Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

Approximately 550,000 babies born prematurely each year in the United States suffer from
birth at a time in development when the respiratory tract and immune system would normally
be protected and maintained in a naïve state. This project is a component of the NIH
Prematurity and Respiratory Outcomes Program (PROP) whose goals are the identification of
disease mechanisms and biomarkers to stratify premature infants, at the time of discharge,
for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC)
project will investigate prematurity-dependent alterations in cellular innate and adaptive
immune systems resulting in increased susceptibility to respiratory infections and
environmental irritants, and leading to respiratory morbidity in the first year of life.
Prior studies have established developmental (maturity) and disease-related changes in
circulating and pulmonary lymphocyte populations but a comprehensive assessment of their
relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular
and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by
premature birth in such a way as to reduce resistance to viral infections and to promote
cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively
phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the
time of discharge from the hospital and at twelve months corrected age. The lymphocytic
phenotype will be analyzed particularly in the context of gestational age and maternal-fetal
stressors capable of modulating oxidative stress (oxygen exposure, infection and
environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular
phenotype of isolated CD8 lymphocytes, a cell type preferentially recruited to the lungs of
premature infants and capable of contributing to disease pathogenesis, by genome-wide
expression profiling, in order to uncover novel disease pathways and define a gene
expression signature associated with disease risk. Finally, we propose to build a
statistical model, using cellular and molecular phenotypes and additional clinical
variables, for stratifying risk of lung morbidity within the first year of life.

Inclusion Criteria:

1. Premature infants born at gestational age 24 0/7 to 35 6/7 week and admitted to the
Neonatal Intensive Care Unit or normal newborn nursery at URMC or UB

2. Healthy term infants 37 0/7 to 41 6/7 recruited from the birthing centers or Ob/Gyn
floors (3-1200 at URMC) prior to discharge

3. Infants who are less than or equal to 7 days old

Exclusion Criteria:

1. The infant is not considered to be viable (therapies limited due to futility decision
made by clinical care team)

2. Congenital heart disease (not including PDA and hemodynamically insignificant VSD or
ASD)

3. Structural abnormalities of the upper airway, lungs or chest wall

4. Other congenital malformations or syndromes that adversely affect life expectancy or
cardio-pulmonary development

5. Family is unlikely to be available for long-term follow-up as determined by the site
investigators dependent on the distance of the infant's residence from the follow-up
center and/or family plans to move out of the region

6. Family does not speak or understand English