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.

Hemosiderin-Laden Macrophages in Bronchoalveolar Lavage Samples of Children with Bronchopulmonary Dysplasia.

OBJECTIVES: To evaluate the prevalence of hemosiderin-laden macrophages in children with bronchopulmonary dysplasia (BPD) and assess for an association between hemosiderin-laden macrophages and pulmonary arterial hypertension. STUDY DESIGN: Retrospective case-control study of infants and children with and without BPD who underwent bronchoscopy with bronchoalveolar lavage (BAL) the at Children's Hospital of Philadelphia between 2012 and 2021. RESULTS: BAL from 205 children with BPD and 106 controls without BPD matched for tracheostomy, infection, and age were reviewed for hemosiderin-laden macrophages. Seventy-one individuals (34.6%) with BPD had a BAL with 10% or more hemosiderin-laden macrophages compared with 3 (2.8%) controls (P < .0001; OR, 18.19; 95% CI, 5.57-59.41). Patients with pulmonary hypertension by echocardiogram (P = .04; OR, 3.69; 95% CI, 1.05-12.96) or an elevated mean pulmonary artery pressure during cardiac catheterization, rs (14) = 0.56, P = .04, were more likely to have elevated hemosiderin-laden macrophages on BAL samples less than 60 days from bronchoscopy. After adjusting for birth weight, gestational age, BPD grade, and age at the time of bronchoscopy using logistic regression, pulmonary hypertension was associated with a higher odds of hemosiderin-laden macrophages of 10% or more (P = .02; OR, 6.37; 95% CI, 1.28-31.87). No association was observed between hemosiderin-laden macrophages and sex, race, gestational age, birth weight, tracheostomy, or infectious studies. CONCLUSIONS: This retrospective study revealed increased hemosiderin-laden macrophages in BAL samples from patients with BPD and a significant association with pulmonary arterial hypertension. It is unclear whether elevated hemosiderin-laden macrophages within BPD contributes to the pathogenesis of lung and pulmonary vascular disease or is simply a biomarker of pulmonary arterial hypertension.

Pediatric Aerodigestive Medicine: Advancing Collaborative Care for Children With Oropharyngeal Dysphagia.

OBJECTIVES: Aerodigestive disorders encompass various pathological conditions affecting the lungs, upper airway, and gastrointestinal tract in children. While advanced care has primarily occurred in specialty centers, many children first present to general pediatric gastroenterologists with aerodigestive symptoms necessitating awareness of these conditions. At the 2021 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the aerodigestive Special Interest Group held a full-day symposium entitled, Pediatric Aerodigestive Medicine: Advancing Collaborative Care of Children with Aerodigestive Disorders. The symposium aimed to underline the significance of a multidisciplinary approach to achieve better outcomes for these complex patients. METHODS: The symposium brought together leading experts to highlight the growing aerodigestive field, promote new scientific and therapeutic strategies, share the structure and benefits of a multidisciplinary approach in diagnosing common and rare aerodigestive disorders, and foster multidisciplinary discussion of complex cases while highlighting the range of therapeutic and diagnostic options. In this article, we showcase the diagnostic and therapeutic approach to oropharyngeal dysphagia (OPD), one of the most common aerodigestive conditions, emphasizing the role of a collaborative model. CONCLUSIONS: The aerodigestive field has made significant progress and continues to grow due to a unique multidisciplinary, collaborative model of care for these conditions. Despite diagnostic and therapeutic challenges, the multidisciplinary approach has enabled and greatly improved efficient, high-quality, and evidence-based care for patients, including those with OPD.

Pediatric 129 Xe Gas-Transfer MRI-Feasibility and Applicability.

BACKGROUND: 129 Xe gas-transfer MRI provides regional measures of pulmonary gas exchange in adults and separates xenon in interstitial lung tissue/plasma (barrier) from xenon in red blood cells (RBCs). The technique has yet to be demonstrated in pediatric populations or conditions. PURPOSE/HYPOTHESIS: To perform an exploratory analysis of 129 Xe gas-transfer MRI in children. STUDY TYPE: Prospective. POPULATION: Seventy-seven human volunteers (38 males, age = 17.7 ± 15.1 years, range 5-68 years, 16 healthy). Four pediatric disease cohorts. FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional-radial one-point Dixon Fast Field Echo (FFE) Ultrashort Echo Time (UTE). ASSESSMENT: Breath hold compliance was assessed by quantitative signal-to-noise and dynamic metrics. Whole-lung means and standard deviations were extracted from gas-transfer maps. Gas-transfer metrics were investigated with respect to age and lung disease. Clinical pulmonary function tests were retrospectively acquired for reference lung disease severity. STATISTICAL TESTS: Wilcoxon rank-sum tests to compare age and disease cohorts, Wilcoxon signed-rank tests to compare pre- and post-breath hold vitals, Pearson correlations between age and gas-transfer metrics, and limits of normal with a binomial exact test to compare fraction of subjects with abnormal gas-transfer. P ≤ 0.05 was considered significant. RESULTS: Eighty percentage of pediatric subjects successfully completed 129 Xe gas-transfer MRI. Gas-transfer parameters differed between healthy children and adults, including ventilation (0.75 and 0.67) and RBC:barrier ratio (0.31 and 0.46) which also correlated with age (ρ = -0.76, 0.57, respectively). Bone marrow transplant subjects had impaired ventilation (90% of reference) and increased dissolved 129 Xe standard deviation (242%). Bronchopulmonary dysplasia subjects had decreased barrier-uptake (69%). Cystic fibrosis subjects had impaired ventilation (91%) and increased RBC-transfer (146%). Lastly, childhood interstitial lung disease subjects had increased ventilation heterogeneity (113%). Limits of normal provided detection of abnormalities in additional gas-transfer parameters. DATA CONCLUSION: Pediatric 129 Xe gas-transfer MRI was adequately successful and gas-transfer metrics correlated with age. Exploratory analysis revealed abnormalities in a variety of pediatric obstructive and restrictive lung diseases. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Bronchopulmonary dysplasia from chest radiographs to magnetic resonance imaging and computed tomography: adding value.

Bronchopulmonary dysplasia (BPD) is a common long-term complication of preterm birth. The chest radiograph appearance and survivability have evolved since the first description of BPD in 1967 because of improved ventilation and clinical strategies and the introduction of surfactant in the early 1990s. Contemporary imaging care is evolving with the recognition that comorbidities of tracheobronchomalacia and pulmonary hypertension have a great influence on outcomes and can be noninvasively evaluated with CT and MRI techniques, which provide a detailed evaluation of the lungs, trachea and to a lesser degree the heart. However, echocardiography remains the primary modality to evaluate and screen for pulmonary hypertension. This review is intended to highlight the important findings that chest radiograph, CT and MRI can contribute to precision diagnosis, phenotyping and prognosis resulting in optimal management and therapeutics.

Magentic Resonance Imaging Evaluation of Regional Lung Vts in Severe Neonatal Bronchopulmonary Dysplasia.

Rationale: Bronchopulmonary dysplasia is a heterogeneous lung disease characterized by regions of cysts and fibrosis, but methods for evaluating lung function are limited to whole lung rather than specific regions of interest.Objectives: Respiratory-gated, ultrashort echo time magnetic resonance imaging was used to test the hypothesis that cystic regions of the lung will exhibit a quantifiable Vt that will correlate with ventilator settings and clinical outcomes.Methods: Magnetic resonance images of 17 nonsedated, quiet-breathing infants with severe bronchopulmonary dysplasia were reconstructed into end-inspiration and end-expiration images. Cysts were identified and measured by using density threshold combined with manual identification and segmentation. Regional Vts were calculated by subtracting end-expiration from end-inspiration volumes in total lung, noncystic lung, total-cystic lung, and individual large cysts.Measurements and Main Results: Cystic lung areas averaged larger Vts than noncystic lung when normalized by volume (0.8 ml Vt/ml lung vs. 0.1 ml Vt/ml lung, P < 0.002). Cyst Vt correlates with cyst size (P = 0.012 for total lung cyst and P < 0.002 for large cysts), although there was variability between individual cyst Vt, with 22% of cysts demonstrating negative Vt. Peak inspiratory pressure positively correlated with total lung Vt (P = 0.027) and noncystic Vt (P = 0.015) but not total lung cyst Vt (P = 0.8). Inspiratory time and respiratory rate did not improve Vt of any analyzed lung region.Conclusions: Cystic lung has greater normalized Vt when compared with noncystic lung. Ventilator pressure increases noncystic lung Vt, but inspiratory time does not correlate with Vt of normal or cystic lung.

Quantitative Assessment of Regional Dynamic Airway Collapse in Neonates via Retrospectively Respiratory-Gated 1 H Ultrashort Echo Time MRI.

BACKGROUND: Neonatal dynamic tracheal collapse (tracheomalacia, TM) is a common and serious comorbidity in infants, particularly those with chronic lung disease of prematurity (bronchopulmonary dysplasia, BPD) or congenital airway or lung-related conditions such as congenital diaphragmatic hernia (CDH), but the underlying pathology, impact on clinical outcomes, and response to therapy are not well understood. There is a pressing clinical need for an accurate, objective, and safe assessment of neonatal TM. PURPOSE: To use retrospectively respiratory-gated ultrashort echo-time (UTE) MRI to noninvasively analyze moving tracheal anatomy for regional, quantitative evaluation of dynamic airway collapse in quiet-breathing, nonsedated neonates. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Twenty-seven neonatal subjects with varying respiratory morbidities (control, BPD, CDH, abnormal polysomnogram). FIELD STRENGTH/SEQUENCE: High-resolution 3D radial UTE MRI (0.7 mm isotropic) on 1.5T scanner sited in the neonatal intensive care unit. ASSESSMENT: Images were retrospectively respiratory-gated using the motion-modulated time-course of the k-space center. Tracheal surfaces were generated from segmentations of end-expiration/inspiration images and analyzed geometrically along the tracheal length to calculate percent-change in luminal cross-sectional area (A % ) and ratio of minor-to-major diameters at end-expiration (r D,exp ). Geometric results were compared to clinically available bronchoscopic findings (n = 14). STATISTICAL TESTS: Two-sample t-test. RESULTS: Maximum A % significantly identified subjects with/without a bronchoscopic TM diagnosis (with: 46.9 ± 10.0%; without: 27.0 ± 5.8%; P < 0.001), as did minimum r D,exp (with: 0.346 ± 0.146; without: 0.671 ± 0.218; P = 0.008). Subjects with severe BPD exhibited a far larger range of minimum r D,exp than subjects with mild/moderate BPD or controls (0.631 ± 0.222, 0.782 ± 0.075, and 0.776 ± 0.030, respectively), while minimum r D,exp was reduced in CDH subjects (0.331 ± 0.171) compared with controls (P < 0.001). DATA CONCLUSION: Respiratory-gated UTE MRI can quantitatively and safely evaluate neonatal dynamic tracheal collapse, as validated with the clinical standard of bronchoscopy, without requiring invasive procedures, anesthesia, or ionizing radiation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:659-667.

Leveraging electronic health records to assess the role of ADRB2 single nucleotide polymorphisms in predicting exacerbation frequency in asthma patients.

Asthma is the leading chronic disease in children. Several studies have identified genetic biomarkers associated with susceptibility and severity in both adult and pediatric cases. In this study, we evaluated outcomes in 400 African American and European American pediatric cases all of whom were regular users of inhaled corticosteroids. Patients were stratified by genotype using two single nucleotide polymorphisms in the ß-2-adrenergic receptor (ADRB2) gene - rs1042713 and rs1042714, previously associated with asthma outcome. These correspond to nonsynonymous single nucleotide polymorphisms at positions 16 [arginine to glycine (Arg16Gly); rs1042713] and 27 [glutamic acid to glutamine (Glu27Gln); rs1042714], which are relatively common (minor allele frequencies ∼40-50%), and have been well characterized in asthma pharmacogenetics. We controlled for adherence to the National Heart, Lung and Blood Institute guidelines using deep mining of electronic health record data to determine treatment course. We found no significant effect for rs1042713 (Arg16Gly) but did identify an effect for rs1042714, where participants homozygous for Gln27 had increased exacerbations while taking inhaled corticosteroids in comparison with those who were either heterozygous or homozygous for Glu27. This is consistent with previous studies and demonstrates for the first time that the Glu27 variant in the ADRB2 gene is associated with increased frequencies of asthma exacerbations. Moreover, this study also lends an important proof-of-principle on how electronic health records linked to genotype can be efficiently and systematically mined to delineate health outcomes.

The Impact of Pulmonary Hypertension in Preterm Infants with Severe Bronchopulmonary Dysplasia through 1 Year.

OBJECTIVES: To assess the effect of pulmonary hypertension on neonatal intensive care unit mortality and hospital readmission through 1 year of corrected age in a large multicenter cohort of infants with severe bronchopulmonary dysplasia. STUDY DESIGN: This was a multicenter, retrospective cohort study of 1677 infants born <32 weeks of gestation with severe bronchopulmonary dysplasia enrolled in the Children's Hospital Neonatal Consortium with records linked to the Pediatric Health Information System. RESULTS: Pulmonary hypertension occurred in 370 out of 1677 (22%) infants. During the neonatal admission, pulmonary hypertension was associated with mortality (OR 3.15, 95% CI 2.10-4.73, P < .001), ventilator support at 36 weeks of postmenstrual age (60% vs 40%, P < .001), duration of ventilation (72 IQR 30-124 vs 41 IQR 17-74 days, P < .001), and higher respiratory severity score (3.6 IQR 0.4-7.0 vs 0.8 IQR 0.3-3.3, P < .001). At discharge, pulmonary hypertension was associated with tracheostomy (27% vs 9%, P < .001), supplemental oxygen use (84% vs 61%, P < .001), and tube feeds (80% vs 46%, P < .001). Through 1 year of corrected age, pulmonary hypertension was associated with increased frequency of readmission (incidence rate ratio [IRR] = 1.38, 95% CI 1.18-1.63, P < .001). CONCLUSIONS: Infants with severe bronchopulmonary dysplasia-associated pulmonary hypertension have increased morbidity and mortality through 1 year of corrected age. This highlights the need for improved diagnostic practices and prospective studies evaluating treatments for this high-risk population.

Identification of Four Novel Loci in Asthma in European American and African American Populations.

RATIONALE: Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered. OBJECTIVES: To identify additional genetic susceptibility factors of asthma in European American and African American populations. METHODS: A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status. MEASUREMENTS AND MAIN RESULTS: The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient prostaglandin E2 synthesis has been associated with airway remodeling. CONCLUSIONS: This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.

Paediatric Tracheomalacia.

Intrathoracic tracheomalacia is characterized by increased compliance of the central airway within the thorax. This leads to excessive dynamic collapse during exhalation or periods of increased intrathoracic pressure such as crying. Extrathoracic tracheomalacia involves dynamic collapse of the airway between the glottis and sternal notch that occurs during inhalation rather than exhalation. The tone of the posterior membrane of the trachea increases throughout development and childhood, as does the rigidity of the tracheal cartilage. Abnormalities of airway maturation result in congenital tracheomalacia. Acquired tracheomalacia occurs in the normally developed trachea due to trauma, external compression, or airway inflammation. Although tracheomalacia can be suspected by history, physical examination, and supportive radiographic findings, flexible fiberoptic bronchoscopy remains the "gold standard" for diagnosis. Current treatment strategies involve pharmacotherapy with cholinergic agents, positive pressure ventilation, and surgical repair.

Diagnostic yield of endobronchial ultrasound and virtual CT navigational bronchoscopy for biopsy of pulmonary nodules, mediastinal lymph nodes, and thoracic tumors in children.

OBJECTIVE: Endobronchial ultrasound-guided transbronchial biopsy and needle aspiration (EBUS-TBB/EBUS-TBNA) are first line investigative modalities for lung and mediastinal pathology in adults. We aimed to characterize and assess the diagnostic yield of EBUS and virtual CT navigation guided biopsies in children. STUDY DESIGN: This single center, retrospective cohort study included patients who underwent radial or linear EBUS procedures (+/- CT navigation) for biopsy of mediastinal lymph nodes, tumors, and pulmonary nodules. Demographic, procedural, and outcome were collected. RESULTS: Sixty procedures were performed in 56 patients aged 2-22 years of age between January 2015 and May 2023. The most common indications for biopsy were pulmonary nodules (45%) and hilar/mediastinal lymphadenopathy (33%). For cases in which a final diagnosis was ascertained by any means, the diagnostic yield for linear EBUS (mediastinal pathology) was 76% and the diagnostic yield from radial EBUS (pulmonary nodules and lung masses) was 85%. The most common diagnoses were infection (45%), malignancy (17%), and sarcoidosis (11%). Among patients in whom infection was the final diagnosis, a total of 31 pathogens were identified. Eighteen were identified on bronchoalveolar lavage and an additional 14 pathogens identified on EBUS-TBB, representing an increase of 77% (p < .005). The sensitivity, specificity, negative and positive predictive values for malignancy detection were 73%, 100%, 94%, and 100%, respectively. CONCLUSION: EBUS-TBB/TBNA is a safe and effective way to diagnose lung and mediastinal pathology in children. Pediatric interventional pulmonology is a growing field offering minimally-invasive diagnostic opportunities for children in whom more invasive procedures were previously the only option.

Pulmonary and Clinical Outcomes After Bilateral Submandibular Gland Excision and Parotid Duct Ligation for Refractory Sialorrhea.

Importance: Refractory sialorrhea in children can result in pulmonary aspiration and irreversible lung damage. Despite many studies devoted to the surgical treatment of sialorrhea, there is a paucity of objective outcome measures after surgery, especially with regard to pulmonary health. Objectives: To assess whether bilateral submandibular gland excision and bilateral parotid duct ligation ("DROOL" procedure) is associated with reduced pulmonary inflammation in bronchoalveolar lavage (BAL) samples after surgery and to assess patient factors associated with improvement after surgery. Design, Setting, and Participants: This retrospective case series included all 112 patients undergoing the DROOL procedure at a single tertiary care pediatric children's hospital from January 1, 2012, to December 31, 2021. Statistical analysis was performed from March 30 to June 10, 2023, and August 20 to September 23, 2023. Exposure: DROOL procedure for refractory sialorrhea. Main Outcomes and Measures: Degree of pulmonary inflammation (neutrophil percentage) according to BAL cytologic findings and overall bronchoscopy findings up to 12 months before and after the DROOL procedure. Secondary outcomes included number of annual hospitalizations, caregiver report of function before and after the procedure, and need for revision procedures and/or additional operations for secretion management. Results: A total of 112 patients (median age, 3.4 years [IQR, 2.0-7.1 years]; 65 boys [58.0%]) underwent DROOL procedures and had both preoperative and postoperative BAL samples during the study period. Patients demonstrated objective improvement in pulmonary inflammation after surgery, with the median polymorphonuclear neutrophil percentage decreasing from 65.0% (IQR, 14.0%-86.0%) before the surgery to 32.5% (IQR, 3.0%-76.5%) after the surgery (median difference in percentage points, -9.0 [95% CI, -20.0 to 0.0]). Prior to the DROOL procedure, 34 patients (30.4%; 95% CI, 21.8%-38.9%) were hospitalized 2 or more times annually for respiratory illness, which decreased to 10.1% (11 of 109; 95% CI, 4.4%-15.7%) after surgery (3 patients did not have hospitalization data available following surgery). Most caretakers (73 [65.2%]) reported improved secretion management after the procedure. Conclusions and Relevance: This study suggests that patients with impaired secretion management who underwent a DROOL procedure demonstrated improvement in pulmonary inflammation and a reduction in hospitalizations after surgery. Caretakers were also likely to report subjective improvement in secretion management and quality of life. Additional research is necessary to guide optimal timing and patient selection for this procedure.