Chronic Lung Disease Of Prematurity Research Articles

New advances in RSV: Is prevention attainable?

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI), hospitalization, and mortality in infants and young children globally. The greatest burden of severe disease and mortality occurs in low-middle income countries (LMICs), with large and vulnerable childhood populations. The highest rates of RSV-hospitalization occur in healthy-term infants under 3 months of age. Preterm infants, children with chronic lung disease of prematurity, Down's syndrome, congenital heart disease, or immunodeficiency also have a higher risk of severe RSV-LRTI. Early-life RSV-LRTI has also been associated with chronic sequelae, including recurrent LRTI, recurrent wheezing, asthma, and lung function impairment. A RSV pre-fusion (F) maternal vaccine and long-acting monoclonal antibody (nirsevimab) have been licensed for the prevention of RSV-LRTI in infants and young children. Studies show high efficacy and effectiveness particularly for preventing severe RSV-LRTI. Maternal RSV vaccine given at 24-36 weeks of pregnancy was effective in preventing RSV medically attended LRTI and severe RSV-LRTI through 6 months after birth in a phase 3 study conducted in 18 countries over two RSV seasons. Vaccination was safe with no significant difference in adverse events between infants born to mothers who received RSV preF vaccine compared to placebo. A numerical imbalance in preterm births that occurred predominantly in South Africa, unrelated to vaccine timing or gestational age at vaccination and unassociated with mortality, coincided with COVID-19 delta and omicron waves. Nirsevimab, given as a single dose prior or during the RSV season, had high efficacy in preventing RSV-LRTI hospitalization in infants in preterm and in full-term infants, as well as in young children with underlying conditions through 150 days post administration in phase 2 and 3 trials. High effectiveness against hospitalization or severe disease in infants and in at-risk children up to 2 years of age has also been reported in several countries where implementation has occurred. RSV-LRTI is now a preventable disease in infants and young children. Rapid implementation of these highly effective interventions has occurred in many high-income countries, but access remains very limited in LMICs. Access to such RSV preventive interventions is urgently needed for all children to strengthen child health and promote global equity.

6813 Des-Ciclesonide: A Novel Selective Glucocorticoid Receptor Modulator With Therapeutic Potential for Bronchopulmonary Dysplasia, a Chronic Lung Disease of Prematurity

Abstract Disclosure: N. El Khoury: None. J. Jaumotte: None. C. Min: None. C. Madigan: None. J. Wang: None. U. Chandran: None. V. Sampath: None. T.J. Cole: None. P. Monaghan-Nichols: None. R. Houtman: None. K.W. Nettles: None. D.B. DeFranco: None. Infants born before 30 weeks gestation are at risk of developing bronchopulmonary dysplasia (BPD), a prevalent chronic lung disease of prematurity. Glucocorticoids (GCs) such as dexamethasone (DEX) have been a mainstay of BPD prevention as they reduce lung inflammation and injury. However, their use is encumbered with several adverse effects including hyperglycemia, impaired somatic and brain growth and cerebral palsy. These major concerns have resulted in the AAP recommending caution in GC use in preterm infants.Ciclesonide (CIC), an inhaled GC prodrug approved for the treatment of asthma and allergic rhinitis in children, is converted to the potent glucocorticoid receptor (GR) agonist des-ciclesonide (DES) by enzymes enriched in the airways. We previously reported that s.c. delivery of CIC in neonatal rats activated GR transcriptional responses in lung but did not trigger the adverse effects on somatic growth, brain weight or cerebral white matter loss caused by DEX leading us to propose CIC as a potential new pharmacotherapy for BPD. To determine whether limited systemic metabolism of CIC in neonatal rats was solely responsible for its enhanced safety profile, we assessed various outcomes in neonatal rats followed s.c. delivery of its active metabolite DES. Consistent with previous studies, five daily s.c. injections of DEX led to a reduction in body and brain weight as well as reduced serum levels of insulin-like growth factor-1 and chronic hyperglycemia. Surprisingly, analogous s.c. injection of neonatal rats with DES, which has a higher binding affinity for GR than DEX, did not trigger any of these adverse effects. However, DES is as effective as DEX in reducing the expression of various proinflammatory cytokine mRNAs in neonatal rat lung induced by an 11-day systemic treatment with bleomycin. Bulk RNAseq analyses revealed transcriptional responses of neonatal lung and liver to DES, although less robust than that observed to DEX (i.e., 25% and 13% in lung and liver, respectively). Nonetheless, a NAPing assay for coregulator peptide binding showed increased binding of all the DES responsive peptide interactions relative to DEX and cortisol. All-atom molecular dynamics simulations revealed site-specific H-bonding changes within the GR ligand binding domain (LBD) caused by the bulky C16/C17substitution within DES, which was translated into broader changes in LBD structure, specifically revealed as differences in RMSF in helix 7/8 and the surfaces interacting with the NCOA2 peptide. Furthermore, network pathway analysis illustrated that DES mobility at helix 7/8 uniquely generated a meaningful allosteric signaling pathway between Q642 and NCOA2 peptide. In conclusion, the pharmacokinetic properties of the GR prodrug CIC coupled with the tissue-selective pharmacodynamic properties of its active metabolite DES make this FDA approved drug a potential new therapeutic agent for BPD. Presentation: 6/3/2024

RSV Neutralizing Antibodies Following Nirsevimab and Palivizumab Dosing.

Data describing respiratory syncytial virus (RSV) neutralizing antibody (nAb) levels for nirsevimab, a recently approved, extended half-life, anti-RSV fusion protein (F protein) monoclonal antibody, relative to the previous standard of care, palivizumab, have not been reported. The MEDLEY trial was a randomized, palivizumab-controlled, phase 2/3 study of nirsevimab during 2 RSV seasons (season 1 and 2) in infants born preterm (≤35 weeks' gestational age; dosed season 1 only) or with congenital heart disease or chronic lung disease of prematurity (dosed seasons 1 and 2). Participants were randomly assigned to receive a single dose of nirsevimab followed by 4 monthly placebo doses, or 5 once-monthly doses of palivizumab. Anti-RSV fusion protein serology (ie, levels of prefusion [pre-F]/postfusion [post-F] conformation antibodies), nirsevimab and palivizumab serum concentrations, and RSV nAbs were measured in participant samples collected at baseline (pre-dose) and days 31, 151, and 361. Serologic data were similar in seasons 1 and 2. Nirsevimab predominately conferred pre-F antibodies, whereas palivizumab conferred pre-F and post-F antibodies. Nirsevimab and palivizumab serum concentrations were highly correlated with nAb levels in both seasons. In season 1, the nAb levels in nirsevimab recipients were highest in day 31 samples and gradually declined but remained 17-fold above baseline at day 361. nAb levels in palivizumab recipients increased incrementally with monthly doses to day 151. nAb levels followed similar patterns in season 2. nAb levels were ∼10-fold higher with nirsevimab compared with palivizumab across both seasons. Nirsevimab prophylaxis confers ∼10-fold higher and more sustained RSV nAb levels relative to palivizumab.

Striving for healthy lungs: Enhancing respiratory outcomes of prematurity.

Infants born prematurely are born in a critical developmental time period and because of arrest of lung maturation at that period their pulmonary functions are below the normal for their age. Early lung development has a lifelong effect on respiratory health and disease. Can we affect that sequence of events and change the outcome of chronic lung disease of prematurity?

The respiratory consequences of preterm birth: from infancy to adulthood.

Survival of preterm-born infants, especially at extremes of prematurity (less than 28 weeks gestation), is now common, particularly in the developed world. Despite advances in neonatal care, short-term respiratory morbidity, termed bronchopulmonary dysplasia (also called chronic lung disease of prematurity), remains an important clinical outcome. As survival during the neonatal period has improved, preterm-born individuals are now entering childhood, adolescence and adulthood in far greater numbers, and adverse longer-term respiratory outcomes following birth at an immature stage of lung development are becoming increasingly apparent. In this article, we shall review the background of the major respiratory complications in the neonatal period, bronchopulmonary dysplasia, and the current evidence regarding its prevention and management. In addition, we shall review the emerging literature on the respiratory morbidity experienced in childhood, adolescence, and adulthood by preterm-born survivors, with reduced lung function and a risk of developing chronic obstructive pulmonary disease in early adult life. As this population of preterm-born individuals increases, an understanding of the respiratory consequences of preterm birth will become increasingly important not only for neonatologists, paediatricians and paediatric pulmonologists but also for physicians and healthcare professionals involved in the care of adults who were born preterm.

A lactobacilli-based inhaled live biotherapeutic product attenuates pulmonary neutrophilic inflammation

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurity. Exposure to noxious stimuli such as hyperoxia, volutrauma, and infection in infancy can have long-reaching impacts on lung health and predispose towards the development of conditions such as chronic obstructive pulmonary disease (COPD) in adulthood. BPD and COPD are both marked by lung tissue degradation, neutrophil influx, and decreased lung function. Both diseases also express a change in microbial signature characterized by firmicute depletion. However, the relationship between pulmonary bacteria and the mechanisms of downstream disease development has yet to be elucidated. We hypothesized that murine models of BPD would show heightened acetylated proline-glycine-proline (Ac-PGP) pathway and neutrophil activity, and through gain- and loss-of-function studies we show that Ac-PGP plays a critical role in driving BPD development. We further test a inhaled live biotherapeutic (LBP) using active Lactobacillus strains in in vitro and in vivo models of BPD and COPD. The Lactobacillus-based LBP is effective in improving lung structure and function, mitigating neutrophil influx, and reducing a broad swath of pro-inflammatory markers in these models of chronic pulmonary disease via the MMP-9/PGP (matrix metalloproteinase/proline-glycine-proline) pathway. Inhaled LBPs show promise in addressing common pathways of disease progression that in the future can be targeted in a variety of chronic lung diseases.

Azithromycin for the prevention of chronic lung disease of prematurity: not a silver bullet

Azithromycin for the prevention of chronic lung disease of prematurity: not a silver bullet

Comprehensive Summary of Safety Data on Nirsevimab in Infants and Children from All Pivotal Randomized Clinical Trials.

Nirsevimab is approved in the US for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants during their first RSV season and in children aged ≤24 months who remain vulnerable to severe RSV disease through their second RSV season. We summarize a pre-specified analysis of nirsevimab safety data from three randomized controlled trials: Phase 2b (NCT02878330; healthy infants born ≥29 to <35 weeks' gestational age [wGA]); Phase 3 MELODY (NCT03979313; healthy infants born ≥35 wGA); and Phase 2/3 MEDLEY (NCT03959488; infants with congenital heart disease [CHD] and/or chronic lung disease of prematurity [CLD] or born ≤35 wGA). Participants (randomized 2:1) received a single intramuscular dose of nirsevimab or comparator (placebo, Phase 2b/MELODY; 5× once-monthly palivizumab, MEDLEY) before their first RSV season (recipients < 5 kg, nirsevimab 50 mg; ≥5 kg, nirsevimab 100 mg). In MEDLEY, children with CHD/CLD continued to a second RSV season: first-season nirsevimab recipients received nirsevimab 200 mg; first-season palivizumab recipients were re-randomized 1:1 to receive nirsevimab 200 mg or 5× once-monthly palivizumab. The incidence, severity, and nature of AEs were similar across treatments (nirsevimab, n = 3184; placebo, n = 1284; palivizumab, n = 304). Most AEs were mild to moderate in severity, with ≥98% unrelated to treatment. AEs of special interest occurred infrequently (<1%): no anaphylaxis or thrombocytopenia were treatment-related, and no immune complex disease was reported. Deaths (incidence < 1.0%) were all unrelated to treatment. A single dose per season of nirsevimab for the prevention of RSV disease had a favorable safety profile, irrespective of wGA or comorbidities.

The Role of the Airway and Gut Microbiome in the Development of Chronic Lung Disease of Prematurity.

Chronic lung disease (CLD) of prematurity, a common cause of morbidity and mortality in preterm-born infants, has a multifactorial aetiology. This review summarizes the current evidence for the effect of the gut and airway microbiota on the development of CLD, highlighting the differences in the early colonisation patterns in preterm-born infants compared to term-born infants. Stool samples from preterm-born infants who develop CLD have less diversity than those who do not develop CLD. Pulmonary inflammation, which is a hallmark in the development of CLD, may potentially be influenced by gut bacteria. The respiratory microbiota is less abundant than the stool microbiota in preterm-born infants. There is a lack of clear evidence for the role of the respiratory microbiota in the development of CLD, with results from individual studies not replicated. A common finding is the presence of a single predominant bacterial genus in the lungs of preterm-born infants who develop CLD. Probiotic preparations have been proposed as a potential therapeutic strategy to modify the gut or lung microbiota with the aim of reducing rates of CLD but additional robust evidence is required before this treatment is introduced into routine clinical practice.

Azithromycin therapy for prevention of chronic lung disease of prematurity (AZTEC): a multicentre, double-blind, randomised, placebo-controlled trial

Systematic reviews have reported conflicting evidence on whether macrolide antibiotics reduce rates of chronic lung disease of prematurity (CLD) in at-risk preterm infants born at less than 30 weeks' gestation, including in those colonised with pulmonary Ureaplasma spp. Since an adequately powered trial has been lacking, we aimed to assess if the macrolide azithromycin improved survival without the development of physiologically defined moderate or severe CLD in preterm infants. AZTEC was a multicentre, double-blind, randomised, placebo-controlled trial conducted in 28 tertiary neonatal intensive care units in the UK. Infants were eligible if they were born at less than 30 weeks' gestation and had received at least 2 h of either non-invasive (continuous positive airway pressure or humidified high flow nasal cannula therapy) or invasive respiratory support (via endotracheal tube) within 72 h of birth. Eligible infants were randomly allocated in a 1:1 ratio using random permuted blocks of four to receive either intravenous azithromycin at 20 mg/kg per day for 3 days followed by 10 mg/kg for 7 days, or to placebo. Allocation was stratified by centre and gestational age at birth (<28 weeks vs ≥28 weeks). Azithromycin and placebo vials were encased in tamper-evident custom cardboard cartons to ensure masking for clinicians, parents, and the research team. The primary outcome was survival without development of physiologically defined moderate or severe CLD at 36 weeks' postmenstrual age. Outcomes and safety were analysed on an intention-to-treat basis (all randomly allocated infants, regardless of any post-randomisation events). The study was registered with ISRCRN (11650227) and is closed. Infants were recruited between Oct 9, 2019, and March 22, 2022. 799 (53·1%) of 1505 eligible infants underwent random allocation; three infants were withdrawn, including consent to use their data, leaving 796 infants for analysis. Survival without moderate or severe CLD occurred in 166 (42%) of 394 infants in the intervention group and 179 (45%) of 402 in the placebo group (three-level adjusted OR [aOR] 0·84, 95% CI 0·55-1·29, p=0·43). Pulmonary Ureaplasma spp colonisation did not influence treatment effect. Overall, seven serious adverse events were reported for the azithromycin group (five graded as severe, two as moderate), and six serious adverse events were reported in the placebo group (two severe, two moderate, and two mild), as assessed by the local principal investigators. Since prophylactic use of azithromycin did not improve survival without development of physiologically-defined CLD, regardless of Ureaplasma spp colonisation, it cannot be recommended in clinical practice. UK National Institute for Health and Care Research.

The role of nutritional interventions in the prevention and treatment of chronic lung disease of prematurity.

Chronic lung disease of prematurity or bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Nutrition may affect incidence and severity of BPD. In this context, the Section on Nutrition, Gastroenterology and Metabolism, the Pulmonary Section of the European Society for Paediatric Research (ESPR) and SPR have joined forces to review the current knowledge on nutritional issues related to BPD. The aim of this narrative review is to discuss the clinical implications for nutritional practice. Nutrient deficiencies may influence pathogenesis of BPD. Adequate nutrition and growth can play a crucial role in the prevention of and recovery from BPD. Optimal nutrition strategy is an important principle, especially in the early postnatal period. As optimal energy intake in infants at risk of BPD or with evolving BPD is not yet defined, further research with well-designed studies on nutritional strategies for preterm infants with BPD is urgently needed. IMPACT: Based on current evidence it seems reasonable to recommend that BPD diagnosed infants should receive an energy supply ranging from 120 to 150 Kcal/kg/d. Exclusive MOM feed with adequate fortification should be encouraged as this is associated with a significant reduction in the risk of BPD. Suboptimal nutritional delivery is often seen in preterm infants with BPD compared to controls.

Antenatal Endotoxin Induces Dysanapsis in Experimental Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, is characterized by impaired lung development with sustained functional abnormalities due to alterations of airways and the distal lung. Although clinical studies have shown striking associations between antenatal stress and BPD, little is known about the underlying pathogenetic mechanisms. Whether dysanapsis, the concept of discordant growth of the airways and parenchyma, contributes to late respiratory disease as a result of antenatal stress is unknown. We hypothesized that antenatal endotoxin (ETX) impairs juvenile lung function as a result of altered central airway and distal lung structure, suggesting the presence of dysanapsis in this preclinical BPD model. Fetal rats were exposed to intraamniotic ETX (10 μg) or saline solution (control) 2 days before term. We performed extensive structural and functional evaluation of the proximal airways and distal lung in 2-week-old rats. Distal lung structure was quantified by stereology. Conducting airway diameters were measured using micro-computed tomography. Lung function was assessed during invasive ventilation to quantify baseline mechanics, response to methacholine challenge, and spirometry. ETX-exposed pups exhibited distal lung simplification, decreased alveolar surface area, and decreased parenchyma-airway attachments. ETX-exposed pups exhibited decreased tracheal and second- and third-generation airway diameters. ETX increased respiratory system resistance and decreased lung compliance at baseline. Only Newtonian resistance, specific to large airways, exhibited increased methacholine reactivity in ETX-exposed pups compared with controls. ETX-exposed pups had a decreased ratio of FEV in 0.1 second to FVC and a normal FEV in 0.1 second, paralleling the clinical definition of dysanapsis. Antenatal ETX causes abnormalities of the central airways and distal lung growth, suggesting that dysanapsis contributes to abnormal lung function in juvenile rats.

Energizing the Lung Vasculature in the Premature Infant to Promote Alveolar Formation

Background/Objective: Chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD) occurs when infants born with underdeveloped immature lungs are forced to navigate the expansion of future air spaces, with irregular vascular formation proceeding development of BPD. Lung development has distinct and dynamic metabolic requirements. We recently identified by mass spectrometry that nicotinamide adenine dinucleotide (NAD+), generated from vitamin B3 ‘Nicotinamide’ (NAM), was significantly reduced in a hyperoxia murine model of BPD. As NAM/NAD+ are dynamic regulators of tissue regenerating neovascularization in otherdisease processes, we hypothesized that NAM/NAD+ metabolic deficiencies contribute to compromised angiogenesis formation and alveolar formation.&#x0D; Methods: Impact of NAM supplementation on circulating human neonatal endothelial colonyforming cells (ECFCs) were assessed for differential capillary formation properties of angiogenesis (Matrigel), migration (wound healing), proliferation (WST1 and crystal violetstaining), and mitochondrial function in normoxia and hyperoxia (85% oxygen) conditions.&#x0D; Results: Hyperoxia suppresses ECFC angiogenesis, while NAM supplementation in hyperoxia significantly rescued vascular networks, branched nodes, and branch points (p&lt;0.001). Wound healing assays suggest that NAM promotes cell migration in normoxia and hyperoxia (p&lt;0.0001). Although NAM increased WST1 activity in hyperoxia, crystal violet analysis determined that NAM had no impact on ECFC proliferation. Lastly, NAM significantly reduced hyperoxia induced mitochondrial oxidative stress in a dose dependent manner (p&lt;0.05).&#x0D; Conclusion and Clinical Implications: Lung development has specific metabolic needs during different stages of development that are disrupted by premature birth. Replenishment of NAM promotes angiogenesis and migration in hyperoxia while reducing mitochondrial activity. Future studies are necessary to explore the role of NAM/NAD+ axis in the developing lung.

Types of home respiratory support in children with bronchopulmonary dysplasia and factors determining its duration: A scoping review.

Bronchopulmonary dysplasia also known as chronic lung disease of prematurity has changed as a disease entity over the last five decades and children with "new bronchopulmonary dysplasia (BPD)" have better survival rates. This necessitates strategies to prevent severe BPD and provide organized home support. Home respiratory support in these children varies from home oxygen to noninvasive ventilation and tracheostomy ventilation. This review was conducted utilizing Joanna Briggs Institute publications on evidence synthesis and presentation of results for a scoping review. The Preferred Reporting Items for Systematic Review and Meta-Analyses were used to report the results. The risk of bias assessment was done using "The Cochrane Handbook for Systematic Reviews tool for interventional studies." After screening for the duplication of results and applying inclusion and exclusion criteria, twenty-seven studies were assessed by reading the full texts. Out of these, eleven were finally included in this systematic review. The total sample size from all studies was 4794, including 2705 males. The 4/11 studies home oxygen, one study reported continuous positive airway pressure/bilevel positive airway pressure and seven studies used tracheostomy or tracheostomy ventilation. The median duration of post-natal invasive ventilation was higher in those discharged on home oxygen compared to those who did not need oxygen at discharge. There is a significant proportion of children who are tracheostomy ventilated (8.65%) at home. In the absence of established guidelines, these children are vulnerable when it comes to care at home and the timing of decannulation. For home oxygen alone, guidelines by ERS, ATS and BTS have streamlined weaning protocols and the need for having a multi-disciplinary team to care for these children.

Association and risk factors of pediatric pulmonary hypertension with obstructive sleep apnea: A national study utilizing the Kids' Inpatient Database (KID)

Study objectiveAssess the prevalence of and risk factors for pediatric pulmonary hypertension (PH) in the 2016 Kids' Inpatient Database (KID), including obstructive sleep apnea (OSA) and obesity. MethodsRetrospective cross-sectional cohort study utilizing 6,081,132 weighted pediatric discharges from the 2016 KID. Study variables included age, length of stay, mortality, gender, hospital region, primary payer, race, median household income for patient's ZIP code, OSA, central sleep apnea (CSA), obesity, Down syndrome, sickle cell disease (SCD), thalassemia, congenital heart disease (CHD), hypertension, asthma and chronic lung disease of prematurity (CLDP). PH was the primary outcome of interest. Bivariate and multivariable logistic regression models were utilized with odds ratios and 95 % confidence intervals. ResultsThe mean age was 3.76 years, the mean hospital length of stay was 3.85 days, 48.9 % were male, 52.6 % had government health insurance, 51.0 % were White, 16.1 % were Black, 21.1 % were Hispanic, 5.0 % were Asian or Pacific Islander, 0.80 % were Native American and 6.1 % identified as “other”. The prevalence of PH was 0.21 % (12,777 patients). There were 37,631 patients with OSA and the prevalence of PH among this cohort was 3.3 %, over 10x greater than the overall prevalence of PH in the 2016 KID (0.21 %). Risk factors associated with PH included CLDP, CHD, Down syndrome, asthma, OSA, CSA, hypertension, SCD, obesity, race/ethnicity, government insurance, age, male gender (p < 0.0001), and hospital region (p = 0.0002). ConclusionsSeveral risk factors were independently associated with PH, such as OSA, CSA, obesity, asthma, and insurance status. Prospective multi-institutional studies are needed to assess the relationships between these risk factors, severity metrics, and causative links in the development of PH; in addition to identifying children with OSA who are most likely to benefit from cardiopulmonary screening prior to adenotonsillectomy. Level of evidenceLevel III.

Effect of Speaking Valves on Tracheostomy Decannulation.

Introduction Despite several pediatric tracheostomy decannulation protocols there remains tremendous variability in practice. The effect of tracheostomy capping on decannulation has been studied but the role of speaking valves (SVs) is unknown. Objective Given the positive benefits SVs have on rehabilitation, we hypothesized that SVs would decrease time to tracheostomy decannulation. The purpose of the present study was to evaluate this in a subset of patients with chronic lung disease of prematurity (CLD). Methods A retrospective chart review was performed at a tertiary care children's hospital. A total of 105 patients with tracheostomies and CLD were identified. Data collected included demographics, gestational age, congenital cardiac disease, airway surgeries, granulation tissue excisions, SV and capping trials, tracheitis episodes, and clinic visits. Statistics were performed with logistic and linear regression. Results A total of 75 patients were included. The mean gestational age was 27 weeks (standard deviation [SD] = 3.6) and the average birthweight was 1.1 kg (SD = 0.6). The average age at tracheostomy was 122 days (SD = 63). A total of 70.7% of the patients underwent decannulation and the mean time to decannulation (TTD) was 37 months (SD = 19). A total of 77.3% of the patients had SVs. Those with an SV had a longer TTD compared to those without (52 versus 35 months; p = 0.008). Decannulation was increased by 2 months for every increase in the number of hospital presentations for tracheitis ( p = 0.011). Conclusion The present study is the first, to our knowledge, to assess the effect of SVs on tracheostomy decannulation in patients with CLD showing a longer TTD when SVs are used.

An Update on Lung Function of Extremely and Very Preterm Infants in Later Life: The Role of Early Nutritional Interventions.

Birth occurring at ≤32 weeks' gestation ("very preterm") or at ≤28 weeks' gestation ("extremely preterm") potentially poses considerable health problems for the neonate, including respiratory sequelae, not only during the immediate newborn period, but throughout childhood and into adulthood. With the progressive improvements in neonatal care, the survival of extremely preterm and very preterm neonates has improved substantially. However, a considerable percentage of these infants suffer dysfunctions that may trigger, at some stage later in life, the onset of respiratory morbidities. The interruption of the normal development of the respiratory tract caused by preterm birth, in combination with postnatal lung injury caused by various interventions, e.g., mechanical ventilation and oxygen therapy, increases the risk ofthe development of long-term respiratory deficits in survivors. Those infants that are most affected are those who develop chronic lung disease of prematurity (also called bronchopulmonary dysplasia, BPD), but impaired lung function can develop irrespective of BPD diagnosis. Apart from indicating abnormal lung function in survivors of extreme prematurity, recent long-term follow-up studies also emphasize the crucial role of early nutritional intake as an effective strategy, which promotes lung growth and repair. This article will update the associations between extremely/very preterm birth with long-term respiratory outcomes. It will also discuss the protective effect of nutritional interventions, focusing on recently published follow-up data.

Prospective epigenome and transcriptome analyses of cord and peripheral blood from preterm infants at risk of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease of prematurity with limited treatment options. To uncover biomarkers of BPD risk, this study investigated epigenetic and transcriptomic signatures of prematurity at birth and during the neonatal period at day 14 and 28. Peripheral blood DNAs from preterm infants were applied to methylation arrays and cell-type composition was estimated by deconvolution. Covariate-adjusted robust linear regression elucidated BPD- and prolonged oxygen (≥ 14 days) exposure-associated CpGs. RNAs from cord and peripheral blood were sequenced, and differentially expressed genes (DEGs) for BPD or oxygen exposure were determined. Estimated neutrophil–lymphocyte ratios in peripheral blood at day 14 in BPD infants were significantly higher than nonBPD infants, suggesting an heightened inflammatory response in developing BPD. BPD-DEGs in cord blood indicated lymphopoiesis inhibition, altered Th1/Th2 responses, DNA damage, and organ degeneration. On day 14, BPD-associated CpGs were highly enriched in neutrophil activation, infection, and CD4 + T cell quantity, and BPD-DEGs were involved in DNA damage, cellular senescence, T cell homeostasis, and hyper-cytokinesis. On day 28, BPD-associated CpGs along with BPD-DEGs were enriched for phagocytosis, neurological disorder, and nucleotide metabolism. Oxygen supplementation markedly downregulated mitochondrial biogenesis genes and altered CpGs annotated to developmental genes. Prematurity-altered DNA methylation could cause abnormal lymphopoiesis, cellular assembly and cell cycle progression to increase BPD risk. Similar pathways between epigenome and transcriptome networks suggest coordination of the two in dysregulating leukopoiesis, adaptive immunity, and innate immunity. The results provide molecular insights into biomarkers for early detection and prevention of BPD.

A Novel Phenotype of Calvarial Thickening and Increased Rates of Premature Calvarial Suture Closure in Children With Chronic Lung Disease.

The purpose of this study was to characterize a novel type of calvarial thickening and provide objective measurements of skull thickness and calvarial suture morphology in patients with bronchopulmonary dysplasia. Infants with severe bronchopulmonary dysplasia who also had undergone computed tomography (CT) scans were identified from the neonatal chronic lung disease program database. Thickness analysis was performed using Materialise Mimics. The chronic lung disease team treated 319 patients during the study interval of which, 58 patients (18.2%) had head CT available. Twenty-eight (48.3%) were found to have calvarial thickening. The rate of premature suture closure in the study population was 36.2% (21 of 58 patients), with 50.0% of affected cohort having evidence of premature suture closure on the first CT scan. Multivariate logistic regression identified 2 risk factors, requiring invasive ventilation at 6 months of age and fraction of inspired oxygen requirement at 6 months of age. Increased head circumference at birth protected against the development of calvarial thickening. We have described a novel subset of patients with chronic lung disease of prematurity who have calvarial thickening with remarkably high rates of premature closure of cranial sutures. The exact etiology of the association is unknown. In this patient population with radiographic evidence of premature suture closure, operative decision should be made after considering unequivocal evidence of elevated intracranial pressure or dysmorphology and balanced against the risk of the procedure.

Development and Disorders of the Airway in Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD), a disorder characterized by arrested lung development, is a frequent cause of morbidity and mortality in premature infants. Parenchymal lung changes in BPD are relatively well-characterized and highly studied; however, there has been less emphasis placed on the role that airways disease plays in the pathophysiology of BPD. In preterm infants born between 22 and 32 weeks gestation, the conducting airways are fully formed but still immature and therefore susceptible to injury and further disruption of development. The arrest of maturation results in more compliant airways that are more susceptible to deformation and damage. Consequently, neonates with BPD are prone to developing airway pathology, particularly for patients who require intubation and positive-pressure ventilation. Airway pathology, which can be divided into large and small airways disease, results in increased respiratory morbidity in neonates with chronic lung disease of prematurity.