Bronchopulmonary Dysplasia Cases Research Articles

Melatonin Supplementation as Adjuvant Therapy for the Prevention of Bronchopulmonary Dysplasia in Neonates

Background: Neonatal bronchopulmonary dysplasia (BPD) is a chronic chest disease caused by prolonged ventilation and oxygenation which leads to neonatal disability.Methods: It was a prospective randomized clinical trial (RCT) (Study ID: TCTR20191211004) which was conducted in Tanta University Hospital (TUH) from July 2016 to March 2018 on 100 preterm neonates who exhibited severe respiratory distress (RD) on mechanical ventilation (MV). The studied neonates were assigned to two groups: group one which received melatonin supplementation and group two which did not. Urinary β2-microglobulin (B2M) and serum Krebs von den Lungen-6 (KL-6) levels were measured 3 and 10 days after hospitalization. The length of neonates’ stay in incubator was determined, and the number of newborns with established BPD was calculated.Results: Significant decreases were detected in urinary B2M and serum KL-6 levels of neonates in group one who received melatonin, as compared to their counterparts in group two who did not take melatonin (P< 0.05). In addition, there was a significant decline in the length of incubator stay of neonates in group one, in comparison to that of newborns in group two (P<0.05). Moreover, neonates in group one who received melatonin displayed a significant decline in the development of established cases of BPD, as compared to group two who did not take melatonin (P<0.05).Conclusion: As evidenced by the obtained results, melatonin supplementation could be used as adjuvant therapy for the prevention of BPD in preterm neonates. Nonetheless, further studies involving a larger number of neonates must be performed on this topic in order to recommend melatonin administration for ventilated premature neonates who are susceptible to the development of neonatal BPD.

Новая форма бронхолегочной дисплазии: реалии сегодняшнего дня

Study Objective: to analyse the dynamics in morbidity of the classic and New forms of bronchopulmonary dysplasia (BPD) in children hospitalised to the National Medical Research Centre of Children Health during previous 8 years. Study Design: retrospective analysis of medical records. Materials and Methods. In 2012–2019, we analysed 369 cases of children with the new BPD and 231 cases of children with the classic disease. Study Results. The article contains the information on the 8-year observation demonstrating prevalence of the new BPD and describes disease characteristics and course in premature infants. The retrospective analysis of 2012–2019 data shows that the number of paediatric patients with the new BPD is gradually increasing. Whereas in 2012 the classic BPD prevailed (156 (68.4%) out of 228 children with confirmed diagnosis), later the new form accounted for more BPD cases (p &lt; 0.05). According to information available, an equal ratio (50% for the classic form and 50% for the new form) is demonstrated in 2013, the period when the Russian Federation started using the live birth and dead birth criteria proposed by the World Health Organisation (WHO). Conclusion. Improved neonatal intensive care methods and transition of the Russian Federation to the WHO live birth and dead birth criteria in 2012 were pre-conditions for BPD pathomorphism. The of rate of the classic form in the Russian Federation has been decreasing year after year. It is essential to identify the long-term complications from the new BPD, especially functional capabilities of the respiratory tract in older patients with the history of disease. Study of the features and long-term complications from this new form is a burning issue of paediatric pulmonology and requires careful attention. Keywords: bronchopulmonary dysplasia, new form, classic form, premature infants.

Analysis of the respiratory therapy in newborns with extremely low body weight at birth

Respiratory therapy is the main component of intensive care for premature newborns, it has a great influence on nursing outcomes.Characteristics of children and research methods. The authors carried put a retrospective analysis of the intensive care effectiveness in 44 infants with extremely low body mass at birth.Results. They found the cases of bronchopulmonary dysplasia and evaluated the treatment effectiveness depending on the weight and gestational age. The children with birth weight of 500–699 grams demonstrated low efficiency of intensive care and adverse course of bronchopulmonary dysplasia. This group of premature infants was characterized by a prolonged stay in the intensive care unit, mechanical ventilation, low body mass dynamics, and, as a result, had a high mortality rate in the late neonatal period compared to the group of children born with a birth weight of more than 700 g (p &lt;0.05).Conclusion. Effective nursing of preterm infants with a birth weight less than 700g requires a combination of an individual approach to the auxiliary ventilation methods and a non-invasive ventilation regimen along with pharmacotherapy that stimulates the respiratory center of the newborn and promotes the maturation of surfactant to prevent complications of respiratory therapy.

Association of Chorioamnionitis With Bronchopulmonary Dysplasia Among Preterm Infants

Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, remains one of the major and most common complications of very preterm birth. Insight into factors associated with the pathogenesis of BPD is key to improving its prevention and treatment. To perform a systematic review, meta-analysis, and metaregression of clinical studies exploring the association between chorioamnionitis (CA) and BPD in preterm infants. PubMed and Embase were searched without language restriction (last search, October 1, 2018). Key search terms included bronchopulmonary dysplasia, chorioamnionitis, and risk factors. Included studies were peer-reviewed studies examining preterm (<37 weeks' gestation) or very low-birth-weight (<1500 g) infants and reporting primary data that could be used to measure the association between exposure to CA and the development of BPD. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guideline was followed. Data were independently extracted by 2 researchers. A random-effects model was used to calculate odds ratios (ORs) and 95% CIs. Heterogeneity in effect size across studies was studied using multivariate, random-effects metaregression analysis. The primary outcome was BPD, defined as supplemental oxygen requirement on postnatal day 28 (BPD28) or at the postmenstrual age of 36 weeks (BPD36). Covariates considered as potential confounders included differences between CA-exposed and CA-unexposed infants in gestational age, rates of respiratory distress syndrome (RDS), exposure to antenatal corticosteroids, and rates of early- and late-onset sepsis. A total of 3170 potentially relevant studies were found, of which 158 met the inclusion criteria (244 096 preterm infants, 20 971 CA cases, and 24 335 BPD cases). Meta-analysis showed that CA exposure was significantly associated with BPD28 (65 studies; OR, 2.32; 95% CI, 1.88-2.86; P < .001; heterogeneity: I2 = 84%; P < .001) and BPD36 (108 studies; OR, 1.29; 95% CI, 1.17-1.42; P < .001; heterogeneity: I2 = 63%; P < .001). The association between CA and BPD remained significant for both clinical and histologic CA. In addition, significant differences were found between CA-exposed and CA-unexposed infants in gestational age, birth weight, odds of being small for gestational age, exposure to antenatal corticosteroids, and early- and late-onset sepsis. Chorioamnionitis was not significantly associated with RDS (48 studies; OR, 1.10; 95% CI, 0.92-1.34; P = .24; heterogeneity: I2 = 90%; P < .001), but multivariate metaregression analysis with backward elimination revealed that a model combining the difference in gestational age and the odds of RDS was associated with 64% of the variance in the association between CA and BPD36 across studies. The results of this study confirm that among preterm infants, exposure to CA is associated with a higher risk of developing BPD, but this association may be modulated by gestational age and risk of RDS.

Clinical characteristics and risk factors of very low birth weight and extremely low birth weight infants with bronchopulmonary dysplasia: multicenter retrospective analysis

Objective: To analyze clinical characteristics and risk factors of very low birth weight and extremely low birth weight infants with bronchopulmonary dysplasia (BPD). Methods: A retrospective epidemiological study was performed in 768 neonates (376 males) with birth weights<1 500 g and gestational age ≤ 34 weeks who survived ≥28 days. Clinical data were obtained from the multi-center clinical database of neonatal intensive care units (NICU) in 19 hospitals of Jiangsu Province between January 1, 2017 and December 31, 2017. These infants were divided into non-BPD group and BPD group according to BPD diagnositic criteria. Clinical features and potential risk factors were compared between groups with Chi-square test or nonparametric test. Risk factors for BPD were analyzed with Logistic regression analysis. Results: Among the total of 768 eligible neonates, 577 without BPD, 191 with BPD (24.9%). Mild, moderate and severe BPD accounted for 73.3% (140/191), 23.6% (45/191) and 3.1% (6/191) of all BPD cases respectively. There were significant differences in the average gestational age (29 (28, 30) vs. 30 (29, 31) weeks) or the average birth weight (1 170 (990, 1 300) vs. 1 300 (1 160, 1 400) g) between BPD group and non-BPD group (Z=-9.959,-7.202, both P=0.000). The incidences of BPD in the infants with gestational age of<28 weeks, 28-31 weeks and 32-34 weeks were 51.7% (46/89), 24.8% (139/561), 5.1% (6/118) respectively. The incidences of BPD in infants with birth weight<1 000 g, 1 000- 1 249 g and 1 250-1 500 g were 62.3% (48/77), 25.9% (70/270) and 17.3% (73/421) respectively. Proportion of male (55.5% (106/191) vs. 46.8% (270/577)), rate and length of conventional mechanical ventilation (48.7% (93/191) vs. 14.9% (86/577), 120 (72, 259) vs. 80 (29, 144)h), initial inhaled oxygen concentration and maximum inhaled oxygen concentration (0.35 (0.30, 0.40) vs. 0.30(0.25, 0.40), 0.40 (0.30, 0.50) vs. 0.30 (0.30, 0.40)) and volume of red blood cell transfusion (53(30, 90) vs.38(28, 55) ml) were higher in BPD group than in non-BPD group (χ(2)=4.350, 91.640, Z=-3.557, -2.848, -3.776, -4.677, all P<0.05). Rate of continuous positive airway pressure (12.6%(24/191) vs. 19.4%(112/577)) during neonatal resuscitation in delivery room was lower in BPD group than that in non-BPD group (χ(2)=4.614, P=0.032). The incidences of complications in BPD group including severe asphyxia, neonatal respiratory distress syndrome (NRDS), persistent pulmonary hypertension in newborns (PPHN), patent ductus arteriosus, anemia of prematurity, early onset sepsis, clinical sepsis and ventilator associated pneumonia were higher than that in non-BPD group (15.2%(29/191) vs. 4.5% (26/577), 91.1% (174/191) vs. 56.7% (327/577), 2.6% (5/191) vs. 0.2% (1/577), 43.5% (83/191) vs. 34.2% (197/577), 88.0% (168/191) vs. 58.8% (339/577), 15.7% (30/191) vs. 9.9% (57/577), 42.9% (82/191) vs. 18.6% (107/577), 14.1% (27/191) vs. 2.3% (13/577); χ(2)=24.605, 74.993, 9.167, 5.373, 61.866, 4.557, 43.149, 34.315, all P<0.05). Multivariate logistic regression analysis showed that NRDS (OR=4.651, 95%CI: 1.860-11.625), clinical sepsis (OR=1.989, 95%CI: 1.067-3.708), ventilator associated pneumonia (OR=3.155, 95%CI: 1.060-9.388), conventional mechanical ventilation (OR=2.298, 95%CI: 1.152-4.586), and volume of red blood cell transfusion (OR=1.013, 95%CI: 1.002-1.024) were risk factors of BPD. Conclusions: BPD is more common in very low birth weight infants of male with gestational age less than 32 weeks. Using CPAP in the delivery room, active treatment of NRDS, preventing nosocomial infection, and reducing invasive ventilation and red blood cell transfusion may decrease the incidence of BPD.

Relationship between clinical severity of "new" bronchopulmonary dysplasia and HRCT abnormalities in VLBW infants.

To assess the relationship between HRCT abnormalities and the clinical severity of "new" bronchopulmonary dysplasia (BPD) and respiratory assistance in <1500 g preterm infants. HRCT was performed at the time of discharge in 109 preterm infants with BPD who were born between 2008 and 2014. BPD severity was defined as mild, moderate, or severe according to the NIH diagnostic criteria. Total HRCT scores for each infant were obtained from the sum of the number of BPD lobes assessed by two radiologists: a hyperaeration score (Hs) composed of decreased attenuation, mosaic attenuation, and bulla/bleb, and a parenchyma score (Ps) composed of linear lesions, consolidation, bronchial wall thickening, and bronchiectasis. We compared HRCT scores based on BPD severity and respiratory modes, such as invasive mechanical ventilation (IMV), non-invasive MV (NIMV), and oxygen therapy. Among the group of included infants (n = 101), mild BPD was found in 46.5%, moderate BPD in 45.5%, and severe BPD in 7.9%. When partial correlation was adjusted by gestational age (GA) and birth weight, the duration of NIMV was correlated with Ps (r = 0.382, P < 0.001), Hs (r = 0.223, P = 0.027), and total score (r = 0.384, P < 0.001). The duration of oxygen therapy was correlated with Ps (r = 0.374, P < 0.001) and Hs (r = 0.227, P = 0.023). Ps showed a correlation with BPD severity (r = 0.381, P = 0.007) in infants born at ≤26 weeks (GA) and those born at >27 weeks GA (r = 0.298, P = 0.042). Parenchymal changes showed a greater correlation with the clinical severity of "new" BPD cases, especially in infants born at ≤26 weeks GA. The use of NIMV showed a greater correlation with Ps than Hs.

Association of cytokine gene polymorphisms with bronchopulmonary dysplasia in Han Chinese newborns.

To investigate the association of 14 cytokine gene polymorphisms with bronchopulmonary dysplasia (BPD) among Han Chinese newborns. The 14 polymorphisms investigated were IL18 rs1946519, rs1946518, rs187238, rs360718, and rs360717 polymorphisms, IL10 rs3024493 polymorphism, IL6 rs1800795, rs1800796, and rs1800797 polymorphisms, TNF rs361525 and rs1800629 polymorphisms, and TGFB1 rs1800469, rs1800468, and rs1800471 polymorphisms. The polymorphisms could be associated with the risk of BPD among Han Chinese newborns. This is a retrospective study. Genotyping of these polymorphisms were performed on BPD cases (N = 1022) and non-BPD controls (N = 1039) who were ascertained using the established Jobe and Bancalari criteria. The odds ratios (ORs) of polymorphisms whose genotype distribution in the controls fulfilled the Hardy-Weinberg equilibrium (HWE) were calculated to evaluate the strengths of genetic association. Genotype distributions of IL6 rs1800795 and rs1800797 polymorphisms deviated significantly from HWE and were omitted from the analysis. Among the 12 remaining polymorphisms, only TNF rs361525 polymorphism demonstrated a statistically significant association with BPD risk. The heterozygous GA genotype of TNF rs361525 polymorphism showed an OR of 1.932 (1.512-2.470), while the homozygous AA variant genotype showed an OR of 2.927 (1.216-7.048) (P = 0.000 and P = 0.017, respectively). Besides, the allelic OR was also analyzed, and it was found that the variant A allele of TNF rs361525 polymorphism showed an OR of 2.146 (1.718-2.680) (P = 0.000). TNF rs361525 polymorphism could influence BPD risk among Han Chinese newborns.

Long-term outcomes of extremely preterm infants and extremely low birth weight infants with low one-minute Apgar score

Objective To investigate the relationships between low one-minute Apgar score and the prognosis of extremely preterm infants (EPI) and extremely low birth weight infants (ELBWI). Methods Altogether 50 EPI and ELBWI who had a low one-minute Apgar score (≤7) and were admitted to the Neonatal Intensive Care Unit (NICU) of Peking University Third Hospital from January 1,2010 to December 31, 2015 were enrolled in this study. All of them were divided into two groups according to their Apgar score: mild group (4-7) and severe group (0-3). Medical records of the subjects were reviewed and an at least 18 months follow up study was conducted. Conditions of all subjects during perinatal period and hospitalization were summarized. Outcomes and follow-up results were compared between the two groups by using Fisher exact test. Results (1) General information: Fifty infants were involved, among which 37 had a mild low Apgar score and 13 had a severe low Apgar score. The mean gestational age was (27.7±2.1) weeks and the mean birth weight was (884.4±174.3) grams. (2) Main complications (some infants with more than one complication): There were 42 cases of neonatal respiratory distress syndrome, 12 cases of pulmonary hemorrhage, 21 cases of bronchopulmonary dysplasia, 31 cases of patent ductus arteriosus, 36 cases of intraventricular hemorrhage, 22 cases of white matter damage and six cases of retinopathy of prematurity. (3) Outcomes: The survival rate was 48% (24/50) and the mortality rate was 52% (26/50). Among the 26 infants, five died despite treatment and 21 died within 72 hours after their parents giving up treatment. There were no significant differences in the survival rates, mortality rates and rates of abandon treatment between the two groups [43% (16/37) vs 8/13; 11% (4/37) vs 1/13; 46% (17/37) vs 4/13; Fisher exact test, all P>0.05]. (4) Follow-up results: Twenty-one infants were followed-up to at least 18 months of age, among which four were normal, 10 had growth retardation and recurrent respiratory tract infection and seven had motor development retardation. The incidence of motor development retardation in severe group was higher than that in mild group, and the difference between them was statistically significant (5/8 vs 2/13, Fisher exact test, P=0.046). Conclusions EPI or ELBWI with a low one-minute Apgar score have many nosocomial complications, resulting in high mortality and high incidence of motor development retardation. Key words: Infant, extremely low birth weight; Apgar score; Survival rate; Treatment outcome

Vitamin A Supplementation for Prevention of Bronchopulmonary Dysplasia: Cornerstone of Care or Futile Therapy?

To review the evidence on vitamin A supplementation (VAS) and bronchopulmonary dysplasia (BPD) in extremely-low-birth-weight infants. We also discuss the impact of a vitamin A shortage on BPD rates. A PubMed search inclusive of dates 1946 to March 2016 was performed using the search terms bronchopulmonary dysplasia, chronic lung disease (CLD), and vitamin A STUDY SELECTION AND DATA EXTRACTION: All English-language studies were evaluated. Only those investigating VAS by intramuscular administration were included. A total of 6 studies were evaluated. Additionally, a report on the incidence of BPD during a national shortage was reviewed. Investigators found mixed results with VAS and incidence of CLD or death in a varying number of neonates. In the largest evaluation, investigators found a statistically significant decrease in the rate of death or BPD: 55% in the VAS group versus 62% in the placebo group. The number needed to treat to prevent 1 case of BPD was 15 infants. Few studies found an increased incidence of adverse events following VAS. A report over a 2-year shortage period found that whereas the rate of VAS declined dramatically, BPD rates remained stable. This large observational evaluation calls into question the place of vitamin A in BPD prevention. VAS has been identified as a strategy to decrease the incidence of BPD. Initial large-scale prospective evaluations have shown clear benefit of VAS in reducing the incidence of CLD or death. However, changing definitions of BPD and implementation of noninvasive ventilation strategies limit the application of early studies. During a drug shortage, VAS declined dramatically, but BPD rates remained stable. With concerns of sepsis and necrotizing enterocolitis in small-scale studies, and in light of the recent shortage evidence, further evaluations are necessary before VAS can be recommended as a cornerstone of BPD prevention.

Quantitative Magnetic Resonance Imaging of Bronchopulmonary Dysplasia in the Neonatal Intensive Care Unit Environment.

Bronchopulmonary dysplasia (BPD) is a prevalent yet poorly characterized pulmonary complication of premature birth; the current definition is based solely on oxygen dependence at 36 weeks postmenstrual age without objective measurements of structural abnormalities across disease severity. We hypothesize that magnetic resonance imaging (MRI) can spatially resolve and quantify the structural abnormalities of the neonatal lung parenchyma associated with premature birth. Using a unique, small-footprint, 1.5-T MRI scanner within our neonatal intensive care unit (NICU), diagnostic-quality MRIs using commercially available sequences (gradient echo and spin echo) were acquired during quiet breathing in six patients with BPD, six premature patients without diagnosed BPD, and six full-term NICU patients (gestational ages, 23-39 wk) at near term-equivalent age, without administration of sedation or intravenous contrast. Images were scored by a radiologist using a modified Ochiai score, and volumes of high- and low-signal intensity lung parenchyma were quantified by segmentation and threshold analysis. Signal increases, putatively combinations of fibrosis, edema, and atelectasis, were present in all premature infants. Infants with diagnosed BPD had significantly greater volume of high-signal lung (mean ± SD, 26.1 ± 13.8%) compared with full-term infants (7.3 ± 8.2%; P = 0.020) and premature infants without BPD (8.2 ± 6.4%; P = 0.026). Signal decreases, presumably alveolar simplification, only appeared in the most severe BPD cases, although cystic appearance did increase with severity. Pulmonary MRI reveals quantifiable, significant differences between patients with BPD, premature patients without BPD, and full-term control subjects. These methods could be implemented to individually phenotype disease, which may impact clinical care and predict future outcomes.

Genes Encoding Vascular Endothelial Growth Factor A (VEGF-A) and VEGF Receptor 2 (VEGFR-2) and Risk for Bronchopulmonary Dysplasia

Background: Bronchopulmonary dysplasia (BPD) is one of the main consequences of prematurity, with notably high heritability. Vascular endothelial growth factor A (VEGF-A) and its main receptor, vascular endothelial growth factor receptor 2 (VEGFR-2), have been implicated in the pathogenesis of BPD. Objective: To study whether common polymorphisms of the genes encoding VEGF-A and VEGFR-2 are associated with BPD. Methods: In this association study, six tagging single nucleotide polymorphism (tSNPs) for VEGFA and 25 tSNPs for VEGFR2 were genotyped in a prospectively collected, genetically homogeneous discovery population of 160 infants (44 infants with grade 2-3 BPD) born before 30 completed gestational weeks. The replication population of 328 infants included 120 cases of BPD. Results:VEGFR2 SNP rs4576072 was associated with BPD grade 2-3 with a minor allele frequency in 23.9% of the cases compared to 9.1% in controls (p = 0.0005, odds ratio 3.15, 95% CI: 1.62-6.12) in the discovery population. This association was not observed in the more heterogeneous replication population. Conclusions: In line with the results of recent large-scale genetic studies, our findings indicate that common polymorphisms of the genes encoding VEGF-A and VEGFR-2 are not consistently associated with BPD. This finding does not rule out the involvement of VEGFA and VEGFR2 in BPD pathogenesis since, in addition to common variations within the gene region, other mechanisms also play important roles in the regulation of gene function.

Perinatal conditions related to growth restriction and inflammation are associated with an increased risk of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a frequent chronic lung disease in preterm infants, and we aimed to identify factors associated with this condition in infants with respiratory distress syndrome (RDS). This case-control study, using national Swedish data, included 2255 preterm infants, born before 33 gestational weeks. The 667 BPD cases were oxygen dependent at 36 weeks' postmenstrual age, and the 1558 controls only had RDS. Comparisons included perinatal conditions and pharmacological treatments. Adjusted odds ratios with 95% confidence intervals were calculated in a conditional logistic regression model, with gestational age as the conditioning term. An increased risk of BPD was associated with prelabour preterm rupture of membranes of more than 1 week (3.35, 2.16-5.19), small for gestational age (2.73, 2.11-3.55), low Apgar score (1.37, 1.05-1.81), patent ductus arteriosus (1.70, 1.33-2.18), persistent pulmonary hypertension (5.80, 3.21-10.50), pulmonary interstitial emphysema (2.78, 1.37-5.64), pneumothorax (2.95, 1.85-4.72), late onset infections (2.69, 1.82-3.98), intubation (1.56, 1.20-2.03), chest compressions (2.05, 1.15-3.66) and mechanical ventilation (2.16, 1.69-2.77), but not antenatal corticosteroids. Growth restriction and inflammation increased the risk of BPD in preterm infants and prelabour preterm rupture of membranes, small for gestational age, low Apgar score or need for resuscitation should raise clinical suspicions.

Airway Metabolic Anomalies in Adolescents with Bronchopulmonary Dysplasia: New Insights from the Metabolomic Approach

To assess a group of adolescents with bronchopulmonary dysplasia (BPD) from a biochemical-metabolic standpoint, applying the metabolomic approach to studying their exhaled breath condensate (EBC). Twenty adolescents with BPD (mean age 14.8 years) and 15 healthy controls (mean age 15.2 years) were recruited for EBC collection, exhaled nitric oxide measurement, and spirometry. The EBC samples were analyzed using a metabolomic approach based on mass spectrometry. The obtained spectra were analyzed using multivariate statistical analysis tools. A reliable Orthogonal Projections to Latent Structures-Discriminant Analysis model showed a clear discrimination between cases of BPD and healthy controls (R(2) = 0.95 and Q(2) = 0.92). The search for putative biomarkers identified an altered complex lipid profile in the adolescents with BPD. The metabolomic analysis of EBC distinguishes cases of BPD from healthy individuals, suggesting that the lung of survivors of BPD is characterized by long-term metabolic abnormalities. The search for putative biomarkers indicated a possible role of an altered surfactant composition, which may persist far beyond infancy.

Leukotriene Receptor Blockade as a Life-Saving Treatment in Severe Bronchopulmonary Dysplasia

Background: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in infants with an extremely low birth weight. Because there is no effective therapy, the mortality of this condition in severely affected patients is high. Therapeutic blocking of the leukotriene system seems to be a logical approach due to the known pathophysiology of BPD. Objectives: The aim of this study was to examine the therapeutic effect of montelukast in preterm children suffering from severe BPD. Methods: We performed an unblinded, prospective trial including infants born between 23 and 27 weeks of gestation suffering from severe BPD. The study drug was montelukast (1 mg/kg of body weight as a single dose daily in the 1st week of therapy, increasing to 1.5 mg/kg of body weight in the 2nd week and finally to 2 mg/kg of body weight in the 3rd week). Treatment was continued until the radiological signs and the clinical symptoms of BPD disappeared or the patient was discharged from the hospital. Each patient included in this study was matched for gestational age, birth weight, and pulmonary severity score to a control. Results: Until March 2014, a total of 22 infants were enrolled into the study. The rates of the primary outcome differed significantly between the montelukast-treated group and the control group. All but 1 of the children in the treatment group survived (91%), whereas 7 of the 11 children in the control group died (survival rate 36%; p = 0.002 using Fisher's exact test). The mean mechanical ventilation time (41.2 ± 25.3 vs. 103.7 ± 90.6 days) was significantly shorter and the mean preterm complication score (3.0 ± 1.7 vs. 5.6 ± 1.4) was significantly lower in treated patients compared to the control group. (p = 0.05 for both items; Wilcoxon's matched-pairs test). Conclusion: Based on the clinical observations, the statistical results, and the relatively low risk of the study drug montelukast, we recommend using this treatment in severe cases of BPD for infants facing a high risk of death.

Case of acquired lobar emphysema mimicking pneumothorax in a neonate

Despite the improvements in prevention of acute respiratory disease in preterm infants, the incidence of bronchopulmonary dysplasia (BPD) remains largely unchanged. Acquired lobar emphysema (ALE) is an increasingly recognized complication of advanced BPD. Barotrauma, oxygen toxicity and lung immaturity are presumed to play an important role in the development of ALE in children with BPD and most cases present overinflation [1,2]. We report on an infant with BPD who developed ALE mimicking pneumothorax.

Histologic Evidence of Intrapulmonary Anastomoses by Three-Dimensional Reconstruction in Severe Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is the chronic lung disease of infancy that occurs in premature infants after oxygen and ventilator therapy for acute respiratory disease at birth. Despite improvement in current therapies, the clinical course of infants with BPD is often characterized by marked hypoxemia that can become refractory to therapy. Preacinar anatomic and functional communications between systemic and pulmonary vascular systems has been established in fetal lungs, but whether increased intrapulmonary anastomotic vessels or their failure to regress after birth contributes to hypoxemia in preterm infants with BPD is unknown. We sought to find histologic evidence of intrapulmonary anastomotic vessels in lungs of patients who died of severe BPD. We collected lung tissues from fatal BPD cases and performed histology, immunohistochemistry, and high-precision three-dimensional reconstruction techniques. We report histologic evidence of intrapulmonary vessels that bridge pulmonary arteries and veins in the distal lungs of infants dying with severe BPD. These prominent vessels appear similar to "misaligned pulmonary veins" described in the lethal form of congenital lung disorder, alveolar capillary dysplasia. We found striking histological evidence of precapillary arteriovenous anastomotic vessels in the lungs of infants with severe bronchopulmonary dysplasia. We propose that persistence or expansion of these vessels after premature birth provides the anatomic basis for intrapulmonary shunt and hypoxemia in neonates with severe bronchopulmonary dysplasia and may play a significant role in the morbidity and mortality of BPD.

A Genome-Wide Association Study (GWAS) for Bronchopulmonary Dysplasia

Twin studies suggest that heritability of moderate-severe bronchopulmonary dysplasia (BPD) is 53% to 79%, we conducted a genome-wide association study (GWAS) to identify genetic variants associated with the risk for BPD. The discovery GWAS was completed on 1726 very low birth weight infants (gestational age = 25(0)-29(6/7) weeks) who had a minimum of 3 days of intermittent positive pressure ventilation and were in the hospital at 36 weeks' postmenstrual age. At 36 weeks' postmenstrual age, moderate-severe BPD cases (n = 899) were defined as requiring continuous supplemental oxygen, whereas controls (n = 827) inhaled room air. An additional 795 comparable infants (371 cases, 424 controls) were a replication population. Genomic DNA from case and control newborn screening bloodspots was used for the GWAS. The replication study interrogated single-nucleotide polymorphisms (SNPs) identified in the discovery GWAS and those within the HumanExome beadchip. Genotyping using genomic DNA was successful. We did not identify SNPs associated with BPD at the genome-wide significance level (5 × 10(-8)) and no SNP identified in previous studies reached statistical significance (Bonferroni-corrected P value threshold .0018). Pathway analyses were not informative. We did not identify genomic loci or pathways that account for the previously described heritability for BPD. Potential explanations include causal mutations that are genetic variants and were not assayed or are mapped to many distributed loci, inadequate sample size, race ethnicity of our study population, or case-control differences investigated are not attributable to underlying common genetic variation.

Genomic risk factors for bronchopulmonary dysplasia (BPD) in preterm neonates

Current studies indicate that the frequency of BPD in very preterm neonates is in about 15 to 20 % in Europe. Main risk factors have been identified to be the degree of maturity, intrauterine growth restriction and perinatal infections. However, all models can only explain about 60 to 70 % of cases of BPD. Thus, genetic factors must be operative, which will be addressed below.

Genetic predisposing factors to bronchopulmonary dysplasia: preliminary data from a multicentre study

Bronchopulmonary dysplasia (BPD) is the most frequent chronic lung disease in preterm newborn infants. It is a multifactorial disease caused by the interaction between environmental and genetic factors. The aim of this study is to identify genetic variants contributing to BPD development using next-generation sequencing (NGS) technology. We prospectively evaluated 378 premature newborn infants with a gestational age <32 weeks in a multicentre study from 12 Italian neonatal intensive care unit from 2009 to 2012. Infants were divided into two groups: normal controls (225) and BPD-affected infants (141) with mild (65, 46.1%), moderate (40, 28.4%) and severe (36, 25.5%) BPD. BPD was more frequent in infants with lower weight and gestational age. Antenatal steroid administration was more frequent in the control group. Postnatal infection, respiratory distress syndrome, patent ductus arterious, cerebral haemorrhage, surfactant administration, ventilatory support, diuretics and postnatal steroid administration correlated with severity of BPD. Among BPD, moderate and severe cases will be selected as BPD “extreme phenotypes”, and in fact variations in 28-day oxygen need-based BPD were previously shown to be fully attributable to environmental effects whereas dependence on supplemental oxygen at 36 weeks seems to better reflect underlying genetic susceptibility. Exome analysis by NGS is in progress. Identifications of genetic markers predisposing to BPD may allow development of personalized and preventive treatments.

Encouraging Pulmonary Outcome for Surviving, Neurologically Intact, Extremely Premature Infants in the Postsurfactant Era

The aim of this study was to determine the long-term pulmonary outcome of extreme prematurity at a single tertiary-care center from 1997 to 2001 in the postsurfactant era. We assessed symptoms, exhaled nitric oxide, spirometry, methacholine challenge (provocative concentration of methacholine required to decrease FEV₁ by 20% [PC(20)]), lung volumes, diffusion, and cardiopulmonary exercise tolerance. Of 279 infants born, 192 survived to discharge, and 79 of these developed bronchopulmonary dysplasia (BPD) (65 mild, 12 moderate, two severe). We studied a subgroup of 53 neurologically intact preterm subjects aged 10 ± 1.5 years (28 with BPD [born, 26.2 ± 1.4 weeks; birth weight, 821 ± 164 g] and 25 without BPD [born, 27.2 ± 1 weeks; birth weight, 1,050 ± 181 g]) and compared them with 23 term control subjects. Of the BPD cases, 21 were mild, seven were moderate, and none was severe; 77.4% of subjects received antenatal steroids, and 83% received postnatal surfactant. Sixty percent of the preterm subjects wheezed at age < 2 years compared with 13% of the control subjects (P < .001), but only 13% wheezed in the past year compared with 0% of control subjects (not significant). For preterm and control subjects, respectively (mean ± SD), FEV₁ % predicted was 85% ± 10% and 94% ± 10% (P < .001), with limited reversibility; residual volume/total lung capacity was 29.3% ± 5.5% and 25% ± 8% (P < .05); diffusing capacity/alveolar volume was 89.6% ± 9.2% and 97% ± 10% (P < .005); and PC(20) was 6.5 ± 5.8 mg/mL and 11.7 ± 5.5 mg/mL (P < .001). PC(20) was < 4 mg/mL in 49% of preterm subjects despite normal exhaled nitric oxide. Most measurements were similar in premature subjects with and without BPD. Peak oxygen consumption and breathing reserve were normal, but % predicted maximal load (measured in Watts) was 69% ± 15% for subjects with BPD compared with 88% ± 23% for subjects without and 86% ± 20% for control subjects (P < .01). Pulmonary outcome was encouraging at mid-childhood for neurologically intact survivors in the postsurfactant era. Despite mechanical ventilation and oxygen therapy, most had no or mild BPD. Changes found probably reflect the hypoplastic lungs of prematurity.