High Risk For Bronchopulmonary Dysplasia Research Articles

The Bronchopulmonary Dysplasia score: A predictive model for bronchopulmonary dysplasia or death in high-risk preterm infants.

Progressive respiratory deterioration in infants at high risk of bronchopulmonary dysplasia (BPD) is associated with patent ductus arteriosus (PDA) exposure. This study aimed to design an early predictive model for BPD or death in preterm infants using early echocardiographic markers and clinical data. Infants born with gestational age (GA) ≤ 29 weeks and/or birth weight (BW) < 1500 g at Cork University Maternity Hospital, Ireland were retrospectively evaluated. Those with echocardiography performed between 36 h and 7 days of life were eligible for inclusion. Exclusion criteria were pulmonary hypertension and major congenital anomalies. The primary outcome was a composite of BPD and death before discharge. The study included 99 infants. A predictive model for the primary outcome was developed, which included three variables (BW, Respiratory Severity Score and flow pattern across the PDA), and yielding an area under the curve of 0.98 (95% CI 0.96-1.00, p < 0.001). Higher scores were predictive of the primary outcome. A cut-off of -1.0 had positive and negative predictive values of 89% and 98%, and sensitivity and specificity of 98% and 88%, respectively. Our prediction model is an accessible bedside tool that predicts BPD or death in premature infants.

Association between chronic diuretics and postnatal growth in preterm infants with bronchopulmonary dysplasia

BackgroundChronic diuretics such as thiazides and spironolactone are frequently used off-label in preterm infants with evolving or established bronchopulmonary dysplasia (BPD). Infants who are high risk for BPD are already predisposed to poor postnatal growth and the effect of chronic diuretics on postnatal growth is not well studied. ObjectiveExploratory study to determine the association between chronic diuretic exposure and short-term postnatal growth in preterm infants born at less than ≤ 29 weeks gestational age (GA). MethodsSingle-center retrospective cohort study in a level IV neonatal intensive care unit over a 2-year period (2021–22). Eligible infants exposed to chronic diuretics > 5 days for BPD (diuretic group) were compared to infants who were not (non-diuretic group). ResultsIn total, 53 infants (19 diuretic, and 35 non-diuretic group) were identified. The GA (25.3 vs 27.0 weeks) and birth weight (780 vs. 995 gs) were significantly lower in diuretic vs. non-diuretic group (p = 0.01). Diuretic group had higher intubation rate at birth, more days on non-invasive ventilation, higher incidence of moderate/severe BPD, and longer hospital stay (all p < 0.05). The GA adjusted z-scores for weight, length, and head circumference at birth, at 36-week corrected GA, and at discharge were similar in both groups. Also, the z-score change from birth at 36-week corrected GA, and at discharge were similar in both groups. There was no significant short-term change in weight z-score in the 2 weeks following chronic diuretic exposure. ConclusionsChronic diuretic exposure has no significant association with short-term postnatal growth in preterm infants.

Prediction of bronchopulmonary dysplasia in very preterm infants: competitive risk model nomogram.

To develop predictive clinical models of bronchopulmonary dysplasia (BPD) through competing risk analysis. Retrospective observational cohort study, including preterm newborns ≤32 weeks gestational age, conducted between January 1, 2013 and September 30, 2022 in a third-level Neonatal Intensive Care Unit in Spain. A prediction study was carried out using competing risk models, where the event of interest was BPD and the competing event was death. A multivariate competing risk model was developed separately for each postnatal day (days 1, 3, 7 and 14). Nomograms to predict BPD risk were developed from the coefficients of the final models and internally validated. A total of 306 patients were included in the study, of which 73 (23.9%) developed BPD and 29 (9.5%) died. On day 1, the model with the greatest predictive capacity was that including birth weight, days since rupture of membranes, and surfactant requirement (area under the receiver operating characteristic (ROC) curve (AUC), 0.896; 95% CI, 0.792-0.999). On day 3, the final predictive model was based on the variables birth weight, surfactant requirement, and Fraction of Inspired Oxygen (FiO2) (AUC, 0.891; 95% CI, 0.792-0.989). Competing risk analysis allowed accurate prediction of BPD, avoiding the potential bias resulting from the exclusion of deceased newborns or the use of combined outcomes. The resulting models are based on clinical variables measured at bedside during the first 3 days of life, can be easily implemented in clinical practice, and can enable earlier identification of patients at high risk of BPD.

CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia

Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10−/−) and wild-type mice to an experimental model of hyperoxia (85% O2)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10−/− mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10−/− mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD.

Risk factors for bronchopulmonary dysplasia infants with respiratory score greater than four: a multi-center, prospective, longitudinal cohort study in China

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity involving both pre- and post-natal factors. A large, prospective, longitudinal cohort study was conducted to determine whether inflammation-related factors are associated with an increased risk of BPD in preterm infants who were born at a gestational age < 32 weeks, < 72 h after birth and respiratory score > 4. The study included infants from 25 participating hospitals in China between March 1, 2020 and March 31, 2022. The primary outcomes were BPD and severity of BPD at 36 weeks post-menstrual age. A total of 1362 preterm infants were enrolled in the study. After exclusion criteria, the remaining 1088 infants were included in this analysis, of whom, 588 (54.0%) infants were in the BPD group and 500 (46.0%) were in the non-BPD group. In the BPD III model, the following six factors were identified: birth weight (OR 0.175, 95% CI 0.060–0.512; p = 0.001), surfactant treatment (OR 8.052, 95% CI 2.658–24.399; p < 0.001), mean airway pressure (MAP) ≥ 12 cm H2O (OR 3.338, 95% CI 1.656–6.728; p = 0.001), late-onset sepsis (LOS) (OR 2.911, 95% CI 1.514–5.599; p = 0.001), ventilator-associated pneumonia (VAP) (OR 18.236, 95% CI 4.700–70.756; p < 0.001) and necrotizing enterocolitis (NEC) (OR 2.725, 95% CI 1.182–6.281; p = 0.019). Premature infants remained at high risk of BPD and with regional variation. We found that post-natal inflammation-related risk factors were associated with an increased risk of severe BPD, including LOS, VAP, NEC, MAP ≥ 12 cm H2O and use of surfactant.

Establishment of a prediction model for histological chorioamnionitis and its association with outcomes of premature infants.

This study aims to construct a prediction model for histological chorioamnionitis (HCA) and analyze the associations between the predicted risk of HCA and adverse outcomes in preterm infants. In total, 673 subjects were included in this cohort study and divided into HCA group (n = 195) and non-HCA group (n = 478). A stepwise method was used to screen the predictors for HCA, binary logistic regression was used to construct the prediction model, and the associations between the predicted risk of HCA and adverse outcomes were analyzed. HCA occurred in 195 patients, accounting for 29.0%. The sensitivity of the prediction model was 0.821 [95% confidence interval (CI): 0.767-0.874)], the specificity was 0.684 (95% CI: 0.642-0.726), the positive predictive value was 0.514 (0.459-0.570), the negative predictive value was 0.903 (95% CI: 0.873-0.934), the area under the curve was 0.821 (95% CI: 0.786-0.855), and the accuracy was 0.724 (95% CI: 0.690-0.757). The predicted risk of HCA was associated with a higher risk of bronchopulmonary dysplasia (BPD) [odds ratio (OR) = 3.48, 95% CI: 1.10-10.95)], sepsis (OR = 6.66, 95% CI: 2.17-20.43), and neonatal infections (OR = 9.85, 95% CI: 3.59-26.98), but not necrotizing enterocolitis (OR = 0.67, 95% CI: 0.24-1.88), retinopathy of prematurity (OR = 1.59, 95% CI: 0.37-6.85), and brain damage (OR = 1.77, 95% CI: 0.82-3.83). After adjusting for confounders including gestational week at birth and birth weight, the risk of neonatal infections (OR = 5.03, 95% CI: 2.69-9.41) was increased in preterm infants' exposure to HCA. The model showed good predictive performance for identifying pregnant women with a higher risk of HCA. In addition, HCA was associated with the risk of BPD, sepsis, and infections in neonates.

Assessment of Corticosteroid Therapy and Death or Disability According to Pretreatment Risk of Death or Bronchopulmonary Dysplasia in Extremely Preterm Infants

Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended. To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants. This cohort study analyzed data on 482 matched pairs of infants from 45 participating US hospitals in the National Institute of Child Health and Human Development Neonatal Research Network Generic Database (GDB). Infants were included in the cohort if they were born at less than 27 weeks' gestation between April 1, 2011, and March 31, 2017; survived the first 7 postnatal days; and had 2-year death or developmental follow-up data collected between January 2013 and December 2019. Corticosteroid-treated infants were propensity score matched with untreated controls. Data were analyzed from September 1, 2019, to November 30, 2022. Systemic corticosteroid therapy to prevent BPD that was initiated between day 8 and day 42 after birth. The primary outcome was death or moderate to severe neurodevelopmental impairment at 2 years' corrected age. The secondary outcome was death or moderate to severe cerebral palsy at 2 years' corrected age. A total of 482 matched pairs of infants (mean [SD] gestational age, 24.1 [1.1] weeks]; 270 males [56.0%]) were included from 656 corticosteroid-treated infants and 2796 potential controls. Most treated infants (363 [75.3%]) received dexamethasone. The risk of death or disability associated with corticosteroid therapy was inversely associated with the estimated pretreatment probability of death or grade 2 or 3 BPD. The risk difference for death or neurodevelopmental impairment associated with corticosteroids decreased by 2.7% (95% CI, 1.9%-3.5%) for each 10% increase in the pretreatment risk of death or grade 2 or 3 BPD. This risk transitioned from estimated net harm to benefit when the pretreatment risk of death or grade 2 or 3 BPD exceeded 53% (95% CI, 44%-61%). For death or cerebral palsy, the risk difference decreased by 3.6% (95% CI, 2.9%-4.4%) for each 10% increase in the risk of death or grade 2 or 3 BPD and transitioned from estimated net harm to benefit at a pretreatment risk of 40% (95% CI, 33%-46%). Results of this study suggested that corticosteroids were associated with a reduced risk of death or disability in infants at moderate to high pretreatment risk of death or grade 2 or 3 BPD but with possible harm in infants at lower risk.

Sex differences in clinical outcomes of extremely preterm infants/extremely low birth weight infants: a propensity score matching study

To study the effect of sex on the clinical outcome of extremely preterm infants (EPIs)/extremely low birth weight infants (ELBWIs) by propensity score matching. A retrospective analysis was performed for the medical data of 731 EPIs or ELBWIs who were admitted from January 1, 2011 to December 31, 2020. These infants were divided into two groups: male and female. A propensity score matching analysis was performed at a ratio of 1:1. The matching variables included gestational age, birth weight, percentage of withdrawal from active treatment, percentage of small-for-gestational-age infant, percentage of use of pulmonary surfactant, percentage of 1-minute Apgar score ≤3, percentage of mechanical ventilation, duration of mechanical ventilation, percentage of antenatal use of inadequate glucocorticoids, and percentage of hypertensive disorders in pregnancy. The two groups were compared in the incidence rate of main complications during hospitalization and the rate of survival at discharge. Before matching, compared with the female group, the male group had significantly higher incidence rates of neonatal respiratory distress syndrome, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and patent ductus arteriosus (P<0.05), while after matching, the male group only had a significantly higher incidence rate of BPD than the female group (P<0.05). There was no significant difference in the rate of survival at discharge between the two groups before and after matching (P>0.05). Male EPIs/ELBWIs have a higher risk of BPD than female EPIs/ELBWIs, but male and female EPIs/ELBWIs tend to have similar outcomes.

Epidemiology and risk factors for bronchopulmonary dysplasia in preterm infants born at or less than 32 weeks of gestation

ObjectivesTo describe risk factors of bronchopulmonary dysplasia in very preterm infants in the first weeks of life. Material and methodsRetrospective cohort study of preterm infants ≤ 32 weeks of gestational age and birth weight ≤ 1500 g. A multivariate logistic regression analysis was performed to identify independent risk factors for bronchopulmonary dysplasia in the first weeks of life. ResultsA total of 202 newborns were included in the study (mean gestational age 29.5 ± 2.1 weeks), 61.4% never received invasive mechanical ventilation. The incidence of bronchopulmonary dysplasia was 28.7%, and 10.4% of the patients were diagnosed with moderate-severe bronchopulmonary dysplasia. Bronchopulmonary dysplasia was independently associated with gestational age (P < 0.001; OR = 0.44 (95% CI = 0.30–0.65)), the need for mechanical ventilation on the first day of life (P = 0.001; OR = 8.13 ((95% CI = 2.41–27.42)), nosocomial sepsis (P < 0.001; OR = 9.51 ((95% CI = 2.99–30.28)) and FiO2 on day 14 (P < 0.001; OR = 1.39 ((95% CI = 1.16–1.66)). Receiving mechanical ventilation at the first day of life (P = 0.008; OR = 5.39 ((95% CI = 1.54–18.89)) and at the third day of life (P = 0.001; OR = 9.99 ((95% CI = 2.47–40.44)) and nosocomial sepsis (P = 0.001; OR = 9.87 ((95% CI = 2.58–37.80)) were independent risk factors for moderate-severe bronchopulmonary dysplasia. ConclusionsGestational age, mechanical ventilation in the first days of life and nosocomial sepsis are early risk factors for bronchopulmonary dysplasia. The analysis of simple and objective clinical data, allows us to select a group of patients at high risk of bronchopulmonary dysplasia in whom it could be justified to act more aggressively, and shows areas for improvement to prevent its development or reduce its severity.

Efficacy and safety of intratracheal administration of budesonide combined with pulmonary surfactant in preventing bronchopulmonary dysplasia: a prospective randomized controlled trial.

To study the efficacy and safety of early intratracheal administration of budesonide combined with pulmonary surfactant (PS) in preventing bronchopulmonary dysplasia (BPD). A prospective randomized controlled trial was designed. A total of 122 infants with a high risk of BPD who were admitted to the neonatal intensive care unit of the Third Affiliated Hospital of Zhengzhou University from January to July 2021 were enrolled. The infants were randomly divided into a conventional treatment group with 62 infants (treated with PS alone at an initial dose of 200 mg/kg, followed by a dose of 100 mg/kg according to the condition of the infant) and an observation group with 60 infants (treated with PS at the same dose as the conventional treatment group, with the addition of budesonide 0.25 mg/kg for intratracheal instillation at each time of PS application). The two groups were compared in terms of the times of PS use, ventilator parameters at different time points, oxygen inhalation, incidence rate and severity of BPD, incidence rate of complications, and tidal breathing pulmonary function at the corrected gestational age of 40 weeks. Compared with the conventional treatment group, the observation group had a significantly lower proportion of infants using PS for two or three times (P<0.05). Compared with the conventional treatment group, the observation group had a significantly lower fraction of inspired oxygen at 24 and 48 hours and 3, 7, and 21 days after administration, significantly shorter durations of invasive ventilation, noninvasive ventilation, ventilator application, and oxygen therapy, a significantly lower incidence rate of BPD, and a significantly lower severity of BPD (P<0.05). There was no significant difference in the incidence rate of glucocorticoid-related complications between the two groups (P>0.05). Compared with PS use alone in preterm infants with a high risk of BPD, budesonide combined with PS can reduce repeated use of PS, lower ventilator parameters, shorten the duration of respiratory support, and reduce the incidence rate and severity of BPD, without increasing the incidence rate of glucocorticoid-related complications.

Corticosteroids in the prevention and treatment of infants with bronchopulmonary dysplasia: Part II. Inhaled corticosteroids alone or in combination with surfactants

This paper is the second in a two-part State-of-the-Art series that reviews the latest relevant clinical trials investigating the short-term and long-term effects of corticosteroids in the prevention and treatment of bronchopulmonary dysplasia (BPD). Inhaled postnatal corticosteroids demonstrate low systemic bioavailability and rapid systemic clearance with high pulmonary deposition and were expected to reduce the incidence of BPD with reduced adverse effects, however, increased rate of mortality in the neonatal period and at the 18-24 months follow-up was observed. In a milestone study, intratracheal instillation of corticosteroids combined with surfactant decreased the incidence of BPD without increasing the mortality or the long-term neurodevelopmental adverse outcomes. However, subsequent trials using different types of surfactants, different surfactant to budesonide ratio, different time of the drug administration for infants with different severity of respiratory distress syndrome could not reproduce all the beneficial effects. Future perspectives for the identification of premature infants at high risk of BPD and the prevention or treatment of established BPD are discussed.

9 The Burden of Bronchopulmonary Dysplasia and Pulmonary Vascular Disease in Premature Infants

Abstract Primary Subject area Neonatal-Perinatal Medicine Background Extremely premature infants are at a high risk of bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension (PH). Prolonged patency of the ductus arteriosus (PDA) may worsen PH; however, due to the lack of evidence supporting improvement in outcomes after strategies to promote ductal closure, our center has adopted a strict non-intervention policy since 2013. Objectives Assess PH prevalence and severity, as well as the impact of BPD on echocardiographic parameters of cardiac performance. Design/Methods Retrospective cohort of infants &amp;lt;29 weeks gestational age at birth, admitted between 2015 and 2019, and without genetic/congenital anomalies. Measurements from the echocardiography acquired closest to 36 weeks were done by masked experts. Severe BPD was defined as positive pressure support at 36 weeks. PH was defined as an estimated systolic pulmonary pressure (SPAP) ≥40 mmHg or an abnormal septal curvature by eccentricity index (EI) (&amp;gt;1.3). Results Out of 387 infants, 222 were included, of which 27 (12%) were categorized as severe BPD and 78 (35%) had PH. Severe BPD was associated with lower birth weight (704±214 vs 842±229g, p&amp;lt;0.01), longer hospitalization (median 138 [IQR 108-167] vs 103 [IQR 86-125] days, p&amp;lt;0.01) and longer mechanical ventilation duration (median 82 [IQR 33-107] vs 17 [IQR 2-32] days, p&amp;lt;0.01), with no difference in gestational age at birth. Severe BPD was associated with PH (70% vs 43%, p&amp;lt;0.01). The combined outcome of death (after the 36 weeks echocardiography) or severe BPD was associated with PH (68% vs 30%, p&amp;lt;0.01), smaller left ventricle length in diastole (2.8±0.5 vs 3.0±0.5 cm, p=0.03), decrease in the tricuspid annular plane systolic excursion (0.7±0.2 vs 0.9±0.2 cm, p&amp;lt;0.01), abnormal EI (1.31±0.25 vs 1.17±0.18, p&amp;lt;0.01) and smaller right ventricle fraction area change (41.3±5.8 vs 47.8±7.6%, p&amp;lt;0.01), without a significant increase on SPAP (35±21 vs 35±14, p=0.15). Other echocardiographic markers were similar. Conclusion In the context of a PDA non-intervention policy, a third of our population was affected by PH at 36 weeks. Furthermore, those with severe BPD or death had signs of RV dysfunction (despite similar SPAP estimate), indicating that the effect of BPD on pulmonary vascular remodelling and cardiac function may be underestimated.

Should Vitamin A Injections to Prevent Bronchopulmonary Dysplasia or Death Be Reserved for High-Risk Infants? Reanalysis of the National Institute of Child Health and Human Development Neonatal Research Network Randomized Trial

To determine whether infants at higher risk of bronchopulmonary dysplasia (BPD) or death benefit more from vitamin A therapy than those at lower risk. We conducted a post hoc reanalysis of a landmark phase III randomized controlled trial conducted from January 1996 to July 1997 at 14 university-affiliated neonatal intensive care units in the US. Data analysis was performed from October 2019 to October 2020. Infants born weighing 401-1000g and receiving respiratory support at 24hours of age were assigned to intramuscular vitamin A 5000 IU or sham procedure 3 times weekly for 4weeks. The primary outcome was BPD, defined as use of supplemental oxygen, or death at 36weeks postmenstrual age. An externally validated model for predicting BPD or death was used to estimate the risk of these outcomes for each infant. As previously reported, 222 of 405 infants (54.8%) assigned vitamin A therapy and 248 of 402 infants (61.7%) in the control group developed BPD or died (relative risk [RR], 0.89 [95% CI, 0.80-0.99]; risk difference [RD], -6.9% [95% CI, -13.0 to -0.7]). The predicted individual risks of BPD or death ranged from 7.1% to 98.6% (median, 61.5%; mean, 60.9%). The effect of vitamin A therapy on BPD or death depended on infants' risk of the primary outcome (P=.03 for interaction): for example, a RR of 0.73 (RD, -14.5%) for infants with a 25% predicted risk and a RR of 0.96 (RD, -1.0%) for infants with a 75% risk. There was no difference in the decrease in vitamin A deficiency across risk groups. Contrary to expectations, the effect of vitamin A therapy on BPD or death was greater for lower risk than higher risk infants. ClinicalTrials.gov NCT01203488.

Epidemiología y factores de riesgo asociados a displasia broncopulmonar en prematuros menores de 32 semanas de edad gestacional

ObjectivesTo describe risk factors of bronchopulmonary dysplasia in very preterm infants in the first weeks of life. Material and methodsRetrospective cohort study of preterm infants ≤ 32 weeks of gestational age and birth weight ≤ 1500 g. A multivariate logistic regression analysis was performed to identify independent risk factors for bronchopulmonary dysplasia in the first weeks of life. ResultsA total of 202 newborns were included in the study (mean gestational age 29.5 ± 2.1 weeks), 61.4% never received invasive mechanical ventilation. The incidence of bronchopulmonary dysplasia was 28.7%, and 10.4% of the patients were diagnosed with moderate–severe bronchopulmonary dysplasia.Bronchopulmonary dysplasia was independently associated with gestational age at birth (p < 0.001; OR = 0.44 [95% CI = 0.30–0.65]), the need for mechanical ventilation on the first day of life (p = 0.001; OR = 8.13 [95% CI = 2.41–27.42]), nosocomial sepsis (p < 0.001; OR = 9.51 [95% CI = 2.99–30.28]) and FiO2 on day 14 (p < 0.001; OR = 1.39 [95% CI = 1.16–1.66]). Receiving mechanical ventilation at the first day of life (p = 0.008; OR = 5.39 [95% CI = 1.54–18.89]) and at the third day of life (p = 0.001; OR = 9.99 [95% CI = 2.47–40.44]) and nosocomial sepsis (p = 0.001; OR = 9.87 [95% CI = 2.58–37.80]) were independent risk factors for moderate–severe bronchopulmonary dysplasia. ConclusionsGestational age at birth, mechanical ventilation in the first days of life and nosocomial sepsis are early risk factors for bronchopulmonary dysplasia. The analysis of simple and objective clinical data, allows us to select a group of patients at high risk of bronchopulmonary dysplasia in whom it could be justified to act more aggressively, and shows areas for improvement to prevent its development or reduce its severity.

Umbilical Cord Blood-Derived Exosomes From Very Preterm Infants With Bronchopulmonary Dysplasia Impaired Endothelial Angiogenesis: Roles of Exosomal MicroRNAs.

Premature infants have a high risk of bronchopulmonary dysplasia (BPD), which is characterized by abnormal development of alveoli and pulmonary vessels. Exosomes and exosomal miRNAs (EXO-miRNAs) from bronchoalveolar lavage fluid are involved in the development of BPD and might serve as predictive biomarkers for BPD. However, the roles of exosomes and EXO-miRNAs from umbilical cord blood of BPD infants in regulating angiogenesis are yet to be elucidated. In this study, we showed that umbilical cord blood-derived exosomes from BPD infants impaired angiogenesis in vitro. Next-generation sequencing of EXO-miRNAs from preterm infants without (NBPD group) or with BPD (BPD group) uncovered a total of 418 differentially expressed (DE) EXO-miRNAs. These DE EXO-miRNAs were primarily enriched in cellular function-associated pathways including the PI3K/Akt and angiogenesis-related signaling pathways. Among those EXO-miRNAs which are associated with PI3K/Akt and angiogenesis-related signaling pathways, BPD reduced the expression of hsa-miR-103a-3p and hsa-miR-185-5p exhibiting the most significant reduction (14.3% and 23.1% of NBPD group, respectively); BPD increased hsa-miR-200a-3p expression by 2.64 folds of the NBPD group. Furthermore, overexpression of hsa-miR-103a-3p and hsa-miR-185-5p in normal human umbilical vein endothelial cells (HUVECs) significantly enhanced endothelial cell proliferation, tube formation, and cell migration, whereas overexpressing hsa-miR-200a-3p inhibited these cellular responses. This study demonstrates that exosomes derived from umbilical cord blood of BPD infants impair angiogenesis, possibly via DE EXO-miRNAs, which might contribute to the development of BPD.

A comparison of LISA versus InSurE: A single center experience.

Less invasive surfactant replacement therapy (SRT) methods have been linked to better respiratory outcomes. The primary aim of this study was to determine if Less Invasive Surfactant Administration (LISA) altered the rate of bronchopulmonary dysplasia (BPD) in preterm infants. Secondary objectives were to determine if LISA compared to Intubation Surfactant Extubation (InSurE) resulted in different respiratory outcomes and hospital course. In this retrospective chart review, outcomes were compared in two preterm infant groups (25-32 weeks gestation). Infants in Group 1 received surfactant replacement therapy (SRT) via InSurE method, while infants in Group 2 received SRT via LISA method. Regardless of SRT method utilized, there were no significant differences in rates of BPD between the two groups in infants born at 25-32 weeks gestation (30.6% vs 33.3%; P = 0.47). Despite using LISA method rather than InSurE for SRT, premature infants continue to be at high risk for BPD. LISA shows promise as a safe, noninvasive SRT alternative to invasive methods like InSurE.

Composition and origin of lung fluid proteome in premature infants and relationship to respiratory outcome.

BackgroundInfants born at extremely low gestational age are at high risk for bronchopulmonary dysplasia and continuing lung disease. There are no early clinical biomarkers for pulmonary outcome and limited therapeutic interventions.ObjectivesWe performed global proteomics of premature infant tracheal aspirate (TA) and plasma to determine the composition and source of lung fluid proteins and to identify potential biomarkers of respiratory outcome.MethodsTA samples were collected from intubated infants in the TOLSURF cohort before and after nitric oxide treatment, and plasma was collected from NO CLD infants. Protein abundance was assayed by HPLC/tandem mass spectrometry and Protein Prospector software. mRNA abundance in mid-gestation fetal lung was assessed by RNA sequencing. Pulmonary morbidity was defined as a need for ventilatory support at term and during the first year.ResultsAbundant TA proteins included albumin, hemoglobin, and actin-related proteins. 96 of 137 detected plasma proteins were present in TA (r = 0.69, p<0.00001). Based on lung RNAseq data, ~88% of detected TA proteins in injured infant lung are derived at least in part from lung epithelium with overrepresentation in categories of cell membrane/secretion and stress/inflammation. Comparing 37 infants at study enrollment (7–14 days) who did or did not develop persistent pulmonary morbidity, candidate biomarkers of both lung (eg., annexin A5) and plasma (eg., vitamin D-binding protein) origin were identified. Notably, levels of free hemoglobin were 2.9-fold (p = 0.03) higher in infants with pulmonary morbidity. In time course studies, hemoglobin decreased markedly in most infants after enrollment coincident with initiation of inhaled nitric oxide treatment.ConclusionsWe conclude that both lung epithelium and plasma contribute to the lung fluid proteome in premature infants with lung injury. Early postnatal elevation of free hemoglobin and heme, which are both pro-oxidants, may contribute to persistent lung disease by depleting nitric oxide and increasing oxidative/nitrative stress.

Correlation between chorionic plate vascularization and risk of bronchopulmonary dysplasia in extremely preterm infants

Introduction/objectivesThe chorionic plate vessels of the placenta are in direct continuity with the fetal vasculature, suggesting chorionic and fetal angiogenesis may be subjected to similar regulatory mechanisms. In this study, we determined the correlation between chorionic plate vascularization and complications of prematurity, focusing on bronchopulmonary dysplasia (BPD) and other conditions with important microvascular components. MethodsWe performed a clinicoplacental analysis of 127 extremely preterm infants (23–28 weeks gestation). Chorionic plate vascularization was assessed by number and density of perforating chorionic vessels (PCVs). Charts were reviewed for relevant maternal and neonatal data, including respiratory, neurologic and gastrointestinal complications of prematurity. ResultsThe placentas displayed marked variability in number (36–523/placenta) and density of PCVs (0.46–3.74 PC V/cm2). The median PCV density of infants with severe BPD was significantly higher than that of infants without BPD (1.51 PC V/cm2 versus 1.09 PC V/cm2, P < 0.05). Conversely, the frequency of moderate-to-severe BPD was 33% higher in infants with PCV density ≥1.50 PC V/cm2 than in those with PCV density <1.50 PC V/cm2 (56% versus 40%, P < 0.01). There was no correlation with neonatal neurologic or gastrointestinal complications. ConclusionChorionic plate vascularization correlates with frequency and severity of BPD, supporting a vascular basis that in part is antenatal in origin. Quantitative assessment of chorionic plate vascularization may allow early identification of preterm infants at high risk for BPD (proposed threshold: PCV density ≥1.50 PC V/cm2). The lack of correlation between chorionic vascularization and neurologic/gastrointestinal complications suggests these conditions may have less important antenatal and/or vascular contributions.

Postnatal Corticosteroids Policy for Very Preterm Infants and Bronchopulmonary Dysplasia

Introduction: Postnatal corticosteroids (PNC) are effective for reducing bronchopulmonary dysplasia (BPD) in very preterm neonates but are associated with adverse effects including an increased risk of cerebral palsy. PNC use in Europe is heterogeneous across regions. This study aimed to assess whether European neonatal intensive care units (NICUs) with a low use of PNC or an explicit policy to reduce PNC use had higher risks of mortality or BPD. Methods: We included 3,126 infants in 105 NICUs born between 24 + 0 and 29 + 6 weeks’ gestational age in 19 regions in 11 countries in the EPICE cohort. First, we identified clusters of NICUs using hierarchical clustering based on PNC use and BPD prevalence and compared case mix and mortality between the clusters. Second, a multilevel analysis was performed to evaluate the association between a restrictive PNC policy and BPD occurrence. Results: There were 3 clusters of NICUs: 52 with low PNC use and a low BPD rate, 37 with low PNC use and a high BPD rate, and 16 with high PNC use and a medium BPD rate. Neonatal mortality did not differ between clusters (p = 0.88). A unit policy of restricted PNC use was not associated with a higher risk of BPD (odds ratio 0.68; 95% confidence interval: 0.45–1.03) after adjustment. Conclusion: Up to 49% of NICUs had low PNC use and low BPD rates, without a difference in mortality. Infants hospitalized in NICUs with a stated policy of low PNC use did not have an increased risk of BPD.

Therapeutic Extracellular Vesicles from Mesenchymal Stromal Cells: Can they help us restore lung development and evade BPD?

There is currently no single effective therapy for either the prevention or treatment of bronchopulmonary dysplasia (BPD), whose incidence is on the rise. Therefore, the need for new tools to treat and reduce risks of further complications associated with extreme preterm birth is urgent. Therapies based on transplantation of mesenchymal stromal cells (MSCs) have shown effectiveness in preclinical models, and promise in recent Phase 1 clinical trials of preterm infants at high risk for BPD. Our studies over the past decade have established that the main therapeutic vector of MSCs is present in their secretome, and is comprised by Extracellular Vesicles (EV), including exosomes. These vectors are small (less than 150nm), lipid bilayer‐enclosed structures secreted by almost all cells. Their varied origin, biogenesis and molecular composition implicate them in diverse and pivotal physiological roles, the most intriguing of which is an effective method of cell‐to‐cell communication dubbed the ‘New Endocrinology’. Consequently, MSC exosomes/small EVs (termed MEx) represent promising novel reagents for therapeutic applications. Work from our group has shown that MEx can restore lung function in rodent experimental models of BPD. MEx treatment suppresses lung inflammation and lung emphysema and restores normal lung development when administered either prenatally to a high risk pregnancy (i.e., preeclampsia or chorioamnionitis), or postnatally, to neonatal mice exposed to hyperoxia‐induced lung injury. Importantly, MEx modulate both innate and adaptive immunity through their effect on lung monocyte/macrophage phenotypes and thymic T cell development as well as promoting bone marrow ‐ derived myeloid cells to adopt a non‐classical signature. Our observations support the hypothesis that reprogrammed monocytes, of bone marrow origin, mediate the protective effects of MEx therapy on the lung and other organs. MEx thus provide a novel platform for therapeutic intervention in the perinatal period to treat tissue injury associated with inflammatory insults and to restore lung development to a physiologic path.Support or Funding InformationSupported in part by NIH grants R01HL146128; United Therapeutics Research Grant; and Charles H. Hood Foundation Major Grants Initiative