Patent Ductus Arteriosus and Lung MRI Phenotype in Moderate and Severe Bronchopulmonary Dysplasia-Pulmonary Hypertension.

RATIONALE: A hemodynamically significant patent ductus arteriosus (hsPDA) in premature infants has been associated with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). However, these associations remain incompletely understood. OBJECTIVES: The aim was to assess the association between hsPDA duration with clinical outcomes, PH, and phenotypic differences on lung MRI. METHODS: This retrospective cohort study identified all infants with BPD <32 weeks gestation who also underwent a research lung MRI <48 weeks postmenstrual age (PMA) from 2014-2022. Clinical echocardiograms were reviewed for hsPDA, and categorized into no hsPDA, hsPDA 1-60 days, and hsPDA >60 days. Outcome variables included BPD severity, PH at 36 weeks PMA, PH after 36 weeks PMA in the absence of shunt (PH-PVD), tracheostomy or death, and lung phenotype by MRI via modified Ochiai score, indexed total lung volume (TLVI), and whole lung hyperdensity (WLH). Logistic regression and ANOVA analysis were used. MEASUREMENTS AND MAIN RESULTS: In total, 133 infants born at 26.2 ± 1.9 weeks and 776 ± 276g were reviewed (47 no hsPDA, 44 hsPDA 1-60 days, 42 hsPDA >60 days). hsPDA duration >60 days was associated with BPD severity (p<0.01), PH at 36 weeks PMA (aOR 9.7 [95% CI: 3.3-28.4]), PH-PVD (aOR 6.5 [95% CI: 2.3-18.3]), and tracheostomy or death (aOR 3.0 [95% CI: 1.0-8.8]). Duration of hsPDA > 60 days was associated with higher Ochiai score (p=0.03) and TLVI (p=0.01), but not WLH (p=0.91). CONCLUSIONS: In infants with moderate or severe BPD, prolonged exposure to hsPDA is associated with BPD severity, PH-PVD, and increased parenchymal lung disease by MRI.

Neurodevelopmental outcomes of extremely preterm infants with bronchopulmonary dysplasia (BPD) - A retrospective cohort study.

OBJECTIVE: To investigate the neurodevelopmental outcomes for preterm infants born < 29 weeks gestation with/without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Preterm infants < 29 weeks' gestation born 2007-2018 in New South Wales and the Australian Capital Territory, Australia, were included. Infants who died < 36 weeks' postmenstrual age and those with major congenital anomalies were excluded. Subjects were assessed at 18-42 months corrected age using the Bayley Scales of Infant Development, 3rd edition. RESULTS: 1436 infants without BPD (non-BPD) and 1189 infants with BPD were followed. The BPD group, 69 % infants were discharged without respiratory support (BPD1), 29 % on oxygen (BPD2) and 2 % on pressure support/tracheostomy (BPD3). Moderate neurodevelopmental impairment (NDI) was evident in 5.7 % of non-BPD infants, 11 % BPD1, 15 % BPD2, 15 % BPD3 infants. Severe NDI was seen in 1.7 % non-BPD infants, 3.4 % BPD1, 7.3 % BPD2, 35 % BPD3 infants. After adjusting for confounders, infants with BPD2 (OR 2.24, 99.9 % CI 1.25 to 5.77) or BPD3 (OR 5.99, 99.9 % CI 1.27 to 46.77) were more likely to have moderate-severe NDI compared to non-BPD infants. CONCLUSION: The majority of infants with BPD were discharged home without respiratory support and had better neurocognitive outcomes in early childhood compared to those that required home-based oxygen or respiratory support.

Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model.

Rationale: Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. Objectives: To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Methods: Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, in vitro differentiation ability, and transcriptional profiles. Measurements and Main Results: The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased in vitro neurosphere formation and altered neural progenitor cell transcriptional signatures. Conclusions: Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.

Bronchopulmonary dysplasia and carbon dioxide retention.

AIM: The aim of this study was to determine the pre-discharge carbon dioxide (CO2 ) levels of preterm neonates with bronchopulmonary dysplasia (BPD) requiring ongoing nasal cannulae oxygen therapy and who were ready for discharge home. METHODS: We studied a retrospective cohort of infants born <30 weeks gestational age (GA) at ≥36 weeks corrected GA who had established BPD requiring ongoing nasal cannulae oxygen therapy and were ready for discharge home. Neonates were born and admitted between May 2014 and December 2018. Demographic data at the time of birth and at the time of the last blood gas sampled were collected. RESULTS: One hundred five neonates had median GA of 26.1 weeks and birth weight of 775 g. Median (IQR) CO2 level was 54 (49-58) mmHg. Ninety-nine (94%) neonates had CO2 levels exceeding the normal range and 91 (87%) neonates had a CO2 between 45 and 65 mmHg. CONCLUSION: Ninety-four per cent of neonates <30 weeks GA at ≥36 weeks corrected GA requiring ongoing nasal cannulae oxygen therapy for established BPD, who were ready for discharge home, have CO2 levels outside of normocapnia (35-45 mmHg), with 87% having CO2 levels between 45 and 65 mmHg.

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Cardiac Magnetic Resonance Imaging Evaluation of Neonatal Bronchopulmonary Dysplasia-associated Pulmonary Hypertension.

Rationale: Patients with bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) have increased morbidity and mortality. Noninvasive assessment relies on echocardiograms (echos), which are technically challenging in this population. Improved assessment could augment decisions regarding PH therapies.Objectives: We hypothesized that neonatal cardiac magnetic resonance imaging (MRI) will correlate with BPD severity and predict short-term clinical outcomes, including need for PH therapies for infants with BPD.Methods: A total of 52 infants (31 severe BPD, 9 moderate BPD, and 12 with either mild or no BPD) were imaged between 39 and 47 weeks postmenstrual age on a neonatal-sized, neonatal ICU-sited 1.5-T magnetic resonance (MR) scanner. MR left ventricular eccentricity index (EI), main pulmonary artery-to-aorta (PA/AO) diameter ratio, and pulmonary arterial blood flow were determined. Echos obtained for clinical indications were reviewed. MRI and echo indices were compared with BPD severity and clinical outcomes, including length of stay (LOS), duration of respiratory support, respiratory support at discharge, and PH therapy.Measurements and Main Results: PA/AO ratio increased with BPD severity. Increased PA/AO ratio, MR-EI, and echo-EIs were associated with increased LOS and duration of respiratory support. No correlation was seen between pulmonary arterial blood flow and BPD outcomes. Controlling for gestational age, birth weight, and BPD severity, MR-EI was associated with LOS and duration of respiratory support. Increased PA/AO ratio and MR-EI were associated with PH therapy during hospitalization and at discharge.Conclusions: MRI can provide important image-based measures of cardiac morphology that relate to disease severity and clinical outcomes in neonates with BPD.

Cardiovascular magnetic resonance imaging derived septal curvature in neonates with bronchopulmonary dysplasia associated pulmonary hypertension.

BACKGROUND: Bronchopulmonary dysplasia (BPD) associated with pulmonary hypertension (PH) is a significant source of morbidity and mortality in premature infants. Recent advances have allowed the use of cardiovascular magnetic resonance (CMR) in the assessment of respiratory and cardiac disease in infants with BPD. In adults and older pediatric patients, decreased CMR interventricular septal curvature correlates with increased mean pulmonary artery pressure and pulmonary vascular resistance. The current study sought to determine the relationship of CMR derived septal curvature in neonates with BPD and BPD-PH with a need for PH therapy. METHODS: Forty moderate or severe BPD and 12 mild BPD or control infants were imaged without contrast between 38 and 47 weeks post-menstrual age on a neonatal-sized, neonatal intensive care unit-sited 1.5 T CMR scanner. CMR indices including eccentricity index (CMR-EI) and septal curvature were measured and compared to BPD severity and clinical outcomes including hospital length of stay (LOS), duration of respiratory support, respiratory support level at discharge and PH therapy. RESULTS: CMR-EI was directly associated and septal curvature was inversely associated with BPD severity. In a univariate analysis, CMR-EI and septal curvature were associated with increased hospital LOS, duration of respiratory support, respiratory support at hospital discharge, and need for PH therapy. In multivariable analysis CMR-EI was associated with hospital LOS and duration of respiratory support and septal curvature was associated with respiratory support at hospital discharge. Septal curvature was the only clinical or CMR variable associated with need for PH therapy (R2 = 0.66, p = 0.0014) in multivariable analysis demonstrating improved discrimination beyond CMR-EI. CONCLUSIONS: CMR derived septal curvature correlates significantly with clinical outcomes including hospital LOS, duration of respiratory support, respiratory support level at hospital discharge, and PH therapy in neonates with BPD and BPD-PH. Further, CMR derived septal curvature demonstrated improved discrimination of need for PH therapy and respiratory support at discharge compared to clinical variables and other CMR indices, supporting septal curvature as a non-invasive marker of PH in this population with potential to guide management strategies.

Expert consensus on palivizumab use for respiratory syncytial virus in developed countries.

Respiratory syncytial virus (RSV) infection is a leading cause of hospitalisation in early childhood and palivizumab is the only licensed intervention for prevention. Palivizumab guidelines should reflect the latest evidence, in addition to cost-effectiveness and healthcare budgetary considerations. RSV experts from Europe, Canada and Israel undertook a systematic review of the evidence over the last 5 years and developed recommendations regarding prophylaxis in industrialised countries. Almost 400 publications were reviewed. This group recommended palivizumab for: preterm infants (<29 and ≤31 weeks gestational age [wGA] and ≤9 and ≤6 months of age, respectively; high-risk 32-35wGA), former preterm children ≤24 months with chronic lung disease/bronchopulmonary dysplasia, children ≤24 months with significant congenital heart disease; and other high-risk populations, such as children ≤24 months with Down syndrome, pulmonary/neuromuscular disorders, immunocompromised, and cystic fibrosis. Up to 5 monthly doses should be administered over the RSV season. It is our impression that the adoption of these guidelines would help reduce the burden of RSV.

Introduction of point-of-care neonatal lung ultrasound in a developing country.

Despite neonatal lung ultrasound (LU) being diffused worldwide, its introduction in limited-resource areas has not been formally investigated. We conceived a project to introduce it in a level 3 NICU of a developing country and verify if, after a short protocolized training, clinicians may efficaciously use LU. Inter-rater agreement between ultrasound trainees and trainers was analyzed within both the local test and the diffusion phases of the project. High inter-rater agreements were found between expert trainers and the two neonatologists who were trained in a skilled European center (Cohen's Kappa, 0.951; 95%CI, 0.882-0.999), as well as between the two and the second round of locally trained colleagues (Cohen's Kappa, 0.896; 95%CI, 0.797-0.996). Moreover, a high agreement was found between the clinical respiratory diagnosis (used as the "gold standard") and the LU diagnosis given by the first two trainees (intraclass correlation, 0.992; 95%CI, 0.987-0.996) and the locally trained physicians (intraclass correlation, 0.97; 95%CI, 0.95-0.98). A final survey demonstrated that the project was perceived as efficacious and that LU was going to be integrated into routine clinical practice.Conclusions: А short LU training provided sufficient proficiency and allowed the LU introduction in clinical practice in the neonatal intensive care unit in a developing country.What is Known:• Lung ultrasound is a promising technique for evaluating neonatal respiratory distress at least in high-income countries. Previous studies revealed high specificity and sensitivity in diagnosing specific neonatal disorders.• An important barrier to the more extensive use of lung ultrasound in neonatal critical care is a lack of efficient and suitable training solutions.What is New:• Descriptive LU performed by neonatologist in a developing country after a short formal training is feasible with good quality.• A short formal LU training program provided good proficiency and allowed a correct descriptive diagnosis in a neonatal unit in a developing country.

Using continuous overnight pulse oximetry to guide home oxygen therapy in chronic neonatal lung disease.

AIM: The aims of this study are: (i) to survey the knowledge of paediatric clinicians using overnight continuous pulse oximetry data to guide management of infants with chronic neonatal lung disease (CNLD); (ii) to assess the ability of paediatric clinicians to interpret overnight continuous pulse oximetry data; and (iii) to describe the overnight oximetry interpretation practices of paediatric respiratory specialists. METHODS: Paediatric clinicians from three tertiary teaching hospitals completed an anonymous survey regarding overnight continuous pulse oximetry in chronic neonatal lung disease. Using a modified Delphi technique, paediatric respiratory specialists participated in a concordance exercise and discussions to establish consensus interpretations for 25 oximetry studies. Paediatric clinicians were invited to complete the same exercise as a comparison. RESULTS: Self-rated knowledge from 74 surveyed clinicians was proportional to clinical experience. Twenty paediatric clinicians and nine paediatric respiratory specialists completed the oximetry exercise with scores of 64% (κ = 0.25) and 80% (κ = 0.45), respectively. Individual parameters like a mean peripheral arterial haemoglobin saturation (SpO2 ) below 93% and percentage time spent below SpO2 93% correlated poorly with the consensus interpretations. Paediatric respiratory specialists instead relied on visual analysis of SpO2 waveforms, utilising the frequency and depth of desaturations to guide management. CONCLUSION: Interpretation of overnight oximetry data is variable amongst both paediatric clinicians and respiratory specialists. This likely reflects inadequate evidence defining clinically significant intermittent hypoxaemia, whether in terms of desaturation duration, frequency or nadir.

Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity.

The canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full-term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.

Neonatal Pulmonary Magnetic Resonance Imaging of Bronchopulmonary Dysplasia Predicts Short-Term Clinical Outcomes.

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

The use of overnight oximetry in neonates: A literature review.

There is much debate between neonatologists and paediatricians about appropriate oxygen saturation targets for babies with chronic neonatal lung disease (CNLD). Overnight oximetry is used to guide the fraction of inspired oxygen to use. We did this literature review to examine the current literature on the use of overnight oximetry in term infants, preterm infants and babies with CNLD (especially relevant to ex-preterm babies with CNLD going home on oxygen). We reviewed the literature from January 1990 to October 2017 by searching the following databases: Cochrane Central Register of Controlled Trials, The Joanna Briggs Institute, CINAHL, MEDLINE, Scopus, EMBASE, ProQuest and Science Direct. Sixteen articles were included in the review. The literature available on overnight oximetry in neonates is limited, it is not contemporary, and it reports studies that did not use oximeters with modern software for data collection and analysis. It is imperative that reference ranges be defined for overnight oximetry parameters so that babies are not inadvertently administered inappropriate amounts of oxygen.

Refining anti-inflammatory therapy strategies for bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a severe lung disease of preterm infants, which is characterized by fewer, enlarged alveoli and increased inflammation. BPD has grave consequences for affected infants, but no effective and safe therapy exists. We previously showed that prophylactic treatment with interleukin-1 receptor antagonist (IL-1Ra) prevents murine BPD induced by perinatal inflammation and hyperoxia. Here, we used the same BPD model to assess whether an alternative anti-inflammatory agent, protein C (PC), is as effective as IL-1Ra against BPD. We also tested whether delayed administration or a higher dose of IL-1Ra affects its ability to ameliorate BPD and investigated aspects of drug safety. Pups were reared in room air (21% O2 ) or hyperoxia (65% or 85% O2 ) and received daily injections with vehicle, 1200 IU/kg PC, 10 mg/kg IL-1Ra (early or late onset) or 100 mg/kg IL-1Ra. After 3 or 28 days, lung and brain histology were assessed and pulmonary cytokines were analysed using ELISA and cytokine arrays. We found that PC only moderately reduced the severe impact of BPD on lung structure (e.g. 18% increased alveolar number by PC versus 34% by IL-1Ra); however, PC significantly reduced IL-1ß, IL-1Ra, IL-6 and macrophage inflammatory protein (MIP)-2 by up to 89%. IL-1Ra at 10 mg/kg prevented BPD more effectively than 100 mg/kg IL-1Ra, but only if treatment commenced at day 1 of life. We conclude that prophylactic low-dose IL-1Ra and PC ameliorate BPD and have potential as the first remedy for one of the most devastating diseases preterm babies face.

Pathophysiology, screening and diagnosis of pulmonary hypertension in infants with bronchopulmonary dysplasia - A review of the literature.

Bronchopulmonary dysplasia (BPD) is a common complication of extreme prematurity, which has increased over the last 20 years. BPD is associated with increased morbidities and mortality. It has been increasingly recognized that BPD affects overall lung development including the pulmonary vasculature. More recent studies have demonstrated an increased awareness of pulmonary arterial hypertension (PH) in BPD patients and recent international guidelines have advocated for better screening. This review will describe the current understanding of the pathophysiology of PH in infants with BPD, the in-depth assessment of the available literature linking PH and BPD, and propose an approach of screening and diagnosis of PH in infants with BPD.

Impaired alveolarization and intra-uterine growth restriction in rats: a postnatal genome-wide analysis.

Intra-uterine growth restriction (IUGR) dramatically increases the risk of bronchopulmonary dysplasia in preterm babies, a disease characterized by arrested alveolarization and abnormal microvascular angiogenesis. We have previously described a rodent low protein diet (LPD) model of IUGR inducing impaired alveolarization, but failed to demonstrate any modification of the classical factors involved in lung development. We performed a genome-wide microarray analysis in 120 rat pups with LPD-induced IUGR and their controls, at three key time points of the alveolarization process: postnatal day 4 (P4): start of alveolarization; P10: peak of the alveolarization process and P21: end of the alveolarization process. Results were analysed using Arraymining, DAVID and KEGG software and validated by qRT-PCR and western blots. Considering a cut-off of 2:1 as significant, 67 transcripts at P4, 102 transcripts at P10 and 451 transcripts at P21 were up-regulated, and 89 transcripts at P4, 25 transcripts at P10 and 585 transcripts at P21 were down-regulated. Automatic functional classification identified three main modified pathways, 'cell adhesion molecules', 'cardiac muscle contraction' and 'peroxisome proliferator-activated receptor' (PPAR). Protein analysis confirmed involvement of the PPAR pathway, with an increase of FABP4, an activator of this pathway, at P4 and an increase of adiponectin at P21. Other data also suggest involvement of the PPAR pathway in impaired alveolarization. Our results show that deregulation of the PPAR pathway may be an important component of the mechanism inducing impaired alveolarization observed in IUGR. The complete dataset is available as GEO profiles on the Gene Expression Omnibus (GEO) database ( www.ncbi.nih.gov/geo/, GEO Accession No. GSE56956).

Evaluation of regional lung mass and growth in neonates with bronchopulmonary dysplasia using ultrashort echo time magnetic resonance imaging.

RATIONALE: Bronchopulmonary dysplasia (BPD) is the most common long term pulmonary morbidity in premature infants and is characterized by impaired lung growth and development. We hypothesized that lung mass growth is a critical factor in determining outcomes in infants with BPD. OBJECTIVES: To measure regional lung density and mass in infants with BPD and compare to clinical variables. METHODS: We conducted a retrospective cohort study of neonates (n = 5 controls, n = 46 with BPD). Lung mass and lung density were calculated using ultrashort echo time (UTE) magnetic resonance imaging (MRI). MEASUREMENTS AND MAIN RESULTS: Lung mass increased with increasing corrected gestational age at the time of MRI in all patients. Total, right, and left lung mass in infants with BPD trended higher than control infants (65.7 vs. 49.9 g, 36.2 vs. 26.8 g, 29.5 vs. 23.1 g, respectively). Babies with BPD who survived to discharge had higher relative lung mass than control infants and infants with BPD that did not survive to discharge (21.6 vs. 15.7 g/kg, p = .01). There was a significant association between the rate of lung mass growth and linear growth at the time of MRI (p = .034). CONCLUSIONS: Infants with BPD are capable of building lung mass over time. While this lung mass growth in infants with BPD may not represent fully functional lung tissue, higher lung mass growth is associated with increased linear growth.

Neonatal persistent pulmonary hypertension related to a novel TBX4 mutation: case report and review of the literature.

TBX4 gene, located on human chromosome 17q23.2, encodes for T-Box Transcription Factor 4, a transcription factor that belongs to the T-box gene family and it is involved in the regulation of some embryonic developmental processes, with a significant impact on respiratory and skeletal illnesses. Herein, we present the case of a female neonate with persistent pulmonary hypertension (PH) who underwent extracorporeal membrane oxygenation (ECMO) on the first day of life and then resulted to have a novel variant of the TBX4 gene identified by Next-Generation Sequencing. We review the available literature about the association between PH with neonatal onset or emerging during the first months of life and mutations of the TBX4 gene, and compare our case to previously reported cases. Of 24 cases described from 2010 to 2023 sixteen (66.7%) presented with PH soon after birth. Skeletal abnormalities have been described in 5 cases (20%). Eleven cases (46%) were due to de novo mutations. Three patients (12%) required ECMO. Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counselling. We suggest including TBX4 in genetic studies of neonates with pulmonary hypertension, even in the absence of skeletal abnormalities.

Human amnion epithelial cells modulate hyperoxia-induced neonatal lung injury in mice.

BACKGROUND AIMS: Human amnion epithelial cells (hAECs) prevent pulmonary inflammation and injury in fetal sheep exposed to intrauterine lipopolysaccharide. We hypothesized that hAECs would similarly mitigate hyperoxia-induced neonatal lung injury. METHODS: Newborn mouse pups were randomized to either normoxia (inspired O2 content (FiO2) = 0.21, n = 60) or hyperoxia (FiO2 = 0.85, n = 57). On postnatal days (PND) 5, 6 and 7, hAECs or sterile saline (control) was administered intraperitoneally. All animals were assessed at PND 14. RESULTS: Hyperoxia was associated with lung inflammation, alveolar simplification and reduced postnatal growth. Administration of hAECs to hyperoxia-exposed mice normalized body weight and significantly attenuated some aspects of hyperoxia-induced lung injury (mean linear intercept and septal crest density) and inflammation (interleukin-1α, interleukin-6, transforming growth factor-ß and platelet-derived growth factor-ß). However, hAECs did not significantly alter changes to alveolar airspace volume, septal tissue volume, tissue-to-airspace ratio, collagen content or leukocyte infiltration induced by hyperoxia. CONCLUSIONS: Intraperitoneal administration of hAECs to neonatal mice partially reduced hyperoxia-induced lung inflammation and structural lung damage. These observations suggest that hAECs may be a potential therapy for neonatal lung disease.

Atrial septal defect closure is associated with improved clinical status in patients ≤ 10 kg with bronchopulmonary dysplasia.

Patients with bronchopulmonary dysplasia (BPD) have shown clinical improvement after secundum atrial septal defect (ASD) closure. We sought to determine if this post-ASD closure improvement is secondary to the expected course in BPD patients or related to the closure itself. A novel BPD-ASD score was created to assess patients' clinical status (higher score = worse disease) and applied to 10 BPD-ASD inpatients weighing ≤ 10 kg who underwent ASD closure. The score and its subcomponents were retrospectively calculated serially ranging from 8 weeks pre- to 8 weeks post-intervention, and pre- and post-intervention score slopes were created. These slopes were compared using mixed regression modeling with an interaction term. There was a significant difference in pre- versus post-intervention slope with the most score drop the first week post-intervention (-2.1 + /- 0.8, p = 0.014). The mean score also dropped through weeks 2 (slope -0.8 + /- 0.8, p = 0.013) and 4 (slope -1.0 + /- 0.5, p = 0.001) post-intervention. There was a significant difference in pre- and post-intervention slopes for diuretics (p = 0.018) and the combined score of respiratory support, FiO2 need, and respiratory symptoms (p = 0.018). This study demonstrated significant improvement in BPD-ASD score, diuretic need, and respiratory status after ASD closure in BPD-ASD patients ≤ 10 kg that was outside of the natural course of BPD. Our study was limited by its small, single-center, retrospective nature. Future studies should be performed in a larger multicenter population to both validate the scoring system and compare to non-intervention infants.