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Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. Impact PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

Current diagnostic criteria for bronchopulmonary dysplasia rely heavily on the level and duration of oxygen therapy, do not reflect contemporary neonatal care, and do not adequately predict childhood morbidity. To determine which of 18 prespecified, revised definitions of bronchopulmonary dysplasia that variably define disease severity according to the level of respiratory support and supplemental oxygen administered at 36 weeks' postmenstrual age best predicts death or serious respiratory morbidity through 18-26 months' corrected age. We assessed infants born at less than 32 weeks of gestation between 2011 and 2015 at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Of 2,677 infants, 683 (26%) died or developed serious respiratory morbidity. The diagnostic criteria that best predicted this outcome defined bronchopulmonary dysplasia according to treatment with the following support at 36 weeks' postmenstrual age, regardless of prior or current oxygen therapy: no bronchopulmonary dysplasia, no support (  = 773); grade 1, nasal cannula ≤2 L/min (  = 1,038); grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure (  = 617); and grade 3, invasive mechanical ventilation (  = 249). These criteria correctly predicted death or serious respiratory morbidity in 81% of study infants. Rates of this outcome increased stepwise from 10% among infants without bronchopulmonary dysplasia to 77% among those with grade 3 disease. A similar gradient (33-79%) was observed for death or neurodevelopmental impairment. The definition of bronchopulmonary dysplasia that best predicted early childhood morbidity categorized disease severity according to the mode of respiratory support administered at 36 weeks' postmenstrual age, regardless of supplemental oxygen use.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease associated with premature birth that primarily affects infants born at less than 28 weeks' gestational age. BPD is the most common serious complication experienced by premature infants, with more than 8,000 newly diagnosed infants annually in the United States alone. In light of the increasing numbers of preterm survivors with BPD, improving the current state of knowledge of long-term respiratory morbidity for infants with BPD is a priority. We undertook a comprehensive review of the published literature to analyze and consolidate current knowledge of the effects of BPD that are recognized at specific stages of life, including infancy, childhood, and adulthood. In this review, we discuss both the short-term and long-term respiratory outcomes of individuals diagnosed as infants with the disease and highlight the gaps in knowledge needed to improve early and lifelong management of these patients.

Bronchopulmonary dysplasia (BPD) is a serious neonatal pulmonary condition associated with premature birth, but the underlying parenchymal disease and trajectory are poorly characterized. The current National Institute of Child Health and Human Development (NICHD)/NHLBI definition of BPD severity is based on degree of prematurity and extent of oxygen requirement. However, no clear link exists between initial diagnosis and clinical outcomes. We hypothesized that magnetic resonance imaging (MRI) of structural parenchymal abnormalities will correlate with NICHD-defined BPD disease severity and predict short-term respiratory outcomes. A total of 42 neonates (20 severe BPD, 6 moderate, 7 mild, 9 non-BPD control subjects; 40 ± 3-wk postmenstrual age) underwent quiet-breathing structural pulmonary MRI (ultrashort echo time and gradient echo) in a neonatal ICU-sited, neonatal-sized 1.5 T scanner, without sedation or respiratory support unless already clinically prescribed. Disease severity was scored independently by two radiologists. Mean scores were compared with clinical severity and short-term respiratory outcomes. Outcomes were predicted using univariate and multivariable models, including clinical data and scores. MRI scores significantly correlated with severities and predicted respiratory support at neonatal ICU discharge (P < 0.0001). In multivariable models, MRI scores were by far the strongest predictor of respiratory support duration over clinical data, including birth weight and gestational age. Notably, NICHD severity level was not predictive of discharge support. Quiet-breathing neonatal pulmonary MRI can independently assess structural abnormalities of BPD, describe disease severity, and predict short-term outcomes more accurately than any individual standard clinical measure. Importantly, this nonionizing technique can be implemented to phenotype disease, and has potential to serially assess efficacy of individualized therapies.

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants. This Primer by Thébaud and colleagues discusses the epidemiology, mechanisms, diagnosis and treatment of bronchopulmonary dysplasia, a type of lung disease that can occur in preterm infants.

Bronchopulmonary dysplasia (BPD) is a disease with a multi-factorial pathophysiology; however, current animal models lack complexity. We employed a double-hit model with an antenatal insult of foetal growth restriction paired with milder postnatal hyperoxia exposure. We induced foetal growth restriction (FGR) by injecting N(G)-nitro-L-arginine methyl ester (L-NAME) in the pregnant rabbit, and exposed preterm-born kittens to 70% hyperoxia for 7 days. L-NAME effectively induced FGR, and mortality rates were acceptable. The double-hit group exhibited adverse outcomes, including decreased lung compliance, increased airway resistance, and structural changes such as alveolar simplification and thickened septa. Gene expression analysis in the L-NAME group revealed downregulation of vascular growth factors, suggesting impaired vascular development. In contrast to traditional hyperoxia models, our double-hit approach enables lower hyperoxia exposure, aligning more closely with clinical practice guidelines in neonatology. The findings underscore the importance of antenatal factors in BPD pathophysiology and reinforce the need for refined animal models that accurately reflect the complexities of preterm lung development.

Background Bronchopulmonary dysplasia (BPD) is a chronic lung condition of premature neonates, yet without an established pharmacological treatment. The BPD rabbit model exposed to 95% oxygen has been used in recent years for drug testing. However, the toxicity of the strong hyperoxic hit precludes a longer-term follow-up due to high mortality after the first week of life. This study aimed to extend the preterm rabbit model to postnatal day (PND) 14 to mimic the evolving phase of BPD and enable the investigation of therapeutic interventions at later and more relevant time points. Methods Preterm rabbit pups delivered on the 28th day of gestation were either exposed to room air or different degrees of hyperoxia (50% and 70% O 2 ) for 14 days. Single (immediately after birth) or double (at birth and at PND5) intratracheal lipopolysaccharide (LPS) administrations were also tested in combination with 50% O 2 . Age-matched rabbits delivered vaginally at term were used as controls. Survival, weight gain, lung function, pulmonary artery micro-ultrasound Doppler analysis, lung histology (alveolarization, lung injury score, and design-based stereology), and longitudinal micro-CT imaging were used to compare the outcomes at PND14. Results Premature birth itself, without any other BPD hit, was associated with lung function deficits, delayed lung development, and cardiovascular abnormalities. The BPD-like lung phenotype was enhanced by 70% O 2 but not by 50% O 2 hyperoxia. Intratracheal LPS delivered immediately after birth was associated with significantly higher lung injury scores at PND14 and increased tissue damping, a marker of parenchymal air resistance. Conclusion Several strategies are feasible to extend the preterm rabbit model of BPD to PND14. Preterm birth at the saccular phase itself, even in the absence of other postnatal BPD hits, was associated with lung function deficits, delayed lung development, and cardiovascular abnormalities compared with age-matched term rabbit pups. Enhanced BPD-like phenotypes can be further achieved by continued exposure to moderate hyperoxia (70% O 2 ) and the intratracheal administration of LPS.

Bronchopulmonary dysplasia has become the most common chronic lung disease of infancy. This review summarizes the patterns and pathogenesis of chronic lung impairment that may become clinically significant decades after the use of mechanical ventilation and oxygen supplementation in premature newborns. This review summarizes the patterns and pathogenesis of chronic lung impairment that may become clinically significant decades after the use of mechanical ventilation and oxygen supplementation in premature newborns. In 1967, Northway et al. first described a new chronic respiratory disease, bronchopulmonary dysplasia, that developed in premature infants exposed to mechanical ventilation and oxygen supplementation. 1 Two decades later, the same authors found that clinically significant respiratory symptoms and functional abnormalities persisted into adolescence and early adulthood in a cohort of survivors of bronchopulmonary dysplasia, 2 suggesting that lung injuries early in life may have lifelong consequences. Bronchopulmonary dysplasia is now the most common chronic lung disease of infancy in the United States. Today, newborns consistently survive at gestational ages of 23 to 26 weeks — 8 to 10 weeks younger . . .

Background AVR-48 is a small molecule that modulates toll-like receptor 4 (TLR4) activity, changing macrophage phenotype from pro- to anti-inflammatory and increasing the anti-inflammatory cytokine IL-10. Treatment with AVR-48 via intraperitoneal injection effectively prevented hyperoxia-induced pathology in a newborn mouse model of bronchopulmonary dysplasia (BPD). Objective To evaluate the early and late-stage efficacy of AVR-48 in preventing BPD and associated complications in a mechanically ventilated preterm lamb model that mimics human BPD. Design and methods Preterm lambs were delivered at 128 days (d; about 85% gestation) following the administration of maternal antenatal steroids, intubated, given surfactant, and managed with invasive mechanical ventilation for seven days, followed by three days of noninvasive respiratory support. Either vehicle or AVR-48 was administered to the preterm lambs via intravenous bolus infusion six hours after birth and continued for seven days (every 12 h). Equivalent early (10 d) and late-stage (90 d) endpoints were selected to model human clinical outcomes at 36 weeks and 12–18 months post-natal age, respectively. Survival, growth, pulmonary pathology, respiratory system function, cardiovascular function, and neurobehavioral parameters were evaluated at both early and late stages. The forced oscillation technique was used to assess the resistance and reactance of the respiratory system. Blood samples were collected to determine the pharmacokinetics of AVR-48 and to measure levels of inflammatory and anti-inflammatory cytokines. Lung homogenates were analyzed for TLR4, cleaved caspase-3, p53, PCNA, VEGF, VEGF-R2, and other biomarkers using immunoblot and RT-PCR. Results Compared to the vehicle, AVR-48 at 3.0 mg/kg significantly reduced respiratory severity scores, increased lung compliance, decreased lung resistance, and preserved alveolar formation without inflammation or fibrosis at 10d. In the 90d study, AVR-48 improved respiratory system mechanics, alveolar formation, and neurodevelopmental outcomes compared to vehicle controls. A decrease in the pro-inflammatory cytokines (IL-1β, IL-6) and an increase in the anti-inflammatory cytokine IL-10 in lamb plasma collected between days 1 and 10 were noted. Lung tissue showed decreased TLR4 protein and inflammatory cytokines at 90d. Conclusion AVR-48 is a promising novel candidate drug for further development in preventing BPD and has the potential to reduce the associated adverse neurodevelopmental sequelae in preterm neonates.

Improved survival of extremely preterm newborn infants has increased the number of infants at risk for developing bronchopulmonary dysplasia (BPD). Despite efforts to prevent BPD, many of these infants still develop severe BPD (sBPD) and require long-term invasive mechanical ventilation. The focus of research and clinical management has been on the prevention of BPD, which has had only modest success. On the other hand, research on the management of the established sBPD patient has received minimal attention even though this condition poses large economic and health problems with extensive morbidities and late mortality. Patients with sBPD, however, have been shown to respond to treatments focused not only on ventilatory strategies but also on multidisciplinary approaches where neurodevelopmental support, growth promoting strategies, and aggressive treatment of pulmonary hypertension improve their long-term outcomes. In this review we will try to present a physiology-based ventilatory strategy for established sBPD, emphasizing a possible paradigm shift from acute efforts to wean infants at all costs to a more chronic approach of stabilizing the infant. This chronic approach, herein referred to as chronic phase ventilation, aims at allowing active patient engagement, reducing air trapping, and improving ventilation-perfusion matching, while providing sufficient support to optimize late outcomes. Impact Based on pathophysiological aspects of evolving and established severe BPD in premature infants, this review presents some lung mechanical properties of the most severe phenotype and proposes a chronic phase ventilatory strategy that aims at reducing air trapping, improving ventilation-perfusion matching and optimizing late outcomes.