The pathogenesis of bronchopulmonary dysplasia (BPD) is not well understood. We previously identified differences in the airway microbiome at birth between preterm infants who were BPD-predisposed versus those who were BPD-resistant. In this study, we attempted to identify mechanisms by which the airway microbiome could modify the risk for BPD. We used a software-based method to predict the metagenome of the tracheal aspirate (TA) microbiome from 16s rRNA sequencing data in preterm infants and to identify functional ortholog genes that were differentially abundant in BPD-predisposed and BPD-resistant infants. We also identified metabolites that were differentially enriched in these samples using untargeted mass spectrometry and mummichog to identify the metabolic pathways involved. Microbial metagenome analysis identified specific pathways that were less abundant in the functional metagenome of the microbiota of BPD-predisposed infants compared to BPD-resistant infants. The airway metabolome of BPD-predisposed infants was enriched for metabolites involved in fatty acid activation, androgen and estrogen biosynthesis compared to BPD-resistant infants. These findings suggest that in extremely preterm infants, the early airway microbiome may alter the metabolome thereby modifying the risk of BPD. The differential enrichment of sex steroid metabolic pathways support previous studies suggesting a role for sexual dimorphism in BPD risk. This study also suggests a role for metabolomic and metagenomic profiles to serve as early biomarkers of BPD risk.

Our results indicating that endothelial cells of premature infants who later develop BPD or die have impaired mitochondrial bioenergetic capacity and produce more oxidants at birth suggest that the vascular endothelial mitochondrial dysfunction seen at birth in these infants persists through their postnatal life and contributes to adverse pulmonary outcomes and increased early mortality.

BackgroundB-type natriuretic peptide (BNP) is a strong predictor of mortality in adult patients with various forms of pulmonary hypertension (PH) and may be a strong prognostic marker in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) associated PH as well. We sought to assess the relationship between BNP levels and all-cause mortality in a cohort of ELBW infants with BPD and PH.MethodsWe retrospectively identified ELBW infants with BPD and PH who had serum BNP levels measured as part of routine clinical care in the neonatal intensive care unit. Peak serum BNP levels were correlated with survival to discharge or death.ResultsThirty-six ELBW infants (mean gestational age 26.0 ± 1.9 weeks and mean birth weight 740 ± 290 grams) with BPD and PH had available survival data and had serum BNP levels measured. Peak BNP level was significantly lower among infants who survived than among those who died (128 pg/ml, [IQR 23 to 463] vs. 997 pg/ml, [IQR 278 to 1770], P < 0.004). On multivariate Cox proportional hazard analysis, BNP predicted survival independent of age, gender, and BPD severity. Area under receiver operator characteristic analysis identified a BNP value of 220 pg/ml to have 90% sensitivity and 65% specificity in predicting mortality.ConclusionBNP estimation may be useful as a prognostic marker of all-cause mortality in ELBW infants with BPD associated PH.

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SouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research. Methods: GS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing. Results: Definitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups. Conclusion:We describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.