Patient-oriented research of infections in hematopoietic 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 renewal 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 wil provide the basis for translation into improved management strategies. This proposal will address four areas of transplant infectious diseases: respiratory virus infections, genetics of infections, the microbiome, and human herpesvirus 6 (HHV- 6) disease manifestations.
The Specific Aims are:
Specific Aim 1. To investigate clinical, host and viral factors affecting advers outcomes in HCT recipients with human rhinovirus (HRV) infection, which is now the significant cause of upper and lower respiratory tract disease after HCT. In large cohort study (N=1750) we will define risk factors for progression from upper to lower respiratory tract disease (LRD). We will also examine the role of host responses (cytokines, gene expression profiles) in patients with HRV and correlate with clinical symptoms and outcomes (progression, mortality), and determine the impact of viral load, strain differences and viral shedding on disease progression, morbidity, and mortality.
Specific Aim 2. To determine the impact of donor and recipient innate genetic factors on the risk and outcome of infectious complications following HCT. Using a unique cohort of 5000 donor and recipients we will perform genome-wide association studies. We will define and validate invasive aspergillosis (IA) phenotypes based on fungal antigenemia and clinical outcomes, and then define genetic variants that increase risk for IA acquisition. Using the same cohort, we will define genetic variants that increase the risk of important viral infections.
Specific Aim 3. To determine how the use of antibiotics and dietary fiber intake affect gut microbiota and subsequent infections after HCT. In a prospective cohort study (N=500) we will determine the effect of antibiotic regimens and dietary fiber intake on the gut microbiota and bacterial complications, and determine if changes in gut the microbiota modulate susceptibility to viral infection and affect adaptive immunity.
Specific aim 4. To conduct studies to characterize HHV-6 as a pulmonary pathogen in HCT recipients. In a cohort of patients evaluated for pneumonia by bronchoalveolar lavage (N=725), we will examine HHV-6 viral load, viral integration and cytokine expression profiles of HHV-6 LRD and characterize factors associated with overall mortality and death due to respiratory failure.
These aims support an innovative approach toward POR in the field of transplant infectious diseases and the proposed studies have a high potential of advancing our knowledge of the spectrum of infectious complications, the genetic basis of diseases, and the role of microbiome.

Public Health Relevance

This award will provide protected time for the applicant to mentor trainees in patient-oriented research in infections that occur in patients undergoing stem cell transplantation. Stem cell transplant recipients have a significantly increased risk of fatal infectious complications. This proposal will address four areas of transplant infectious diseases: the impact of the most common respiratory virus (human rhinovirus), genetics of infections, the role of the gut microbiome on infectious risk, and the role human herpesvirus 6 as a cause of pneumonia. The proposed studies will advance our knowledge and may ultimately improve management of these infections.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL093294-08
Application #
9207783
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Chang, Henry
Project Start
2009-09-03
Project End
2019-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Greninger, Alexander L; Knudsen, Giselle M; Roychoudhury, Pavitra et al. (2018) Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6. BMC Genomics 19:204
Ogimi, Chikara; Englund, Janet A; Bradford, Miranda C et al. (2018) Characteristics and Outcomes of Coronavirus Infection in Children: The Role of Viral Factors and an Immunocompromised State. J Pediatric Infect Dis Soc :
Hill, Joshua A; Mayer, Bryan T; Xie, Hu et al. (2018) Kinetics of Double-Stranded DNA Viremia After Allogeneic Hematopoietic Cell Transplantation. Clin Infect Dis 66:368-375
Hill, Joshua Aiden; Pergam, Steven A; Cox, Emily et al. (2018) A Modified Intensive Strategy to Prevent Cytomegalovirus Disease in Seropositive Umbilical Cord Blood Transplantation Recipients. Biol Blood Marrow Transplant 24:2094-2100
Waghmare, Alpana; Xie, Hu; Kuypers, Jane et al. (2018) Human Rhinovirus Infections in Hematopoietic Cell Transplant Recipients: Risk Score for Progression to Lower Respiratory Tract Infection. Biol Blood Marrow Transplant :
Ogimi, Chikara; Xie, Hu; Leisenring, Wendy M et al. (2018) Initial High Viral Load Is Associated with Prolonged Shedding of Human Rhinovirus in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 24:2160-2163
Ogimi, Chikara; Krantz, Elizabeth M; Golob, Jonathan L et al. (2018) Antibiotic Exposure Prior to Respiratory Viral Infection Is Associated with Progression to Lower Respiratory Tract Disease in Allogeneic Hematopoietic Cell Transplant Recipients. Biol Blood Marrow Transplant 24:2293-2301
Seo, Sachiko; Yu, Jeffrey; Jenkins, Isaac C et al. (2018) Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 24:678-686
Fisher, Cynthia E; Hohl, Tobias M; Fan, Wenhong et al. (2017) Validation of single nucleotide polymorphisms in invasive aspergillosis following hematopoietic cell transplantation. Blood 129:2693-2701
Hill, Joshua A; Mayer, Bryan T; Xie, Hu et al. (2017) The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood 129:2316-2325

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