R01HL153108

Penetrating the "Black Box": Prediction of Early Bronchiolitis Obliterans in Pediatric Hematopoietic Stem Cell Transplant Recipients - Abstract

Bronchiolitis obliterans syndrome (BOS) is an obstructive lung disease caused by a combination of inflammation and immune response that is irreversible in its late stage. Children with BOS are typically diagnosed late because they are unable to perform spirometry, and morbidity and mortality are high.

The long-term goal of this work is to improve survival and reduce morbidity from BOS by identifying strategies for accurate screening and prediction of BOS in children and young adults after hematopoietic stem cell transplantation (HSCT). Additionally, this work aims to use these tools to identify novel drug targets for early intervention or prevention of BOS.

The objective of this application is to validate novel predictive plasma protein biomarkers and establish a dynamic prediction model for BOS for early diagnosis, risk stratification, and disease trajectory prediction for BOS after HSCT. This will be achieved through the following specific aims:

1) Validate longitudinal predictive performance of newly discovered plasma biomarkers of BOS risk in samples from banked and prospective studies by mass spectrometry and ELISA in both pediatric and adult cohorts.

2) Optimize and validate our dynamic prediction algorithm using pulmonary function and clinical data, as well as biomarker levels (needed when no spirometry can be obtained), as covariates to project risks of BOS and rapid BOS lung-function decline to inform treatment decisions.

There are currently no biomarkers or predictive tools for BOS, so this work is entirely novel. The use of a dynamic prediction algorithm in this clinical setting is innovative, allowing for the first time the ability to predict and diagnose early lung disease in HSCT subjects prior to the clinical diagnosis of BOS.

Identification of BOS risk and stratification of screening and treatment procedures according to risk and predicted disease course would allow us to modify post-transplant care and reduce morbidity and mortality. We will use our data to inform prospective clinical trials of both early active treatment prior to the development of early fibrosis and to test novel prophylactic therapies to reduce incidence in high-risk individuals.

Our studies will provide blood biomarkers that can be used as frequently as necessary without requiring active participation from small and often very sick children. Our preliminary biomarker and HSCT-specific algorithm data demonstrate detection of BOS as soon as 2 weeks to 6 months prior to the clinical diagnosis of BOS.

This work is both significant and vital because improvements in HSCT techniques and supportive care have led to improved survival. Improved survival increases the number of children at risk for late complications of HSCT that are associated with life-changing morbidity and late mortality, and there is an urgent need to address these issues.

This work will advance prediction and early diagnosis of BOS, as well as providing the framework for future prevention and treatment trials.

Childrens Hospital Medical Center

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Cincinnati, Ohio 45229 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 380% from $649,585 to $3,117,523.