This K23 proposal describes a five-year research training program that will foster Dr. Fisher?s transition into an independent clinically-oriented academic researcher, focusing on viral infections in transplant recipients. Her long-term objective is to improve outcomes following transplantation by performing translational research to define the role of viral infections in chronic lung allograft dysfunction (CLAD). This award will provide the support needed to improve her knowledge in three major areas: 1) prospective cohort design and enrollment, 2) pulmonary transplant, and 3) statistical analysis and modeling of complex data sets. This proposal builds upon her preliminary research and her strong foundation in infectious diseases, epidemiology, and biostatistics. She has assembled an outstanding group of mentors who are dedicated to ensuring the success of her research and her career development, and who have expertise in virology, transplant, pulmonology, immunology, epidemiology, and biostatistics. Dr. Fisher?s goal in this proposal is to define how specific viral and host characteristics, and early pulmonary functional changes, associate with CLAD development in LTR with respiratory virus infection (RVI). In the first aim, Dr. Fisher will prospectively enroll LTR with symptomatic RVI and collect frequent longitudinal nasal swabs, using an innovative patient self-collection methodology, and home spirometry. She will: 1) characterize the detailed virologic course of symptomatic RVI in LTR, including virus type, peak viral load, duration of shedding, rate of viral load change, and area under the curve, 2) Define the course of early lung function changes after RVI, as evidenced by the forced expiratory volume in one second (FEV1), and 3) analyze the association between virologic characteristics and early decline in FEV1. In her second aim, she will use the detailed virologic information from her first aim to identify specific viral and host determinants of CLAD in LTR with symptomatic RVI. In her third aim, she will analyze the detailed spirometry data to assess how the degree and magnitude of early decline in FEV1 after RVI is related to subsequent development of CLAD. Through accomplishing the aims in this proposal, Dr. Fisher will identify virologic, host, and early FEV1 characteristics associated with RVI that can predict subsequent development of CLAD. She will also refine a self-collection method that can be used for future longitudinal RVI studies and provide critical background data on the virologic course of RVI that can be used for the rational design of future interventional trials of novel antiviral agents. Ultimately, this proposal will allow Dr. Fisher to hone her skills as a clinical investigator and transition into an independent researcher who will advance our understanding of viral infections in transplant recipients to improve patient outcomes.
Outcomes following lung transplant are significantly worse than all other organ transplants, with approximately 50% mortality at 5 years. Chronic lung allograft dysfunction (CLAD) is the most common cause of lung graft failure and death following transplantation, but the underlying risk factors are poorly understood. Respiratory virus infection (RVI) is strongly associated with CLAD, and this proposal will characterize the viral and host determinants of CLAD development, and analyze if decreases in lung function directly after RVI can predict future CLAD.
