Bronchopulmonary dysplasia (BPD) is a common morbidity and cause of mortality in extremely low birth weight (ELBW) infants, and is a major contributor to the cost of neonatal care in the United States. C- reactive protein (CRP), a cyclic pentamer produced mainly by hepatocytes, is an acute phase reactant that markedly increases in blood during inflammation and has been used as a biomarker for neonatal sepsis. CRP is not just a marker of inflammation but also modulates inflammatory and immune responses. CRP production is not restricted to the liver, being produced by airway epithelial cells and alveolar macrophages, and is present in normal respiratory secretions. CRP impairs the surface-tension lowering function of lung surfactant in a dose-dependent manner. We have performed preliminary studies demonstrating the novel findings that: (a) serum CRP at 28 days of age strongly predicts death/ BPD at 36 weeks' postmenstrual age (PMA) in ELBW infants [AUC of ROC 0.85], even after excluding infants with sepsis. Infants surviving without BPD had lower CRP than infants with death/BPD [Median (25th-75thiles); 0 (0-3) vs. 11 (4-21) mg/L, p<0.001] (b) CRP in tracheal aspirates on the 1st postnatal day was a prognostic marker for death/BPD and correlated with other mediators of inflammation and lung injury (IL-1p, IL-6, FGF-2, and apoptosis markers). These findings support our overall hypothesis that CRP is an early marker and a mediator of poor outcome (death or BPD) in ELBW infants.
The Specific Aims of this proposed project are (1) to determine if ELBW infants who die or develop BPD have higher serum CRP concentrations in the first postnatal week, (2) to determine if ELBW infants who die or develop BPD have higher tracheal aspirate CRP concentrations in the first postnatal week, and (3) to determine if ELBW infants who die or develop BPD have genetic polymorphisms associated with higher serum CRP concentrations. Methods: 120 ELBW infants surviving > 12 h of age admitted to the Regional Neonatal Intensive Care Unit in Birmingham, AL (a Regional Perinatal center) over 15 months will be prospectively studied. It is estimated that 40 infants will either die or develop BPD. Remnant blood samples (0.05 ml) will be collected on days 1, 3, and 7 for CRP estimation by a sensitive ELISA. Tracheal aspirates will be collected from mechanically ventilated infants on days 1, 3, and 7. Cord blood at birth or a sample of the umbilical cord will be used to obtain DNA for the genetic polymorphism study. Clinical data will be collected on all infants from birth to discharge/36 weeks PMA. Confirming that CRP level is an early marker of death/BPD in ELBW infants, and that CRP genetic polymorphism predisposes ELBW infants to death/BPD (indicating that CRP is a mediator and not just a marker of BPD) will be of major clinical significance and may permit targeted use of anti-inflammatory or anti-CRP therapies for treatment of ELBW infants. ? ? ?
