This proposal describes a five-year research training program that will allow me to achieve my goal of becoming an independent clinically-oriented academic researcher, focusing on respiratory viral infections in immunocompromised hosts. My goal is to improve patient transplant-related infectious disease outcomes through better defining risks for poor outcomes in human rhinovirus (HRV) and other respiratory viral infections, and applying this knowledge to develop biomarkers for disease severity. This proposal builds upon my training in clinical infectious diseases, epidemiologic and biostatistical methods and laboratory-based science, and provides a detailed plan to improve my knowledge of virology, immunology and genetics, conducting prospective cohort studies, and gene expression statistical analysis. This proposal incorporates the expertise of an outstanding group of mentors, including experts in infectious diseases, epidemiology, statistics, and data modeling, who are dedicated to ensuring the success of this project and the development of my career as an independent clinical researcher.
The first aim of this proposal involves the analysis of viral factors that determine disease severity in HRV infection. Specifically, I will determine the role o viral load in serum and respiratory samples, viral species type, and viral shedding on disease outcomes including progression to lower tract disease and mortality. The success of this proposal is bolstered by the unique opportunity to perform uniform molecular testing on both retrospectively and prospectively collected specimens from a large cohort of patients, allowing the opportunity to develop multivariable models and adjust for multiple clinical covariates. For my second aim, I will identify host factors through the analysis of cytokine profiles and gene expression profiles that determine disease severity. Again utilizing access to a large cohort of HCT recipients and established prospective sample collection protocols, I will be able to develop robust biomarkers that will provide important insight into biologic pathways during HRV infection in immunocompromised hosts. Through accomplishing the aims in this proposal, I will contribute significantly to our knowledge of the impact of HRV infection in transplantation, and our ability to use viral and host biomarkers to predict disease severity. Despite improvements in transplant practices, HRV remains a significant cause of infectious mortality in HCT recipients. Identification of biomarkers has the potential to guide early and specific diagnostic tools and wil provide a basis to develop prevention and treatment strategies. Ultimately, the proposal will allow me to develop a larger research program to improve our understanding and affect outcomes of respiratory viral infections in immunocompromised hosts, which can then be applied to other vulnerable populations including infants, the elderly, and individuals with preexisting heart or pulmonary conditions.

Public Health Relevance

Human rhinovirus (HRV) is now the most common respiratory virus detected in hematopoietic cell transplant (HCT) recipients. Despite advances in transplantation practices, HRV causes significant morbidity and mortality in in this population, with mortality rates following HRV pneumonia similar to those seen with known pulmonary pathogens including respiratory syncytial virus, influenza virus, and parainfluenza virus. This proposal seeks to define the viral and host related biomarkers that determine disease severity in HCT recipients with HRV infection. Identification of risk factors has the potential to guide both early and more specific diagnostic tools for risk stratification and to provide the critical basis o develop rational prevention and treatment strategies for immunocompromised patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AI114844-04
Application #
9388307
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Hauguel, Teresa M
Project Start
2014-12-11
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98101
Greninger, Alexander L; Waghmare, Alpana; Adler, Amanda et al. (2017) Rule-Out Outbreak: 24-Hour Metagenomic Next-Generation Sequencing for Characterizing Respiratory Virus Source for Infection Prevention. J Pediatric Infect Dis Soc 6:168-172
Waghmare, Alpana; Englund, Janet A; Boeckh, Michael (2017) Parainfluenza Virus 3-Specific T Cells: Opportunity for Intervention? J Infect Dis 216:147-149
Ogimi, Chikara; Waghmare, Alpana A; Kuypers, Jane M et al. (2017) Clinical Significance of Human Coronavirus in Bronchoalveolar Lavage Samples From Hematopoietic Cell Transplant Recipients and Patients With Hematologic Malignancies. Clin Infect Dis 64:1532-1539
Waghmare, Alpana; Xie, Hu; Kimball, Louise et al. (2017) Supplemental Oxygen-Free Days in Hematopoietic Cell Transplant Recipients With Respiratory Syncytial Virus. J Infect Dis 216:1235-1244
Ogimi, Chikara; Greninger, Alexander L; Waghmare, Alpana A et al. (2017) Prolonged Shedding of Human Coronavirus in Hematopoietic Cell Transplant Recipients: Risk Factors and Viral Genome Evolution. J Infect Dis 216:203-209
Waghmare, Alpana; Englund, Janet A; Boeckh, Michael (2016) How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation. Blood 127:2682-92
Waghmare, Alpana; Pergam, Steven A; Jerome, Keith R et al. (2015) Clinical disease due to enterovirus D68 in adult hematologic malignancy patients and hematopoietic cell transplant recipients. Blood 125:1724-9