Patient-oriented research of infections in hematopoietic stem cell transplantation (HCT) provides the opportunity to directly affect outcome of HCT recipients. Infections continue to be a major cause of morbidity and death after HCT. This award will provide protected time for the applicant to mentor trainees in clinical research that is directly related to understanding the biology of infections after HCT. Results will provide the basis for translation into improved management strategies. This proposal will address three areas of transplant infectious diseases: respiratory virus infections, genetics of infections, and factors associated with outcome of infectious diseases.
The Specific Aims are: 1. To determine the spectrum virologic chracteristics, and risk factors of recently discovered respiratory viruses after HCT, including human metapneumonovirus, coronaviruses (including (NL63, HKU1), rhinoviruses and bocavirus. Studies of these viruses will be done using a prospective observational cohort of 500 HCT recipients who are undergoing weekly PCR surveillance for 12 viruses and assessment of respiratory symptoms. 2. To determine the impact of donor and recipient innate genetic factors on the risk and outcome of infectious complications following HCT by genome-wide analysis and subsequent validation in separate cohorts. Hole genome data are available for 1500 patient/donor pairs. Associations of polymorphisms with infections will be analyzed and validated in separate cohorts. 3. To conduct outcome studies of invasive infections after NCT. We will evaluate pathogen burden, with CMV viral load as an example, as a variable that determines overall outcome of HCT in the current era of antiviral preemptive therapy. We will also determine factors associated wit the outcome of invasive diseases. Using large databases, we will assess factors associated with response to treatment of CMV gastrointestinal disease and RSV pneumonia (using an internet-based survey administered to transplant centers worldwide).

Public Health Relevance

These aims support an innovative approach toward patient-oriented research in the field of transplant infectious disease by utilizing state-of-the-art methodologies including quantitative molecular diagnostics, whole genome analysis, and internet-based data collection for rare disease. The studies conducted under these aims have a high potential of advancing our knowledge of the spectrum of infectious complications, the genetic basis of diseases, and factors that affect outcome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL093294-04
Application #
8296661
Study Section
Special Emphasis Panel (ZHL1-CSR-R (F1))
Program Officer
Welniak, Lisbeth A
Project Start
2009-09-03
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$187,807
Indirect Cost
$13,912
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Seo, Sachiko; Gooley, Ted A; Kuypers, Jane M et al. (2016) Human Metapneumovirus Infections Following Hematopoietic Cell Transplantation: Factors Associated With Disease Progression. Clin Infect Dis 63:178-85
Green, Margaret L; Leisenring, Wendy; Xie, Hu et al. (2016) Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol 3:e119-27
Sedlak, Ruth Hall; Hill, Joshua A; Nguyen, Thuy et al. (2016) Detection of Human Herpesvirus 6B (HHV-6B) Reactivation in Hematopoietic Cell Transplant Recipients with Inherited Chromosomally Integrated HHV-6A by Droplet Digital PCR. J Clin Microbiol 54:1223-7
Fisher, Cynthia E; Preiksaitis, Carl M; Lease, Erika D et al. (2016) Symptomatic Respiratory Virus Infection and Chronic Lung Allograft Dysfunction. Clin Infect Dis 62:313-9
Hill, Joshua A; HallSedlak, Ruth; Magaret, Amalia et al. (2016) Efficient identification of inherited chromosomally integrated human herpesvirus 6 using specimen pooling. J Clin Virol 77:71-6
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
Inamoto, Yoshihiro; Martin, Paul J; Flowers, Mary E D et al. (2016) Genetic risk factors for sclerotic graft-versus-host disease. Blood 128:1516-24
Cohen, S A; Woodfield, M C; Boyle, N et al. (2016) Incidence and outcomes of bloodstream infections among hematopoietic cell transplant recipients from species commonly reported to be in over-the-counter probiotic formulations. Transpl Infect Dis 18:699-705
Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu et al. (2016) Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 22:925-31
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

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