Airway Histopathology of Adolescent Survivors of Bronchopulmonary Dysplasia.

Long-term survivors of bronchopulmonary dysplasia develop chronic obstructive lung disease. Herein we report in vivo histopathology from bronchial biopsies of 3 adolescent survivors of severe bronchopulmonary dysplasia. Thickened basement membranes with lymphocytic infiltrates and signs of immature neoangiogenesis in the absence of T-helper lymphocytes or eosinophils suggest the presence of an ongoing active airway process.

Racial and Ethnic Differences in Pediatric Pulmonary Hypertension: An Analysis of the Pediatric Pulmonary Hypertension Network Registry.

OBJECTIVE: To investigate racial and ethnic differences in pulmonary hypertension subtypes and survival differences in a pediatric population. STUDY DESIGN: This was a retrospective analysis of a cohort of patients with pulmonary hypertension (aged ≤18 years) enrolled in the Pediatric Pulmonary Hypertension Network registry between 2014 and 2018, comprising patients at eight Pediatric Centers throughout North America (n = 1417). RESULTS: Among children diagnosed after the neonatal period, pulmonary arterial hypertension was more prevalent among Asians (OR, 1.83; 95% CI, 1.21-2.79; P = .0045), lung disease-associated pulmonary hypertension among blacks (OR, 2.09; 95% CI, 1.48-2.95; P < .0001), idiopathic pulmonary arterial hypertension among whites (OR, 1.58; 95% CI, 1.06-2.41; P = .0289), and pulmonary veno-occlusive disease among Hispanics (OR, 6.11; 95% CI, 1.34-31.3; P = .0184). Among neonates, persistent pulmonary hypertension of the newborn (OR, 4.07; 95% CI, 1.54-10.0; P = .0029) and bronchopulmonary dysplasia (OR, 8.11; 95% CI, 3.28-19.8; P < .0001) were more prevalent among blacks, and congenital diaphragmatic hernia was more prevalent among whites (OR, 2.29; 95% CI, 1.25-4.18; P = .0070). An increased mortality risk was observed among blacks (HR, 1.99; 95% CI, 1.03-3.84; P = .0396), driven primarily by the heightened mortality risk among those with lung disease-associated pulmonary hypertension (HR, 2.84; 95% CI, 1.15-7.04; P = .0241). CONCLUSIONS: We found significant racial variability in the prevalence of pulmonary hypertension subtypes and survival outcomes among children with pulmonary hypertension. Given the substantial burden of this disease, further studies to validate phenotypic differences and to understand the underlying causes of survival disparities between racial and ethnic groups are warranted.

Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure.

BACKGROUND: Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti-inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH)2D3) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown. OBJECTIVE: The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH)2D3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats. DESIGN/METHODS: Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH)2D3 (1 ng/mL), 1,25-(OH)2D3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue. RESULTS: IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p < 0.0001; birth weight: 4.68 vs. 5.88 g; p < 0.0001). IA 1,25-(OH)2D3 treatment increased birth weight by 12% in ETX-exposed pups (5.25 vs. 4.68 g; p < 0.001). IA ETX decreased placental vessel density by 24% in comparison with controls (1,114 vs. 848 vessels per HPF; p < 0.05). Treatment with IA 1,25-(OH)2D3 increased placenta vessel density twofold after ETX exposure (1,739 vs. 848); p < 0.0001), and increased vessel density compared with saline controls by 56% (1,739 vs. 1,114; p < 0.0001). IA ETX decreased both VDR and CYP27B1 expression by 83 and 35%, respectively (p < 0.01). CONCLUSION: IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH)2D3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH)2D3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth.

Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

Strategic plan for pediatric respiratory diseases research: an NHLBI working group report.

The Division of Lung Diseases of the National Heart, Lung and Blood Institute (NHLBI) recently held a workshop to identify gaps in our understanding and treatment of childhood lung diseases and to define strategies to enhance translational research in this field. Leading experts with diverse experience in both laboratory and patient-oriented research reviewed selected areas of pediatric lung diseases, including perinatal programming and epigenetic influences; mechanisms of lung injury, repair, and regeneration; pulmonary vascular disease (PVD); sleep and control of breathing; and the application of novel translational methods to enhance personalized medicine. This report summarizes the proceedings of this workshop and provides recommendations for emphasis on targeted areas for future investigation. The priority areas identified for research in pediatric pulmonary diseases included: (1) epigenetic and environmental influences on lung development that program pediatric lung diseases, (2) injury, regeneration, and repair in the developing lung, (3) PVD in children, (4) development and adaptation of ventilatory responses to postnatal life, (5) nonatopic wheezing: aberrant large airway development or injury? (6) strategies to improve assessment, diagnosis, and treatment of pediatric respiratory diseases, and (7) predictive and personalized medicine for children.

Strategic plan for pediatric respiratory diseases research: an NHLBI working group report.

The Division of Lung Diseases of the National Heart, Lung, and Blood Institute (NHLBI) recently held a workshop to identify gaps in our understanding and treatment of childhood lung diseases and to define strategies to enhance translational research in this field. Leading experts with diverse experience in both laboratory and patient-oriented research reviewed selected areas of pediatric lung diseases, including perinatal programming and epigenetic influences; mechanisms of lung injury, repair, and regeneration; pulmonary vascular disease; sleep and control of breathing; and the application of novel translational methods to enhance personalized medicine. This report summarizes the proceedings of this workshop and provides recommendations for emphasis on targeted areas for future investigation. The priority areas identified for research in pediatric pulmonary diseases included: (1) epigenetic and environmental influences on lung development that program pediatric lung diseases; (2) injury, regeneration, and repair in the developing lung; (3) pulmonary vascular disease in children; (4) development and adaptation of ventilatory responses to postnatal life; (5) nonatopic wheezing: aberrant large airway development or injury?; (6) strategies to improve assessment, diagnosis, and treatment of pediatric respiratory diseases; and (7) predictive and personalized medicine for children.

Summary proceedings from the bronchopulmonary dysplasia group.

Despite improvements in neonatal care, bronchopulmonary dysplasia (BPD) continues to occur in approximately one third of newborns who have birth weights of <1000 g and contributes to significant morbidity in this population. Gaps in knowledge about the prevention and treatment of BPD remain, resulting in unintended short- and long-term sequelae. In addition to chronic lung disease, preterm newborns with BPD are more likely to develop language delay, cerebral palsy, and cognitive impairments compared with preterm newborns without BPD. The pulmonary group identified 3 critical needs to enhance the design of clinical trials in neonates with BPD: (1) identify the stages of BPD; (2) define BPD more clearly; and (3) identify subtypes of BPD patients. The group determined that trials are needed for 3 areas of BPD: (1) prevention of BPD; (2) treatment of evolving BPD; and (3) treatment of established BPD. The severity of BPD is defined as mild, moderate, and severe, and subgroups among those with BPD are described. Here we identify gaps in basic science and pharmacologic knowledge that hamper investigators' ability to conduct effective BPD clinical trials and provide a list of drugs to be studied in BPD trials. Priorities for drug-class evaluation by stage of BPD are given. The pulmonary group proposes a BPD clinical-trials framework that varies according to the different stages of BPD and describes characteristics of the overall design for BPD clinical trials. Finally, we discuss trial-design issues that are common to all neonatal studies.