The community acquired respiratory viruses (CRV) are well recognized as causes of fatal pneumonia after hematopoietic cell transplantation (HCT). Recent studies, however, suggest that the impact of CRV infection on overall survival after HCT may be far greater than commonly appreciated. Over 25% of long-term survivors of HCT are afflicted by significant decline in pulmonary airflow that is usually associated with the pathologic condition known as bronchiolitis obliterans; patients with such severe airflow obstruction (AFO) have mortality rates that are over twice as high as those without AFO. Though transplant-related AFO is currently believed to represent a pulmonary manifestation of chronic graft vs. host disease (GvHD), our preliminary data suggests that the CRVs are involved in the pathogenesis of this fatal transplant complication. We hypothesize that incident CRV infection after HCT is the trigger that leads to chronic pulmonary injury leading to AFO. We propose a large observational cohort study (N=500) with testing of weekly nasal wash specimens and clinically obtained BAL and lung biopsy specimens by quantitative RT-PCR testing for viral RNA of the major CRVs (RSV; influenza A, B; parainfluenza virus 1-4, RSV A, B; human metapneumovirus, rhinoviruses, coronaviruses, adenoviruses). These results will be correlated with the occurrence of AFO as determined by both scheduled standard pulmonary function tests and weekly measurements using portable electronic spirometers.
Specific Aim 1 will evaluate the association between incident infection with community-acquired respiratory viruses and the subsequent development of airflow obstruction after HCT. Specifically, we will determine the magnitude of the association, the differential risk of different viral species, and if the effect is site-specific (upper vs. lower respiratory tract).
Specific Aim 2 will further define viral factors that are associated with the development of respiratory virus-associated AFO, including whether viral species, viral load, or duration of viral shedding are involved in the pathogenesis of this fatal transplant-related complication; host-specific factors such as recipient age, conditioning regimen and immunosuppressive treatment for GvHD.
Specific Aim 3 will examine the role of leukotrienes in the pathogenesis of virus-induced AFO. These studies will improve our understanding of the interaction between respiratory viruses and late pulmonary complications after HCT, which will ultimately enable us to formulate more rational treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081595-03
Application #
7270038
Study Section
Special Emphasis Panel (ZRG1-CRFS (01))
Program Officer
Peavy, Hannah H
Project Start
2005-09-19
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$615,972
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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