Pediatric lung transplantation treats end-stage lung disease of diverse etiologies in recipients with potential for normal extrapulmonary organ function and development. However, unlike other solid organ recipients, frequencies of adverse outcomes in pediatric lung transplant recipients have not declined over the last decade. Evidence from animal models and limited data in humans support a link between respiratory viral infection (RVI) and adverse allograft outcome due to virus-induced intragraft inflammation and to stimulation of graft-directed alloimmune, autoimmune, and innate immune responses. The recent development of sensitive, high throughput molecular RVI detection methods and immune monitoring techniques permits comprehensive, prospective evaluation of the immune-mediated contribution of RVIs to morbidity and mortality in pediatric lung transplant recipients. We propose to test the hypothesis that post transplant pulmonary respiratory viral infections negatively impact outcomes in pediatric lung transplant recipients by stimulation of innate, cellular, and humoral immune responses. In our observational clinical study, we will use a 6 center Pediatric Lung Transplant Consortium that includes 5 core laboratories, a prospective observational study design of first pediatric lung transplant recipients, and comprehensive molecular viral detection methods to assess RVIs as a risk factor for reaching a primary, composite clinical endpoint of bronchiolitis obliterans, death, and re-transplantation. In the accompanying mechanistic study, we will use state-of-the-art immune assays to assess mechanisms of graft injury in pediatric lung transplant recipients with and without RVI. Our Pediatric Lung Transplant Consortium provides access to a cohort size (N=80) necessary to achieve sufficient statistical power to detect differences in outcome between pediatric lung transplant recipients with and without RVIs and is experienced in performance of time-dependent analyses of innate, cellular, and humoral immune responses necessary to define underlying mechanisms. The results of these studies will lead to the design of innovative viral detection and immune monitoring schema that can be directly integrated into clinical decision-making to predict individualized risk of adverse outcomes and will suggest novel therapeutic targets to improve pediatric lung transplant outcomes. Outcomes of pediatric lung transplant recipients (rejection, death, or re-transplantation) have not improved over the last decade. Using state of the art methods, we will study the ways that common lung viral infections in children cause rejection of transplanted lungs. By determining the rejection-associated viruses and immune responses, these studies will provide new strategies for early diagnosis and preventative treatment that will improve outcomes in pediatric lung transplant recipients.
