, and there is no vaccine."

Earlier research by Welliver and colleagues had shown that pretreating mice with zileuton before exposing them to RSV prevented development of much of the respiratory illness usually associated with the virus. They undertook the current study to determine if the drug would be equally effective when administered after the infection had taken hold.

The study involved two groups of mice that received zileuton after being infected with RSV, as well as mice that were infected, but received no treatment, and that served as controls. One treatment group received the drug on days 3-5 after being infected with the virus, the other received the drug from days 3-9. All mice were monitored for nine days. Researchers collected data on respiratory rate and airway resistance before infection and throughout the trials. The mice also were weighed daily (infants often lose weight during this illness.)

Results from the first group showed that administering the drug for three days significantly reduced airway resistance, but had little effect on respiration rates. Improvement in respiration rates was seen in the second group on days 6-9 of treatment, but continuing treatment this long didn't provide any additional improvement in airway restriction.

Animals receiving treatment lost less weight and were more active than untreated mice, results showed. Treated animals also had fewer inflammatory cells in their lung tissue.

Zileuton currently is approved by the FDA for use in persons 12 and older as a pretreatment to prevent wheezing and other asthma symptoms in persons at risk. It is not approved for use once symptoms of airway constriction have set in. Welliver said trials are underway with similar drugs in children as young as 2, and trials in 6-month-olds are set to begin in the fall.

"This study demonstrates that LT inhibition would not only be effective for prevention of severe RSV disease in groups of infants known to be at risk, but also for treatment of infants with already established, early RSV disease," said Welliver.

Also contributing to the study were Karen H. Hintz and Maria Glori, assistants in Welliver's lab.