Project Summary/Abstract
2.5 million infants are born at less than 32 weeks gestation worldwide every year, with approximately 75,000 of
them born in the US. Many of these preterm infants develop a severe form of lung disease called
Bronchopulmonary Dysplasia (BPD), which manifests as poor lung function requiring prolonged mechanical
ventilation and oxygen therapy, and predisposing to poorer neurodevelopmental outcomes. In addition, these
children exhibit increased fragility to lung infections and often require hospital readmissions in the first year of
life. Severe Bronchopulmonary Dysplasia is one of the most important pediatric pulmonary disorder in the
United States, increasing in incidence as increasing numbers of extremely preterm infants survive to leave the
ICU.
One commonly used drug therapy for BPD is systemic steroids, including the corticosteroids dexamethasone
and hydrocortisone, which produces variable and unpredictable short term pulmonary benefit, but are
associated with neurodevelopmental impairment and other important side effects such as growth stunting,
hypertension and decreased bone mineralization. Given the variable clinical efficacy and high risk for adverse
effects, it is important to identify a group of infants with BPD who will benefit the most from steroid therapy,
making the risk of adverse events more acceptable. There are functionally important genetic variants known to
impact steroid metabolism and response in similar patient populations, so we know that variability in steroid
response likely has, in part, genetic underpinnings.
In a prospectively recruited multi-site cohort (N=150), we will assess genomic and metabolomic markers which
correlate with steroid response in BPD. We will capitalize on prior published knowledge and pilot data, as well
as take an agnostic approach, to identify genomic biomarkers of steroid response among preterm infants
treated with systemic dexamethasone or hydrocortisone for BPD. We will also compare the urine and plasma
pharmacometabolome between steroid responders and non-responders to look for pre-treatment or early
treatment markers of drug efficacy. The overall goal of the research program is to elucidate genomic and
metabolomics biomarkers of clinical response, as a mechanism to identify a group of infants with the most
favorable risk to benefit ratio, moving the field of BPD treatment towards precision medicine. This project fits
well with the mission of the NICHD Obstetric and Pediatric Pharmacology branch, because it addresses a
severe pediatric disease with highly variable and unpredictable drug response (efficacy and toxicity). The
systematic application of modern pharmacology research tools will allow the identification of certain preterm
infants, either a priori or early in the treatment course, who will have clinical benefit >>toxicity risk, allowing for
personalized therapeutics in this group of infants.
