Jonathan M. Klein

Transient surfactant protein B deficiency in a term infant with severe respiratory failure

A 38-day-old male infant with persistent pulmonary hypertension and respiratory failure since birth was found to have a complete absence of surfactant protein B (SP-B) along with an aberrant form of SP-C in his tracheal aspirate fluid, findings consistent with the diagnosis of hereditary SP-B deficiency. Surprisingly, SP-B and SP-B messenger ribonucleic acid were present in lung biopsy tissue. However, DNA sequence analysis demonstrated a point mutation in exon 5 of one of the SP-B gene alleles. The infants mother was found to be a carrier of this mutation. The infants other SP-B allele did not differ from the published DNA sequence for the SP-B gene. We conclude that this patient had a transient deficiency of SP-B, in contrast to that of previously described infants with irreversible respiratory failure caused by hereditary SP-B deficiency. We recommend that infants with suspected SP-B deficiency have serial analysis of tracheal fluid samples for both SP-B and SP-C before lung biopsy, along with genetic analysis for the known SP-B mutations. We speculate that the new mutation found in one of this patients SP-B genes was in part responsible for the transient deficiency of SP-B.

Nasal high‐frequency ventilation for premature infants

Aim: To assess the use of nasal high‐frequency ventilation (HFV) to provide noninvasive ventilatory support for very low birthweight (VLBW) infants.

Glucocorticoid Metabolism in the Human Fetal Lung: Implications for Lung Development and the Pulmonary Surfactant System

It has been nearly 35 years since Liggins and Howie first reported the benefits of antenatal glucocorticoid (GC) treatment to promote the maturation of the human fetal lung, and nearly that long since Pasqualini and colleagues demonstrated that the human fetal lung actively metabolizes GCs. Since that time, our understanding of the effects of GCs on fetal lung maturation and pulmonary surfactant production has increased dramatically. Similarly, characterization of the enzymes involved in GC metabolism has greatly expanded our understanding of GC signaling in target tissues. In man, the biologically active GC (cortisol) and the biologically inactive GC (cortisone) are interconverted by the tissue-specific expression of the type 1 and type 2 11β-hydroxysteroid dehydrogenase enzymes (HSD1 and HSD2). Much of the research on GC metabolism in peripheral target tissues has focused on the role of HSD1 in amplifying the effects of GCs in liver and adipose tissue or on the role of HSD2 in blocking the effects of GCs in the kidney and placenta. In contrast, the role of GC metabolism in modulating the effects of GCs on fetal lung maturation and the pulmonary surfactant system in humans is less understood. The goal of this review article is to present a brief overview of the role of GCs in human fetal lung maturation and pulmonary surfactant production, and to familiarize the reader with the biochemistry of the metabolism of natural and synthetic GCs by the HSD enzymes. In addition, we will review data concerning the expression and activity of the HSD enzymes in the human fetal lung and contrast this to what is known about the HSD enzymes in the fetal rodent lung. Although rodents, rabbits, sheep, and several primates have been invaluable model systems for the study of fetal lung development, we have chosen to largely focus this review on human lung, since there are significant differences in GC metabolism between humans and other species.

Improving survival of extremely preterm infants born between 22 and 25 weeks of gestation.

OBJECTIVE: To estimate observed compared with predicted survival rates of extremely premature infants born during 2000–2009, to identify contemporary predictors of survival, and to determine if improved survival rates occurred during the decade. METHODS: We conducted a retrospective cohort analysis of 237 inborn neonates without major congenital anomalies born from 2000 to 2009 after 22 to 25 completed weeks of gestation. Observed survival rates at each gestational age were compared with predicted survival rates based on gestational age, birth weight, sex, singleton or multiple gestation, and antenatal corticosteroid administration estimated by a Web-based calculator that was derived from 1998 to 2003 outcomes of a large national cohort. Multivariable logistic regression analysis was used to identify significant predictors of survival of the study cohort, including year of birth. RESULTS: Survival rates for the decade by gestational age (compared with predicted rates) were: 22 weeks, 33% (compared with 19%); 23 weeks, 58% (compared with 38%); 24 weeks, 87% (compared with 58%); and 25 weeks, 85% (compared with 70%). Antenatal corticosteroids were administered in 96% of pregnancies. Variables that significantly predicted survival and their odds ratios (OR) with 95% confidence intervals (CI) are: antenatal corticosteroid administration (OR 5.27, CI 1.26–22.08); female sex (OR 3.21, CI 1.42–7.26); gestational age (OR 1.89, CI 1.27–2.81); 1-minute Apgar score (OR 1.39, CI 1.15–1.69); and birth year (OR 1.17, CI 1.02–1.34). The number needed to treat with any antenatal corticosteroid therapy to prevent one death was 2.4. CONCLUSION: In this single-institution cohort treated aggressively (antenatal corticosteroid administration [even if less than 24 weeks], tocolysis until steroid course complete, cesarean for fetal distress) by perinatologists and neonatologists, survival rates at 22–25 weeks of gestation age for inborn infants during the 2000s exceeded predicted rates, with increasing odds of survival during the decade. Antenatal corticosteroid administration had a significant effect on survival. LEVEL OF EVIDENCE: II

Treatment of respiratory failure in an infant with bronchopulmonary dysplasia infected with respiratory syncytial virus using inhaled nitric oxide and high frequency ventilation

A 2‐month‐old, former 28‐week premature infant with brochopulmonary dysplasia infected with respiratory syncytial virus was treated with nitric oxide and high frequency oscillatory ventilation after conventional therapy failed. Nitric oxide and high frequency oscillatory ventilation rapidly improved oxygenation allowing recovery without the need for extracorporeal membrane oxygenation. This treatment regimen should be considered as an option in high‐risk infants with respiratory syncytial virus infection who meet extracorporeal membrane oxygenation criteria.

Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn

Introduction:Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension.Results:PPHN was significantly (P < 0.05) associated with genetic variants in corticotropin-releasing hormone (CRH) receptor 1, CRHR1 and CRH-binding protein, CRHBP. Association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutations were found in the bone morphogenetic protein receptor type II (BMPR2) gene.Discussion:We describe previously unreported genetic associations between PPHN and CRHR1 and CRHBP. These findings may have implications for further understanding the pathophysiology of PPHN and treatment.Methods:We performed a family-based candidate gene study to examine a genetic association with PPHN and sequenced the BMPR2 gene in 72 individuals. We enrolled 110 families with infants diagnosed with PPHN based on inclusion criteria. After medical chart review, 22 subjects were excluded based on predefined criteria, and DNA samples from 88 affected infants and at least one parent per infant were collected and genotyped. Thirty-two single-nucleotide polymorphisms in 12 genes involved in vasoconstriction/vasodilation, lung development, surfactant regulation, or vascular endothelial cell function were investigated using family-based association tests.

Transient improvement of congenital lactic acidosis in a male infant with pyruvate decarboxylase deficiency treated with dichloroacetate

A comatose male newborn infant with congenital lactic acidosis caused by pyruvate decarboxylase deficiency was treated with dichloroacetate (DCA), which stimulated an 88% drop in serum lactate concentration and reversed his coma. The response to DCA was temporary and the lactic acidosis worsened until his death, but DCA may confer more lasting benefit in less severely affected infants.

Localization of Epidermal Growth Factor Receptor in Alveolar Epithelium During Human Fetal Lung Development in Vitro

Epidermal growth factor (EGF) enhances alveolar type II cell differentiation. In human fetal lung explants, EGF stimulates surfactant protein A (SP-A) synthesis. This effect may occur through a direct interaction of the ligand on EGF receptors located within distal pulmonary epithelium during alveolar type II cell differentiation. To determine if EGF receptor is present in alveolar epithelium, immunostaining for EGF receptor and in situ hybridization for EGF receptor mRNA were performed in human fetal lung explants undergoing alveolar type II cell differentiation in vitro. After 4 days in culture, EGF receptor immunostaining was present in alveolar epithelium from human fetal lung explants compared to minimal immunostaining in undifferentiated human fetal lung epithelium prior to culture. In situ hybridization revealed increased EGF receptor mRNA in differentiated type II cells from cultured explants, with minimal EGF receptor mRNA detected in undifferentiated epithelium from tissue prior to culture. Immunogold staining revealed EGF receptors on the cytoplasmic membranes of epithelial cells lining the prealveolar ducts in human fetal lung explants after 2 days in culture. Alveolar type II cell differentiation in vitro was confirmed ultrastructurally by the presence of lamellar bodies and biochemically by an increase in SP-A content. Thus, EGF receptor is found in alveolar epithelium during differentiation, which suggests an important role for EGF during human fetal lung development.

Neonatal survival after prolonged preterm premature rupture of membranes before 24 weeks of gestation.

OBJECTIVE: To evaluate neonatal survival after prolonged preterm premature rupture of membranes (PROM) in the era of antenatal corticosteroids, surfactant, and inhaled nitric oxide. METHODS: A single-center retrospective cohort study of neonates born from 2002–2011 after prolonged (1 week or more) preterm (less than 24 weeks of gestation) rupture of membranes was performed. The primary outcome was survival to discharge. Neonates whose membranes ruptured less than 24 hours before delivery (n=116) were matched (2:1) on gestational age at birth, sex, and antenatal corticosteroid exposure with neonates whose membranes ruptured 1 week or more before delivery (n=58). Analysis used conditional logistic regression for categorical data and Wilcoxon signed rank test for continuous data. RESULTS: The prolonged preterm PROM exposed and unexposed cohorts had survival rates of 90% and 95%, respectively, although underpowered to assess the statistical significance (P=.313). Exposed neonates were more likely have pulmonary hypoplasia (26/58 exposed, 1/114 unexposed, P<.001), pulmonary hypertension (21/56 exposed, 10/112 unexposed, P<.001), and pulmonary air leak (21/58 exposed, 14/114 unexposed, P<.001). Gestational age at rupture (20.4 weeks exposed, 22.3 weeks unexposed, P=.189), length of rupture (3.7 weeks exposed, 6.4 weeks unexposed, P=.717), and lowest maximal vertical pocket before 24 weeks of gestation (0 cm exposed, 1.4 cm unexposed, P=.114) did not discriminate between survivors and nonsurvivors after exposure to prolonged preterm PROM. CONCLUSION: With antenatal steroid exposure and aggressive pulmonary management, survival to discharge after prolonged preterm PROM was 90%. Pulmonary morbidities were common. Of note, the data were limited to women who remained pregnant 1 week or longer after rupture of membranes. LEVEL OF EVIDENCE: II

Prediction of survival in infants with congenital diaphragmatic hernia based on stomach position, surgical timing, and oxygenation index

OBJECTIVE To identify characteristics predictive of survival of patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN Retrospective analysis of clinical characteristics including severity of lung disease measured by oxygenation index (OI) associated with single-center survival in CDH patients (n = 81) from 1992 to 2008. Data were analyzed using univariate and multivariable logistic regression, effect plots, and receiver operating characteristic (ROC) plots. RESULTS No patient died if the stomach was located in the abdomen. A left thoracic stomach position predicted decreased survival with ROC area under the curve (AUC) = 0.70. OI of ≤ 26 averaged over the first 12 hours of life predicted ≥ 50% survival for all patients, with AUC = 0.86. OI effect plots allow prediction of survival over a continuous OI range. No patient survived if mean OI was >51 in the first 12 hours of life. Delaying surgery for a median of 6 days improved survival probability for all patients with presurgery OI values ≤ 51. CONCLUSION Position of the stomach in the abdomen, delayed surgery, and less severe cardiopulmonary disease during the first 12 hours of life, as measured by mean OI, predicted improved survival probability among patients with CDH. Our CDH model, using mean OI, permits specific individual prediction of survival probability over a range of OI values.