Treatment of RSV Bronchiolitis with NSAIDs

DESCRIPTION (provided by applicant): Respiratory Syncytial virus (RSV) is the leading viral cause of death in children under 1 year and is an increasing cause of morbidity and mortality in transplant patients and the elderly. RSV causes upper and lower respiratory tract infections, occasionally leading to severe bronchiolitis and pneumonia. There is no safe and effective vaccine against RSV. Anti-RSV immunotherapy, although effective in prophylactic settings, does not provide any clinically beneficial outcome when applied therapeutically, indicating that RSV-induced pathology is mostly the result of the inflammatory response to infection rather than a direct viral effect. A combined antiviral and anti-inflammatory therapy might represent the most safe and efficient treatment against RSV infection. The expression of COX-2 and its products, prostaglandins and thromboxanes, has been correlated with the development of many inflammatory processes. Our recent studies in the cotton rat, the animal model of choice for previous studies of RSV immunoprophylaxis, strongly support our hypothesis that induction of COX-2 during RSV infection plays a pivotal role during RSV-induced inflammation and pathology and, conversely, that inhibition of COX-2 activity is a beneficial treatment for RSV-induced bronchiolitis. This application is designed to determine efficacy and safety profiles for COX-2 specific, non-steroidal anti-inflammatory drug (NSAID) treatment of RSV-induced lung pathology. Our hypothesis is that inhibition of COX-2 activity generated during RSV infection will be of therapeutic benefit during acute RSV disease, preventing the development of inflammation and pathology. The experiments will focus on primary RSV disease, with two goals in mind. The first will be to determine if COX-2 inhibition can by itself be an effective and safe treatment regimen during the acute phase of primary RSV infection. The second will be to determine whether treatment with COX-2-specific inhibitors can be complemented with antiviral therapy to improve the final outcome of RSV disease. These studies will involve correlating treatment of RSV-infected animals with pulmonary histopathology and inflammation.