The vascular phenotype of BPD: new basic science insights-new precision medicine approaches.

Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. Up to 1/3 of children with BPD develop pulmonary hypertension (PH). PH increases mortality, the risk of adverse neurodevelopmental outcome and lacks effective treatment. Current vasodilator therapies address symptoms, but not the underlying arrested vascular development. Recent insights into placental biology and novel technological advances enabling the study of normal and impaired lung development at the single cell level support the concept of a vascular phenotype of BPD. Dysregulation of growth factor pathways results in depletion and dysfunction of putative distal pulmonary endothelial progenitor cells including Cap1, Cap2, and endothelial colony-forming cells (ECFCs), a subset of vascular progenitor cells with self-renewal and de novo angiogenic capacity. Preclinical data demonstrate effectiveness of ECFCs and ECFC-derived particles including extracellular vesicles (EVs) in promoting lung vascular growth and reversing PH, but the mechanism is unknown. The lack of engraftment suggests a paracrine mode of action mediated by EVs that contain miRNA. Aberrant miRNA signaling contributes to arrested pulmonary vascular development, hence using EV- and miRNA-based therapies is a promising strategy to prevent the development of BPD-PH. More needs to be learned about disrupted pathways, timing of intervention, and mode of delivery. IMPACT: Single-cell RNA sequencing studies provide new in-depth view of developmental endothelial depletion underlying BPD-PH. Aberrant miRNA expression is a major cause of arrested pulmonary development. EV- and miRNA-based therapies are very promising therapeutic strategies to improve prognosis in BPD-PH.

Prevalence of respiratory tract infections, allergies and assessment of humoral immunity within the Malopolska region's cohort of 11- year old children born with extremely low birth weight in comparison with to their term born peers.

BACKGROUND: Children born with extremely low birth weight (ELBW) have more respiratory tract complications during childhood. Little is known about respiratory and allergy problems in ELBW children at the threshold of adolescence. MATERIALS AND METHODS: A follow-up study was conducted at the age of 11 among ELBW children (n=65) and age-matched controls (n=36). The primary outcomes in the study were the occurrence of respiratory and allergy problems and the rate of hospitalization due to respiratory complications at the age of 11 years, assessed with a questionnaire. Secondary outcome variables were serum levels of immunoglobulin classes. RESULTS: ELBW children had more respiratory tract infections (31 vs.11%, p = 0.03), but less allergies (3 vs. 22%, p < 0.01) compared with controls and had lower level of serum tIgE (geometric mean: 46.5 vs. 89.3 kU/l, p = 0.02). The risk factors for the occurrence of respiratory tract disorders in the ELBW group were: low gestational age, need for surfactant therapy and length of ventilatory support in the neonatal period. CONCLUSIONS: ELBW children have more frequent respiratory tract complications, but fewer allergies at the age of 11 years compared with children born at term. Lower respiratory tract problems decrease in ELBW children with age. Respiratory tract infections are not connected with deficiency in humoral immunity.

BPD: Latest Strategies of Prevention and Treatment.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is the most common long-term complication of extreme preterm birth. It is associated with lifelong multisystemic consequences. Advances in neonatal care have not reduced the incidence of BPD and no new breakthrough therapy has been successfully translated into the clinic in recent decades. SUMMARY: Current evidence demonstrates benefit of new modalities of first-line noninvasive positive pressure ventilation, selected strategies of postnatal corticosteroid administration, alternative surfactant delivery methods, and caffeine. Promising emerging therapies that are being translated from bench to bedside include mesenchymal stromal cells (MSCs), insulin-like growth factor 1/binding protein-3 (IGF-1/IGFBP-3), and interleukin 1 receptor (IL-1R) antagonist (anakinra). Strong preclinical data support efficacy of MSCs in attenuating neonatal lung injury. Early-phase clinical trials have already demonstrated safety and feasibility in preterm infants. Phase II studies that aimed at demonstrating efficacy are currently underway. Both IGF-1/IGFBP-3 and IL-1R antagonist present with biological plausibility and animal data of efficacy. Phase I/II clinical trials are currently recruiting patients. KEY MESSAGES: Early noninvasive respiratory support, late systemic dexamethasone, less invasive surfactant administration, and caffeine are proven strategies in reducing the risk of BPD. Potentially disruptive therapies - MSCs, IGF-1/IGFBP-3, and anakinra - are being advanced to clinical trials and their efficacy in remains to be demonstrated. Continued research efforts are needed in the growing population of extremely preterm infants at risk of developing BPD.

Multimodal longitudinal respiratory function assessment in very low birth weight 7-year-old children.

PURPOSE: Preterm birth is associated with adverse pulmonary outcomes. We aimed to evaluate respiratory morbidities and lung function of very low birth weight (VLBW) Polish children followed up at the age of 7 years old, and to compare with electrical impedance segmentography (EIS) results recorded at 4 years of age. MATERIALS AND METHODS: VLBW children were compared with term controls using impulse oscillometry and spirometry. Perinatal data and current respiratory morbidities were analyzed and pulmonary function test results were compared with previous EIS results. RESULTS: We included 40 VLBW children and 30 controls in the analysis. Elevated total airway resistance and forced expiratory volume in the first second below the lower limit of normal were more prevalent in VLBW children compared with term controls (15 vs 0%; 18 vs 0%). A positive bronchodilator response was more common in VLBW children (R5 Hz: 46 vs 13.3%; R5-20 â€‹Hz: 65 vs 36.7%). Children with bronchopulmonary dysplasia (BPD) had higher total airway resistance (R5 Hz/R5 Hz pred: 1.35 vs 0.95; p â€‹< â€‹0.001), large airway resistance (R20 Hz/R20 Hz pred: 0.89 vs 0.66; p â€‹= â€‹0.001), small airway resistance (R5-20 â€‹Hz: 0.57 vs 0.34 â€‹kPa â€‹L-1 â€‹s-1; p â€‹= â€‹0.009), than controls. Strong correlation between BDR in EIS and R5 Hz/R5 Hz pred was observed in children with BPD (r â€‹= â€‹0.7). CONCLUSION: VLBW school-aged children with BPD presented with substantial respiratory morbidity and persistent reduction of lung function, affecting small and large airways and lung parenchyma. EIS may be an alternative tool for lung function assessment in children with BPD.

Regional lung ventilation pattern in preschool children with bronchopulmonary dysplasia is modified by bronchodilator response.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a significant long-term complication of prematurity. A standardized method of pulmonary function testing is still not available in preschool children with BPD. We investigated the feasibility of Electrical Impedance Segmentography (EIS) monitoring in this group and the impact of bronchodilator response (BDR) to salbutamol on the pattern of lung ventilation. METHODS: We conducted a follow-up study of 4-year-old premature children who had been treated in the tertiary NICU. The cohort was divided into two groups based on the presence of BPD. EIS monitoring was performed before and 15 min after the administration of 400 µg of salbutamol (pMDI with spacer) in all subjects during spontaneous tidal breathing in upright position. Data were expressed as median segmental impedance amplitude differences and segmental ventilation inhomogeneity index (II) changes. RESULTS: We included 51 children in our analysis: 33 with BPD (median birth weight-840 g; median gestational age-27 weeks) and 18 without BPD (1,290 g; 30 weeks, respectively). There was a significant increase in median segmental impedance amplitude after salbutamol in gravity non-dependent segments in children with BPD: upper left (UL): 462 versus 534 AU; (P = 0.003); upper right (UR): 481 versus 595 AU (P < 0.001) and II in these segments: UL: 0.046 versus 0.078 (P = 0.003) UR: 0.049 versus 0.064 (P = 0.006). There were no changes in the lower segments. There were no changes in ventilation pattern in children without BPD. CONCLUSION: BDR to salbutamol increases breath amplitude in gravity non-dependent segments of the lungs during spontaneous tidal breathing in preschool children with BPD. Pediatr Pulmonol. 2017;52:353-359. © 2016 Wiley Periodicals, Inc.

Analysis of PD-1 expression in the monocyte subsets from non-septic and septic preterm neonates.

Programmed death-1 (PD-1) receptor system represents a part of recently reported immunoregulatory pathway. PD-1 is an immune checkpoint molecule, which plays an important role in downregulating the immune system proinflammatory activity. Until recently, PD-1 expression was not established on immune cells of the preterm infants. The study objectives were to confirm expression of the PD-1 receptors on the monocytes isolated from very low birth weight newborns (VLBW), and to analyze their expression during the first week of life and late-onset sepsis. Peripheral blood mononuclear cells were isolated from 76 VLBW patients without early-onset sepsis on their 5th day of life (DOL). PD-1 expression was determined on the monocyte subsets (classical, intermediate, non-classical) by flow cytometry. In case of late-onset sepsis (LOS), the same analysis was performed. Our results demonstrated that on the 5th DOL, PD-1 receptors were present in all the monocyte subsets. Children, whose mothers had received antenatal steroids, presented higher absolute numbers of non-classical monocytes with PD-1 expression. Infants born extremely preterm who later developed LOS, initially showed a lower percentage of PD-1 receptor-positive intermediate monocytes in comparison to neonates born very preterm. During LOS, we observed a rise in the percentage of classical monocytes with PD-1 expression. In case of septic shock or fatal outcome, there was a higher percentage and absolute count of intermediate monocytes with PD-1 expression in comparison to children without these complications. In conclusion, monocytes from VLBW children express PD-1 receptors. Antenatal steroid administration seems to induce PD-1 receptor expression in the non-classical monocytes. PD-1 might play a role in immunosuppressive phase of sepsis in the prematurely born children with septic shock and fatal outcome.

Relationship between Proton Magnetic Resonance Spectroscopy of Frontoinsular Gray Matter and Neurodevelopmental Outcomes in Very Low Birth Weight Children at the Age of 4.

Very low birth weight is associated with long term neurodevelopmental complications. Macroscopic brain abnormalities in prematurity survivors have been investigated in several studies. However, there is limited data regarding local cerebral metabolic status and neurodevelopmental outcomes. The purpose of this study was to characterize the relationship between proton magnetic resonance spectra in basal ganglia, frontal white matter and frontoinsular gray matter, neurodevelopmental outcomes assessed with the Leiter scale and the Developmental Test of Visual Perception and selected socioeconomic variables in a cohort of very low birth weight children at the age of four. Children were divided in three groups based on the severity of neurodevelopmental impairment. There were no differences in spectroscopy in basal ganglia and frontal white matter between the groups. Lower concentrations of N-acetylaspartate (NAA), choline (Cho) and myoinositol (mI) were observed in the frontoinsular cortex of the left hemisphere in children with neurodevelopmental impairment compared to children with normal neurodevelopmental outcomes. Higher parental education, daycare attendance and breastfeeding after birth were associated with more favorable neurodevelopmental prognosis, whereas rural residence was more prevalent in children with moderate and severe impairment. Our study demonstrates the role of long term neurometabolic disruption in the left frontoinsular cortex and selected socioeconomic variables in determination of neurodevelopmental prognosis in prematurity survivors.

Relationship between Stereoscopic Vision, Visual Perception, and Microstructure Changes of Corpus Callosum and Occipital White Matter in the 4-Year-Old Very Low Birth Weight Children.

AIM: To assess the relationship between stereoscopic vision, visual perception, and microstructure of the corpus callosum (CC) and occipital white matter, 61 children born with a mean birth weight of 1024 g (SD 270 g) were subjected to detailed ophthalmologic evaluation, Developmental Test of Visual Perception (DTVP-3), and diffusion tensor imaging (DTI) at the age of 4. RESULTS: Abnormal stereoscopic vision was detected in 16 children. Children with abnormal stereoscopic vision had smaller CC (CC length: 53 ± 6 mm versus 61 ± 4 mm; p < 0.01; estimated CC area: 314 ± 106 mm(2) versus 446 ± 79 mm(2); p < 0.01) and lower fractional anisotropy (FA) values in CC (FA value of rostrum/genu: 0.7 ± 0.09 versus 0.79 ± 0.07; p < 0.01; FA value of CC body: 0.74 ± 0.13 versus 0.82 ± 0.09; p = 0.03). We found a significant correlation between DTVP-3 scores, CC size, and FA values in rostrum and body. This correlation was unrelated to retinopathy of prematurity. CONCLUSIONS: Visual perceptive dysfunction in ex-preterm children without major sequelae of prematurity depends on more subtle changes in the brain microstructure, including CC. Role of interhemispheric connections in visual perception might be more complex than previously anticipated.

Development and maturation of the immune system in preterm neonates: results from a whole genome expression study.

To expand the knowledge about the consecutive expression of genes involved in the immune system development in preterm neonates and to verify if the environment changes the gene expression after birth we conducted a prospective study that included three cohorts: (A) extremely (gestational age (GA): 23-26 weeks; n = 41), (B) very (GA: 27-29 weeks; n = 39), and (C) moderately preterm infants (GA: 30-32 weeks; n = 33). Blood samples were drawn from the study participants on the 5th and 28th day of life (DOL). The mRNA samples were evaluated for gene expression with the use of GeneChip Human Gene 1.0ST microarrays. Differential expression analysis revealed small subsets of genes that presented positive or negative monotone trends in both the 5th (138 genes) and 28th DOL (308 genes) in the three subgroups of patients. Based on pathway enrichment analysis, we found that most of the pathways that revealed a positive monotone trend were involved in host immunity. The most significantly GA dependent pathways were T-cell receptor signaling pathway and intestinal immune network for IgA production. Overall 4431 genes were differentially expressed between the 5th and 28th DOL. Despite differences in gestational age, patients with the same postconceptional age have a very similar expression of genes.

Role of electrical impedance tomography in clinical practice in pediatric respiratory medicine.

This paper summarizes current knowledge about electrical impedance tomography (EIT) and its present and possible applications in clinical practice in pediatric respiratory medicine. EIT is a relatively new technique based on real-time monitoring of bioimpedance. Its possible application in clinical practice related to ventilation and perfusion monitoring in children has gaine increasing attention in recent years. Most of the currently published data is based on studies performed on small and heterogenous groups of patients. Thus the results need to be corroborated in future well-designed clinical trials. Firstly a short theoretical overview summarizing physical principles and main advantages and disadvantages is provided. It is followed by a review of the current data regarding EIT application in ventilation distribution monitoring in healthy individuals. Finally the most important studies utilizing EIT in ventilation and perfusion monitoring in critically ill newborns and children are outlined.