Update on Postnatal Corticosteroids to Prevent or Treat Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is a major complication of premature birth that significantly affects mortality and long-term morbidity in numerous immature infants. Corticosteroids are particularly suitable for treating BPD, as lung inflammation is central to its pathogenesis. Corticosteroids have considerable, fast beneficial effects on lung function in premature infants with lung disease, but they are also associated with several serious adverse effects, which may have a detrimental impact on long-term outcome. Dexamethasone is the most often used corticosteroid for systemic administration. Despite its value in preventing and treating BPD, its use is associated with several alarming short-term effects and, worst of all, with an increased rate of cerebral palsy in the long term. Dexamethasone nonetheless remains an important therapeutic option for infants with severe lung disease beyond the second to third week of life. Hydrocortisone is an important alternative to dexamethasone, as its use does not appear to be associated with any neurotoxic effects. Its efficacy in the prevention and treatment of BPD has yet to be clearly demonstrated, however. Inhaled corticosteroids might reduce lung inflammation with fewer systemic adverse effects; however, a recent, large randomized trial showed that inhaled budesonide was associated with an excess mortality, despite its beneficial respiratory effects. In another study, instilling budesonide together with surfactant in the trachea of intubated infants with severe respiratory distress appeared safe and achieved a significant reduction in the rate of BPD at 36 postmenstrual weeks. This important finding needs to be confirmed in a larger trial currently underway.

Total body polyethylene wraps for preventing hypothermia in preterm infants: a randomized trial.

OBJECTIVE: To evaluate whether a polyethylene total body wrapping (covering both the body and head) is more effective than conventional treatment (covering up to the shoulders) in reducing perinatal thermal losses in very preterm infants. STUDY DESIGN: This was a multicenter, prospective, randomized, parallel 1:1, unblinded, controlled trial of infants<29 weeks' gestation age, comprising two study groups: experimental group (total body group; both the body and head covered with a polyethylene occlusive bag, with the face uncovered) and control group (only the body, up to the shoulders, covered with a polyethylene occlusive bag). The primary outcome was axillary temperature on neonatal intensive care unit admission immediately after wrap removal. RESULTS: One hundred randomly allocated infants (50 in the total body group and 50 controls) completed the study. Mean axillary temperature on neonatal intensive care unit admission was similar in the two groups (36.5±0.6°C total body vs 36.4±0.8°C controls; P=.53). The rate of moderate hypothermia (temperature<36°C) was 12% in the total body group and 20% in the control group (P=.41). Three subjects in each group (6.0%) had an axillary temperature>37.5°C on admission, and one subject in control group had an axillary temperature>38°C. CONCLUSION: Total body wrapping is comparable with covering the body up to the shoulders in preventing postnatal thermal losses in very preterm infants.

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification.

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.

Evidence of unexpected oxidative stress in airways of adolescents born very pre-term.

Prematurity and its main respiratory complication, bronchopulmonary dysplasia (BPD), are potentially associated with lifelong respiratory morbidities and/or lung function abnormalities. The mechanisms behind these long-term respiratory problems are still unclear. We assessed airway oxidative stress in adolescents born very pre-term (≤ 32 gestational weeks) by measuring 8-isoprostane concentration in exhaled breath condensate (EBC). In addition, the study protocol included spirometry and measurement of exhaled nitric oxide fraction (F(eNO)). The study groups included 34 ex-pre-term adolescents with BPD, 18 ex-pre-term adolescents without BPD and 34 healthy controls born at term. Regardless of a history of BPD, the ex-premature adolescents had higher EBC 8-isoprostane levels (median (interquartile range) BPD 9.5 (7.3-12.2) pg·mL(-1); pre-term non-BPD 10 (8.1-16) pg·mL(-1)) than the controls (3.2 (1.9-6.5) pg·mL(-1)) (p<0.001). Forced expiratory volume in 1 s was lower in the BPD group (mean ± sd Z-score -2.1 ± 1.58) than in the pre-term non-BPD individuals (-1.13 ± 1.15), who showed in turn significantly lower values than the controls (0.18 ± 0.83; p<0.001). F(eNO) was similar in the three groups (p=0.55). Our data show that, after premature birth, evidence of oxidative stress in the airways may be detected into adolescence, suggesting that long-term respiratory abnormalities after pre-term birth may be associated with an ongoing airway disease and not just a stabilised structural lung damage.

L-citrulline prevents alveolar and vascular derangement in a rat model of moderate hyperoxia-induced lung injury.

BACKGROUND: Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of L-arginine to L-citrulline in endothelial cells. We investigated whether administering L-citrulline by raising the serum levels of L-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury. METHODS: Newborn rats were exposed to FiO(2) = 0.6 or room air for 14 days to induce lung derangement and then were administered L-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed. RESULTS: Serum L-arginine rose in the L-citr + hyperoxia group (p = 0.05), as well as the Von Willebrand factor stained vessels count (p = 0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the L-citr + hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with L-citrulline under exposure to hyperoxia (p = 0.0001). Lung VEGF and eNOS increased in the L-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p = 0.003). CONCLUSIONS: We conclude that administering L: -citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.

Mid-childhood lung function in a cohort of children with "new bronchopulmonary dysplasia".

OBJECTIVE: Recent advances in perinatal care and neonatal respiratory therapy have led to a new phenotype of bronchopulmonary dysplasia ("new BPD"). The long-term respiratory outcome of this new form of BPD has yet to be adequately described. Aim of this study was to provide longitudinal data on lung function of an unselected cohort of children born extremely premature (EP) with an extremely low birth weight in the post-surfactant era. STUDY DESIGN: Respiratory function was assessed twice (at 8 and 12 years) in 48 children born at a gestational age <28 weeks with a birth weight <1,000 g. Twenty-eight of them had BPD (oxygen-dependency at 36 weeks postmenstrual age) (EP-BPD), and 20 not (EP non-BPD). Twenty-seven children born at term served as control group. RESULTS: The EP-BPD group had significantly lower spirometric values (given as z-scores) than controls, especially in parameters indicating airflow obstruction (8 ys: zFEV1:-1.3 ± 1 vs. 0.5 ± 0.8; 12 ys:-1.6 ± 1 vs. 0.5 ± 0.8, P < 0.001). Despite their better spirometric profile, EP-non-BPD children also had significantly lower parameters than controls (8ys: zFEV1:-0.5 ± 0.8; 12 ys:-0.5 ± 0.9, P < 0.001). During the 4-year follow-up, EP-non-BPD and controls had stable mean z-scores, but EP-BPD had a significant decline in mean zFEV1 (from -1.3 ± 1 to -1.6 ± 1, P = 0.03), zFEV1/FVC (from -0.4 ± 1 to -1.1 ± 1, P = 0.008), and zFEF 25-75% (from -1.2 ± 1 to -1.8 ± 1, P = 0.03). CONCLUSION: EP children born in the post-surfactant era showed a significant airflow limitation, particularly pronounced in BPD subjects who in addition, presented an abnormal airway growth trajectory with a decline in lung function between the ages of 8 and 12 years. Pediatr Pulmonol. 2016;51:1057-1064. © 2016 Wiley Periodicals, Inc.

Bronchopulmonary dysplasia: the earliest and perhaps the longest lasting obstructive lung disease in humans.

Bronchopulmonary dysplasia (BPD) is one of the most important sequelae of premature birth and the most common form of chronic lung disease of infancy. From a clinical standpoint BPD subjects are characterized by recurrent respiratory symptoms, which are very frequent during the first years of life and, although becoming less severe as children grow up, they remain more common than in term-born controls throughout childhood, adolescence and into adulthood. From a functional point of view BPD subjects show a significant airflow limitation that persists during adolescence and adulthood and they may experience an earlier and steeper decline in lung function during adulthood. Interestingly, patients born prematurely but not developing BPD usually fare better, but they too have airflow limitations during childhood and later on, suggesting that also prematurity per se has life-long detrimental effects on pulmonary function. For the time being, little is known about the presence and nature of pathological mechanisms underlying the clinical and functional picture presented by BPD survivors. Nonetheless, recent data suggest the presence of persistent neutrophilic airway inflammation and oxidative stress and it has been suggested that BPD may be sustained in the long term by inflammatory pathogenic mechanisms similar to those underlying COPD. This hypothesis is intriguing but more pathological data are needed. A better understanding of these pathogenetic mechanisms, in fact, may be able to orient the development of novel targeted therapies or prevention strategies to improve the overall respiratory health of BPD patients.

Asymmetric dimethylarginine in ELBW newborns exposed to chorioamnionitis.

We measured circulating ADMA concentrations in a group of very premature newborns at birth and during the first week of life. ADMA levels resulted significantly higher in infants born to mothers with histologic chorioamnionitis than in infants delivered for other maternal or fetal indications, both at birth and through the first week of life. We speculate that ADMA might be involved in the complex biological events associated with fetal exposure to chorioamnionitis.

Endothelial progenitor cells, bronchopulmonary dysplasia and other short-term outcomes of extremely preterm birth.

AIM: To evaluate the impact of endothelial progenitor cells (EPCs), a subset of committed circulatory stem cells, on the development of bronchopulmonary dysplasia (BPD) and other short term outcomes in a cohort of extremely premature newborns. METHODS: Progenitor cells were quantified by flow cytometry at birth in 36 neonates born <=28 weeks of gestation and at 36 postmenstrual weeks in 18 of them. Cells expressing the stemness markers CD34, CD133, or both were defined as circulating progenitor cells (CPCs). EPCs were defined as CPCs co-expressing the endothelial marker KDR. RESULTS: Mean (SD) gestational age and birth weight of the infants studied were 26.2(1.5) weeks and 761.6(171.8) grams, respectively. EPC levels at birth did not differ between infants who subsequently developed BPD (n=9) and those who did not (n=24) [CD34(+)KDR(+) EPCs: 81(34-41) vs 80(56-110), p=0.7] and were not correlated with the duration of mechanical ventilation or O2-dependence, nor with the need of surfactant replacement. Infants with a hemodynamically significant patent ductus arteriosus (PDA) (n=22) had significantly lower EPC levels at birth than those with no PDA (n=11) [CD34(+)KDR(+) cells: 47(34-92) vs 142(84.5-221), p=0.008]. Data from the 18 infants studied both at birth and at 36 postmenstrual weeks showed that, while CPCs sharply decline over time, levels of all EPCs phenotypes are preserved after delivery. CONCLUSIONS: Levels of EPCs at birth did not affect the risk of developing BPD in our group of extremely premature neonates. However, the association between low EPC counts at birth and PDA may be clinically relevant, and deserves further studies.

Hearing assessment in high-risk congenital diaphragmatic hernia survivors.

OBJECTIVE: To report results of audiometric evaluations in high-risk congenital diaphragmatic hernia survivors and their exposure to audiological risk factors (mechanical ventilation, high frequency oscillation, aminoglycoside therapy and neuromuscular blocking agents). DESIGN: All newborns with high-risk congenital diaphragmatic hernia born between January 2003 and June 2009 were treated consecutively at the Neonatal Intensive Care Unit, Pediatric Hospital, University of Padova. Thirty-two survived and 26 of them underwent formal audiological evaluation (tonal and speech audiometry, otoacoustic emission, and immitance measurements) and follow up. RESULTS: Twenty-one children had normal hearing; 4 had conductive hearing loss, which was successfully treated; and 1 had severe sensorineural hearing loss and suffers from Turner syndrome. CONCLUSIONS: Our series revealed a lower prevalence of sensorineural hearing loss in high-risk congenital diaphragmatic hernia survivors than in other studies, suggesting that the association between hearing loss and congenital diaphragmatic hernia has yet to be accurately defined and fully elucidated.

Exhaled air temperature in children with bronchopulmonary dysplasia.

BACKGROUND: Because they have similar functional and clinical profiles, bronchopulmonary dysplasia (BPD) survivors are often treated as asthmatic patients. In truth, very little is known about the possible biochemical and inflammatory mechanisms playing a part in BPD survivors' lungs. The aim of this study was to measure exhaled breath temperature in BPD survivors by comparison with asthmatic cases and healthy controls. METHODS: Three groups of age-matched adolescents (n = 17 each), that is, BPD survivors (gestational ages <31 weeks, birth weights <1,500 g), asthmatic subjects and healthy controls, underwent exhaled breath temperature and exhaled nitric oxide measurements, and spirometry. RESULTS: Exhaled breath temperature was significantly lower in the BPD survivors (26.72°C [25.11-27.57]) than in the asthmatic patients (29.60°C [29.20-30.02], P < 0.001), while no significant difference emerged by comparison with healthy controls (26.97°C [26.58-27.38]). Considering the whole study population, a significant correlation was found between exhaled breath temperatures and exhaled nitric oxide concentrations (R = 0.42, P = 0.004). Spirometry revealed an obstructive lung function pattern in both the asthmatic cases and the BPD survivors, with lower parameters in the latter. CONCLUSIONS: Exhaled breath temperatures and exhaled nitric oxide concentrations are significantly lower in BPD survivors than in asthmatic cases, suggesting that different pathogenetic mechanisms characterize these two chronic obstructive lung diseases.

Bronchopulmonary dysplasia: definitions and long-term respiratory outcome.

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that develops as a consequence of perinatal/neonatal lung injury, and it is one of the most important sequelae of premature birth. In this article we discuss recent changes in the definition of BPD, the main differences between the old and the new form and we summarize recent data on long-term respiratory outcome. The diagnosis of BPD is currently based on the need for supplemental oxygen for at least 28 days after birth, and its severity is graded according to the respiratory support required at 36 postmenstrual weeks. The "new BPD" is mainly a developmental disorder in which the immature lung fails to reach its full structural complexity. Longitudinal studies on children with BPD identified, at all ages, a greater need to use inhaled asthma medication and a significant airflow obstruction. Whether survivors of BPD and prematurity have a risk of developing a COPD-like phenotype with aging is a question that only lung function studies extended to middle-age and beyond will answer.

Low exhaled nitric oxide in school-age children with bronchopulmonary dysplasia and airflow limitation.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, may be associated with long-term airflow limitation. Survivors of BPD may develop asthma-like symptoms in childhood, with a variable response to beta(2)-agonists. However, the pathologic pathways underlying these respiratory manifestations are still unknown. The aim of this study was to measure exhaled nitric oxide (FE(NO)) and lung function in a group of 31 school-age survivors of BPD. They showed variable degrees of airflow obstruction (mean FEV(1) 77.8 +/- 2.3% predicted) unresponsive to beta(2)-agonists in 72% of the subjects. Their FE(NO) values (geometric mean [95% confidence interval]: 7.7 [+/- 1.1] ppb) were significantly lower than in a group of healthy matched control subjects born at term (10.7 [+/- 1.1] ppb, p < 0.05) and a group of preterm children without BPD (9.9 [+/- 1.1] ppb, p < 0.05). The children with BPD were also compared with a group of 31 patients with asthma with a comparable airflow limitation (FEV(1) 80.2 +/- 2.1% predicted) and showed FE(NO) values four times lower than in those with asthma (24.9 [+/- 1.2] ppb, p < 0.001). In conclusion, unlike children with asthma, school-age survivors of BPD have airflow limitation associated with low FE(NO) values and lack of reversibility to beta(2)-agonists, probably as a result of mechanisms related to early life structural changes in the airways.

Flow limitation in infants with bronchopulmonary dysplasia and respiratory function at school age.

Bronchopulmonary dysplasia is associated with abnormalities in lung function during infancy, yet many infants recover with no respiratory problems in the long term. We therefore did a longitudinal study of pulmonary function in 18 children with moderate to severe bronchopulmonary dysplasia. Forced expiratory volume in 1 s (FEV1) and forced mid-expiratory flow (FEF25-75) at school age were lower than normal in 15 of 18 children, and both showed a significant positive correlation with the maximal flow at functional residual capacity (Vmax(FRC)) at 24 months of age (r=0.68 and 0.85, respectively). Our results suggest that assessment of respiratory function during infancy can help to identify children with bronchopulmonary dysplasia at risk of incomplete recovery of respiratory function during childhood.