Respiratory syncytial virus (RSV) bronchiolitis : clinical and immunological determinants of short-term and long-term airway morbidity

Abstract

Respiratory syncytial virus (RSV) infection is the most frequent cause of lower respiratory tract infection (LRTI) during infancy. During the winter season RSV bronchiolitis is one the most common causes of hospitalization as well as mechanical ventilation (MV). Following RSV bronchiolitis 30-70% infants develop recurrent episodes of wheezing. The aim of this thesis was to study clinical and immunological predictors of short-term and long-term airway morbidity. New predictors will be useful in the clinical setting as well as understanding mechanisms underlying RSV bronchiolitis and the development of subsequent airway morbidity. Post-conceptional age in mechanically ventilated infants - New strategies have become available to prevent severe RSV infection in prematurely born infants, including palivizumab, a humanized monoclonal antibody. It is not known for how long prevention of RSV infection in preterm infants should be considered. It was shown that preterm infants, without chronic lung disease have increased risk for severe RSV infection until post-conceptional age reaches 44 weeks. Cell-mediated immunity to RSV - We compared the immune response in the blood and nasopharyngeal aspirates between RSV-infected infants with and without the requirement of MV. In vivo IFN-? levels in the nasopharynx were lower in RSV-infected infants requiring MV. In addition, we have shown that monocyte interleukin (IL)-12 production was inversely related to duration of MV. Taken together, these data suggest that severe RSV LRTI is associated with decreased level of CMI and that initiation of CMI is required for the convalescence of MV during RSV LRTI. Prediction of long-term airway morbidity - Studies in the past have shown that clinical parameters, such as sex, age at onset of RSV LRTI and disease severity during RSV LRTI are not related to long term airway morbidity. We demonstrate that airflow limitation during RSV LRTI is the first useful clinical predictor for subsequent recurrent wheezing. Monocyte IL-10 production and long-term airway morbidity – We have shown that monocyte IL-10 production in the blood during the convalescent phase of RSV LRTI predicts subsequent recurrent wheezing. This is one of the major findings presented in this thesis. Conclusion This thesis has provided new determinants of short-term and long-term airway morbidity associated with RSV LRTI. Findings lead to the conclusion that antigen-presenting cells (APC) could play an orchestrating role in the immune response during RSV bronchiolitis. Therefore, we conclude that future research should focus on the role of APC, including dendritic cells, in the pathogenesis in RSV LRTI.