Neonatal Lung Disease Research Articles

Respiratory management of infants with chronic neonatal lung disease beyond the NICU: A position statement from the Thoracic Society of Australia and New Zealand.

ABSTRACTChronic neonatal lung disease (CNLD) is defined as continued need for any form of respiratory support (supplemental oxygen and/or assisted ventilation) beyond 36 weeks PMA. Low‐flow supplemental oxygen facilitates discharge from hospital of infants with CNLD who are hypoxic in air and is widely used despite lack of evidence on the most appropriate minimum mean target oxygen saturations. Furthermore, there are minimal data to guide the home monitoring, titration or weaning of supplemental oxygen in these infants. The purpose of this position statement is to provide a guide for the respiratory management of infants with CNLD, with special emphasis on role and logistics of supplemental oxygen therapy beyond the NICU stay. Reflecting a variety of clinical practices and infant comorbidities (presence of pulmonary hypertension, retinopathy of prematurity and adequacy of growth), it is recommended that the minimum mean target range for SpO2 during overnight oximetry to be 93–95% with less than 5% of total recording time to be below 90% SpO2. Safety of short‐term disconnection from supplemental oxygen should be assessed before discharge, with majority of infants with CNLD not ready for discharge until supplemental oxygen requirement is ≤0.5 L/min. Sleep‐time assessment of oxygenation with continuous overnight oximetry is recommended when weaning supplemental oxygen. Palivizumab is considered safe and effective for the reduction of hospital admissions with RSV infection in this group. This statement would be useful for paediatricians, neonatologists, respiratory and sleep physicians and general practitioners managing children with CNLD.

Generation of novel trimeric fragments of human SP-A and SP-D after recombinant soluble expression in E. coli

Surfactant treatment for neonatal respiratory distress syndrome has dramatically improved survival of preterm infants. However, this has resulted in a markedly increased incidence of sequelae such as neonatal chronic inflammatory lung disease. The current surfactant preparations in clinical use lack the natural lung defence proteins surfactant proteins (SP)-A and D. These are known to have anti-inflammatory and anti-infective properties essential for maintaining healthy non-inflamed lungs.Supplementation of currently available animal derived surfactant therapeutics with these anti-inflammatory proteins in the first few days of life could prevent the development of inflammatory lung disease in premature babies. However, current systems for production of recombinant versions of SP-A and SP-D require a complex solubilisation and refolding protocol limiting expression at scale for drug development.Using a novel solubility tag, we describe the expression and purification of recombinant fragments of human (rfh) SP-A and SP-D using Escherichia coli without the need for refolding. We obtained a mean (± SD) of 23.3 (± 5.4) mg and 86 mg (± 3.5) per litre yield of rfhSP-A and rfhSP-D, respectively. rfhSP-D was trimeric and 68% bound to a ManNAc-affinity column, giving a final yield of 57.5 mg/litre of highly pure protein, substantially higher than the 3.3 mg/litre obtained through the standard refolding protocol. Further optimisation of this novel lab based method could potentially make rfhSP-A and rfhSP-D production more commercially feasible to enable development of novel therapeutics for the treatment of lung infection and inflammation.

Transcriptional profiling of lung macrophages identifies a predictive signature for inflammatory lung disease in preterm infants

Lung macrophages mature after birth, placing newborn infants, particularly those born preterm, within a unique window of susceptibility to disease. We hypothesized that in preterm infants, lung macrophage immaturity contributes to the development of bronchopulmonary dysplasia (BPD), the most common serious complication of prematurity. By measuring changes in lung macrophage gene expression in preterm patients at risk of BPD, we show here that patients eventually developing BPD had higher inflammatory mediator expression even on the first day of life. Surprisingly, the ex vivo response to LPS was similar across all samples. Our analysis did however uncover macrophage signature genes whose expression increased in the first week of life specifically in patients resilient to disease. We propose that these changes describe the dynamics of human lung macrophage differentiation. Our study therefore provides new mechanistic insight into both neonatal lung disease and human developmental immunology.

IL-33-induced neutrophil extracellular traps degrade fibronectin in a murine model of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is the leading cause of chronic lung disease in preterm neonates. Extracellular matrix (ECM) abnormalities reshape lung development, contributing to BPD progression. In the present study, we first discovered that the ECM component fibronectin was reduced in the pulmonary tissues of model mice with BPD induced by lipopolysaccharide (LPS) and hyper-oxygen. Meanwhile, interleukin-33 (IL-33) and other inflammatory cytokines were elevated in BPD lung tissues. LPS stimulated the production of IL-33 in alveolar epithelial cells via myeloid differentiation factor 88 (MyD88), protein 38 (p38), and nuclear factor-kappa B (NF-κB) protein 65 (p65). Following the knockout of either IL-33 or its receptor suppression of tumorigenicity 2 (ST2) in mice, BPD disease severity was improved, accompanied by elevated fibronectin. ST2 neutralization antibody also relieved BPD progression and restored the expression of fibronectin. IL-33 induced the formation of neutrophil extracellular traps (NETs), which degraded fibronectin in alveolar epithelial cells. Moreover, DNase-mediated degradation of NETs was protective against BPD. Finally, a fibronectin inhibitor directly decreased fibronectin and caused BPD-like disease in the mouse model. Our findings may shed light on the roles of IL-33-induced NETs and reduced fibronectin in the pathogenesis of BPD.

Rho/SMAD/mTOR triple inhibition enables long-term expansion of human neonatal tracheal aspirate-derived airway basal cell-like cells.

Bronchopulmonary dysplasia remains one of the most common complications of prematurity, despite significant improvements in perinatal care. Functional modeling of human lung development and disease, like BPD, is limited by our ability to access the lung and to maintain relevant progenitor cell populations in culture. We supplemented Rho/SMAD signaling inhibition with mTOR inhibition to generate epithelial basal cell-like cell lines from tracheal aspirates of neonates. Single-cell RNA-sequencing confirmed the presence of epithelial cells in tracheal aspirates obtained from intubated neonates. Using Rho/SMAD/mTOR triple signaling inhibition, neonatal tracheal aspirate-derived (nTAD) basal cell-like cells can be expanded long term and retain the ability to differentiate into pseudostratified airway epithelium. Our data demonstrate that neonatal tracheal aspirate-derived epithelial cells can provide a novel ex vivo human cellular model to study neonatal lung development and disease. Airway epithelial basal cell-like cell lines were derived from human neonatal tracheal aspirates. mTOR inhibition significantly extends in vitro proliferation of neonatal tracheal aspirate-derived basal cell-like cells (nTAD BCCs). nTAD BCCs can be differentiated into functional airway epithelium. nTAD BCCs provide a novel model to investigate perinatal lung development and diseases.

The Genetic Architecture of Alveolar Formation in the Lung in the Context of Bronchopulmonary Dysplasia

Alveologenesis is the most important and the least understood phase of lung development. Alveolar defects underlie both neonatal and adult lung diseases. Their arrested development is found in infants with BPD (BronchoPulmonary Dysplasia), while their destruction is characteristic of emphysematous lungs in adult COPD. We have developed 3 parallel, postnatal genetically‐based models to analyze the molecular basis of alveologenesis. Conditional postnatal inactivation of genes encoding receptors for TGFb, or PDGFA or IGF1 in a unique cell type we have identified as Secondary Crest Myofibroblasts, or SCMF blocks alveologenesis & produces a phenotype similar to human BPD. We reasoned that due to nearly identical phenotypes, the three BPD phenocopy models must share genetic elements whose role in alveologenesis is indispensable. To test this hypothesis, we have isolated mutant and control SCMF and identified their transcriptomic profile by RNA sequencing (RNAseq). Bioinformatic analysis of the sequencing data identified “pathway‐specific” differentially expressed genes (DEG) for TGFb, PDGFA/PDGFRa and IGF1 mutant models. Most importantly however, as predicted, we identified a cluster of “shared” genes which we propose contains conserved core alveologenesis regulatory genes. The accumulated evidence reveals a constellation of genes that makeup the genetic architecture of alveologenesis in mice with relevance to pathogenesis of BPD in human preterm neonates.Support or Funding InformationNIH/NHLBI & the Hastings Foundation

Bronchopulmonary Dysplasia Patients Have Preserved CT‐Measured Central Airway Luminal Area

ObjectiveBronchopulmonary dysplasia (BPD) is a condition of neonatal chronic lung disease due to disruption or dysregulation of pulmonary development. It is associated with decreased septation, alveolar hypoplasia, and abnormal disruption of pulmonary alveolar capillaries resulting in increased pulmonary resistance. However, the pathophysiology of BPD in the large conducting airways is not fully understood. The objective of our study was to determine if the luminal area of the central airways, measured by imaging, are altered in patients with a history of BPD. We hypothesized that compared to age‐ and sex‐matched controls, BPD patients would have a decreased luminal area of the central conducting airways and lung volume.MethodsFourteen BPD patients (8M/6F; Age=5.7±5.5 yrs) who had undergone a chest computed tomography (CT) scan were retrospectively identified. Age and sex matched controls (8M/6F, Age=5.6±5.3 yrs) who had undergone a CT scan for trauma were used for comparison. Measurement and analysis were performed by a single investigator using commercially available software (Aquarius, TeraRecon Inc.) that reconstructs the airways into 3D. Measurements of luminal airway area were conducted at three points based on anatomic bifurcations (corresponding to the beginning, middle and end of the airway) for each of the following structures: trachea, left main bronchus, left upper lobe, left lower lobe, right main bronchus, intermediate bronchus, and right upper lobe. Each airway’s luminal area was calculated based on the averages of the three measures obtained for each anatomic airway structure. Independent Student’s t‐test was used for statistical analysis.ResultsAirway luminal area was not different between BPD patients and matched controls (trachea: 89.8±57.1 vs 87.4±58.6 mm2; right main bronchus: 58.8±40.8 vs 64.0±44.5 mm2; intermediate bronchus: 33.6±21.2 vs 41.0±28.9 mm2; left main bronchus: 39.3±27.1 vs 46.6±36.5 mm2; left lower lobe: 22.7±14.6 vs 29.9±18.9 mm2; p>0.05 for all comparisons; BPD and controls, respectively). Total lung volume detected in the CT scans was not different between BPD patients and matched controls (3069±1073 vs 3215±984 cm3, p>0.05).ConclusionsOur results suggest the luminal areas of the large conducting airways in patients with BPD are not different from matched controls. Given the degree of respiratory complications and sequelae associated with BPD, our findings suggest future research should focus on alveolar and vascular impaired physiological and anatomic developments versus the large conducting airways.Support or Funding InformationNational Institutes of Health Grants R35‐HL139854 (MJJ), F32 HL‐131151 (SEB), T32 DK‐007352‐39 (CCW) and Mayo Clinic Internal Funding and Natural Science and Engineering Council of Canada RGPIN‐2019‐04615 (PBD)

Neišnešiotų naujagimių nefrokalcinozės rizikos veiksniai. Retrospektyvusis tyrimas

Santrauka. Tikslas. Įvertinti neišnešiotų naujagimių nefrokalcinozės formavimosi rizikos veiksnius. Metodai. Retrospektyvusis tyrimas atliktas Vilniaus universiteto ligoninės Santaros klinikų Neonatologijos centre, analizuoti 2017 m. sausio–spalio mėn. gydytų 77 neišnešiotų naujagimių duomenys. Nefrokalcinozė nustatyta ultragarsiniu tyrimu. Statistinė analizė atlikta SPSS programos 19 versija. Rezultatai. Nefrokalcinozė nustatyta 32,5 proc. atvejų. Didžiausios įtakos (kai p<0,05) nefrokalcinozės rizikai turejo šie veiksniai (tiriamoji ir kontrolinė grupė atitinkamai): mažesnis Apgar įvertis gimus po 1 min. (6,6 ir 7,1) ir po 5 min. (7,9 ir 8,1), gestacinis amžius (27+3 sav ir 28+6 sav.), gimimo svoris (1073,6 g ir 1335,7 g), atviras arterinis latakas (44 proc. ir 13,5 proc.), lėtine plaučių liga (48 proc. ir 17,3 proc.), ilgesnis kvėpuojamosios terapijos poreikis (33,3 dienos ir 20,5 dienos) ir hospitalizacijos trukmė (67 dienos ir 53,8 dienos), didesnis šarminės fosfatazės kiekis kraujo serume (544 U/l ir 443,8 U/l). Išvados. Nefrokalcinozė dažniau formuojasi neišnešiotiems, sunkios buklės naujagimiams, kuriems yra ilgalaikis kvepuojamosios terapijos poreikis ir lėtinė plaučių liga, buklė komplikuojant atviram arteriniam latakui.

Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs.

Neonatal interstitial lung diseases due to abnormal surfactant biogenesis are rare in humans and have never been reported as a spontaneous disorder in animals. We describe here a novel lung disorder in Airedale Terrier (AT) dogs with clinical symptoms and pathology similar to the most severe neonatal forms of human surfactant deficiency. Lethal hypoxic respiratory distress and failure occurred within the first days or weeks of life in the affected puppies. Transmission electron microscopy of the affected lungs revealed maturation arrest in the formation of lamellar bodies (LBs) in the alveolar epithelial type II (AECII) cells. The secretory organelles were small and contained fewer lamellae, often in combination with small vesicles surrounded by an occasionally disrupted common limiting membrane. A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII cells. The substitution resides in the LAMP domain adjacent to a conserved disulfide bond. In summary, this study describes a novel interstitial lung disease in dogs, identifies a new candidate gene for human surfactant dysfunction and brings important insights into the essential role of LAMP3 in the process of the LB formation.

Pediatric lung ultrasound - pros and potentials.

Lung ultrasound (US) cannot be considered a new diagnostic imaging technique anymore, with some articles dating back 50years. The question that hovers over it recently is why it is still not widely accepted, like chest radiography. So, have we wasted a lot of time without using lung US, or are we wasting our time using lung US? The main goals of this article are to underline all the advantages, potentials and reasons to use lung US in everyday clinical practice, but also to address the main concerns linked to this imaging tool. From the standpoint of an experienced pediatric radiologist from a tertiary health care children's hospital who has been performing this examination for more than 10years on a daily basis, this article also addresses the most common applications of lung US, such as detection of pneumonia and neonatal lung diseases.

Neonatal high-frequency oscillatory ventilation

Abstract High frequency oscillatory ventilation (HFOV) is often used as a rescue strategy for neonatal lung disease. In this article we discuss our experience of using HFOV including basic ventilator settings, optimising HFOV with monitoring and how specific diseases alter management. The article is focussed on ensuring understanding and safe use of HFOV by all neonatal staff.

Genetic Disorders of Surfactant Deficiency and Neonatal Lung Disease

Pulmonary surfactant is a heterogeneous combination of lipids and proteins, which prevents alveolar collapse at the end of expiration cycle by decreasing the alveolar surface tension at the air-liquid interface. At birth, the expression of surfactant is very important for normal lung function and it is strictly correlated to gestational age. The best known genetic mutations associated with the onset of respiratory distress in preterm and full-term newborns and with interstitial lung disease later in childhood are those involving the phospholipid transporter (ABCA3) or surfactant proteins C and B (SP-C and SP-B) genes. In particular, mutations in the SP-B gene induce respiratory distress in neonatal period, while alterations on gene encoding for SP-C are commonly associated with diffuse lung disease in children or in adults. Both clinical phenotypes are present, if genetic mutations interest even the phospholipid transporter ABCA3 ambiguity in the sentence. Interstitial lung disease in children (chILD) is defined as a mixed category of mainly chronic and rare respiratory disorders with increased mortality and morbidity. Although genetic alterations are mainly responsible for the onset of these diseases, however, there are also other pathogenic factors that contribute to increase the severity of clinical presentation. In this review, we analyze all clinical features of these rare pulmonary diseases in neonatal and in pediatric age.

Decreasing Chronic Lung Disease Associated with Bubble CPAP Technology: Experience at Five Years.

Introduction:Bubble continuous positive airway pressure (bCPAP) is associated with a decreased risk for chronic lung disease (CLD) in preterm neonates. This report examined the effectiveness of adopting bCPAP to reduce respiratory complications and medication usage in a community hospital NICU.Methods:The efficacy of bCPAP was assessed by retrospective examination and comparison of 45 neonates who received bCPAP and 87 neonates who received conventional ventilation only. Data on medication usage were also collected and analyzed.Results:After introduction of the bCPAP protocol, the median number of days on oxygen decreased in the bCPAP group compared with the conventional ventilation only group (median = 33 days, IQR = 7.5–66 vs median = 0, IQR = 0–0; P < 0.001). The exposure to conventional ventilation decreased in the bCPAP group compared with the conventional ventilation only group (median = 18 days, IQR = 5–42.5 vs median = 0, IQR = 0–7; P < 0.001). Postimplementation of bCPAP revealed decreases in CLD from 26 (30%) in the conventional ventilation only group to 2 (4%) in the bCPAP group (P = 0.002); there was also a significant decrease in the use of sedative medications in the bCPAP group compared with the conventional ventilation only group (mean = 5.20 doses, SD = 31.97 vs mean = 1.43, SD = 9.98; P < 0.001).Conclusion:The use of bCPAP results in significant decreases in the use of conventional ventilation, the risk for CLD, and the need for sedative medication.

Non-invasive nitric oxide inhalation therapy for severe neonatal chronic lung disease

Non-invasive nitric oxide inhalation therapy for severe neonatal chronic lung disease

The Role of LncRNA H19 in MAPK Signaling Pathway Implicated in the Progression of Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease, is an important cause of respiratory illness in preterm newborns that results in significant morbidity and mortality. Long noncoding RNAs (lncRNAs) have been discovered with many biological functions. However, the role of lncRNAs in the pathogenesis of BPD remains poorly understood. Here, we established a mouse lung injury model that mimicked human BPD. Subsequently, we found the lncRNA H19 expression level was significantly increased in BPD compared with normal lung tissues using quantitative real-time polymerase chain reaction. Next, we observed that overexpression of lncRNA H19 enhanced mitogen-activated protein kinase (MAPK) signaling pathway. In addition, we also found that dysfunction of lncRNA H19 altered the expression of inflammatory factors. Thus, our study validates that lncRNA H19 contributes to the progression of BPD by regulating MAPK signaling pathway, which could be used as a potential target for treating BPD.

The Lung Ultrasound Score Cannot Accurately Evaluate the Severity of Neonatal Lung Disease.

The Lung Ultrasound Score Cannot Accurately Evaluate the Severity of Neonatal Lung Disease.

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

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. 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. 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. 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.

Neonatal common lung diseases: lung ultrasound or chest X-ray?

Chest X-ray examination is the traditional methods in the diagnosis of neonatal lung diseases, lung ultrasound (LUS) is the emerging technology in this field.It has confirmed that LUS is more accurate and reliable in diagnosis of lung diseases than X-ray, however, it remains controversy whether or not LUS could replace X-ray as the front-line examination method for neonatal lung diseases.In this paper, we combined the research progress, our clinical application experience and typical cases to elaborate various aspects of the feasibility and necessity of routine use of ultrasound in neonatal wards.We concluded that LUS has many advantages and provides accurate and reliable information, therefore, it might be regularly used in NICUs. Key words: Lung disease; Diagnosis; Differential diagnosis; Lung ultrasound; Chest X-ray; Neonate

Secondary crest myofibroblast PDGFRα controls the elastogenesis pathway via a secondary tier of signaling networks during alveologenesis.

Postnatal alveolar formation is the most important and the least understood phase of lung development. Alveolar pathologies are prominent in neonatal and adult lung diseases. The mechanisms of alveologenesis remain largely unknown. We inactivated Pdgfra postnatally in secondary crest myofibroblasts (SCMF), a subpopulation of lung mesenchymal cells. Lack of Pdgfra arrested alveologenesis akin to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. The transcriptome of mutant SCMF revealed 1808 altered genes encoding transcription factors, signaling and extracellular matrix molecules. Elastin mRNA was reduced, and its distribution was abnormal. Absence of Pdgfra disrupted expression of elastogenic genes, including members of the Lox, Fbn and Fbln families. Expression of EGF family members increased when Tgfb1 was repressed in mouse. Similar, but not identical, results were found in human BPD lung samples. In vitro, blocking PDGF signaling decreased elastogenic gene expression associated with increased Egf and decreased Tgfb family mRNAs. The effect was reversible by inhibiting EGF or activating TGFβ signaling. These observations demonstrate the previously unappreciated postnatal role of PDGFA/PDGFRα in controlling elastogenic gene expression via a secondary tier of signaling networks composed of EGF and TGFβ.

Award-winning nurse’s guideline halves time taken to wean babies with chronic neonatal lung disease off oxygen

Joanna Broderick’s work has enhanced safety and nurse autonomy, as well as saving her trust money