Nintedanib in children and adolescents with fibrosing interstitial lung diseases.

BACKGROUND: Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. METHODS: Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. RESULTS: 26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUCτ,ss for nintedanib was 175 µg·h·L-1 (85.1%) in patients aged 6-11 years and 160 µg·h·L-1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group. CONCLUSIONS: In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

Feeding and Swallowing Characteristics of Children With Esophageal Atresia and Tracheoesophageal Fistula.

OBJECTIVES: This study aimed to characterize feeding/swallowing difficulties in children with esophageal atresia and/or tracheoesophageal fistula (EA/TEF) and evaluate associations among feeding difficulties, pharyngeal dysphagia (PD), and other aerodigestive evaluation findings. METHODS: This was a retrospective cohort study of feeding/swallowing characteristics of 44 patients with EA/TEF treated in the aerodigestive program of a single academic medical institution from 2010 to 2015. Demographics, comorbidities, presence and characteristics of feeding/swallowing difficulties, and results of relevant diagnostic tests [videofluoroscopic swallow studies (VFSS), clinical feeding evaluations (CFEs), chest computerized tomography (CT) scans, pulmonary bronchoscopies, and upper GI (UGI)/esophagrams] were reviewed. RESULTS: Fifty percent of the cohort had PD and 88.6% had feeding difficulties. Across 118 encounters (87 VFSS and 31 CFEs), feeding difficulties suggestive of esophageal dysphagia were most frequently seen in children over 48 months and feeding difficulties suggestive of developmental feeding problems were most frequently seen in children from 24 to 48 months. Abnormal findings were present in 59.8% of VFSS, with aspiration (34.5%) and pharyngeal residue (26.4%) the most frequently observed signs of dysphagia. Abnormal UGI/esophagram findings were not associated with significantly increased risk of feeding difficulties during visits within 3 months (risk ratio, RR = 1.33). Presence of dysphagia was associated with increased risk for some abnormal CT findings (RR= 3.0 for airspace and 3.0 for bronchiectasis). CONCLUSIONS: Feeding/swallowing difficulties are common in EA/TEF, and types of feeding difficulties vary by patient age. The presence of abnormal findings on UGI/esophagram did not increase the risk of feeding complaints; however, the presence of dysphagia increased the risk of abnormal chest CT.

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.

Airwave oscillometry to measure lung function in children with Down syndrome.

BACKGROUND: Children with Down syndrome are at risk for significant pulmonary co-morbidities, including recurrent respiratory infections, dysphagia, obstructive sleep apnea, and pulmonary vascular disease. Because the gold standard metric of lung function, spirometry, may not be feasible in children with intellectual disabilities, we sought to assess the feasibility of both airwave oscillometry and spirometry in children with Down syndrome. METHODS: Thirty-four children with Down syndrome aged 5-17 years were recruited. Participants performed airwave oscillometry and spirometry before and 10 min after albuterol. Outcomes include success rates, airway resistance and reactance pre- and post-bronchodilator, and bronchodilator response. RESULTS: Participants were median age 9.2 years (interquartile range 7.2, 12.0) and 47% male. Airwave oscillometry was successful in 26 participants (76.5%) and 4 (11.8%) were successful with spirometry. No abnormalities in airway resistance were detected, and 16/26 (61.5%) had decreased reactance. A positive bronchodilator response by oscillometry was observed in 5/23 (21.7%) of those with successful pre- and post-bronchodilator testing. CONCLUSIONS: Measures of pulmonary function were successfully obtained using airwave oscillometry in children with Down syndrome, which supports its use in this high-risk population. IMPACT: Children with Down syndrome are at risk for significant pulmonary co-morbidities, but the gold standard metric of lung function, spirometry, may not be feasible in children with intellectual disabilities. This may limit the population's enrollment in clinical trials and in standardized clinical care. In this prospective study of lung function in children with Down syndrome, airwave oscillometry was successful in 76% of participants but spirometry was successful in only 12%. This study reinforces that measures of pulmonary function can be obtained successfully using airwave oscillometry in children with Down syndrome, which supports its use in this high-risk population.

Pulmonary Aptamer Signatures in Children's Interstitial and Diffuse Lung Disease.

Rationale: Biomarker signatures are needed in children with children's interstitial and diffuse lung disease (chILD) to improve diagnostic approaches, increase our understanding of disease pathogenesis, monitor disease progression, and develop new treatment strategies. Proteomic technology using SOMAmer (Slow Off-rate Modified Aptamer) nucleic acid-based protein-binding reagents allows for biomarker discovery.Objectives: We hypothesized that proteins and protein pathways in BAL fluid (BALF) would distinguish children with neuroendocrine cell hyperplasia of infancy (NEHI), surfactant dysfunction mutations, and other chILD diagnoses and control subjects.Methods: BALF was collected for clinical indications and banked in patients with chILD and disease control subjects using standardized protocols over 10 years. BALF supernatant was analyzed using an aptamer assay to measure 1,129 protein levels. Protein levels were compared between groups using an ANOVA and adjusted for multiple comparisons using false discovery rate. Proteins were classified into pathways. Hierarchical clustering was used to define endotypes in the group of children with NEHI.Measurements and Main Results: After correcting for multiple testing, children with NEHI (n = 22) had 202 aptamers that were significantly different (P < 0.05) in BALF compared with control subjects (n = 9). Children with surfactant mutation (n = 8) had 51 aptamers significantly different (P < 0.05) in BALF compared with control subjects (n = 9). Proteins associated with pulmonary fibrosis and inflammation were associated with the surfactant dysfunction group but not the NEHI group. Using hierarchical clustering analysis, two distinct NEHI endotypes were identified.Conclusions: Distinct proteins and protein pathways can be determined from BALF of children with chILD, and these hold promise to further our understanding of chILD.

Approaching Clinical Trials in Childhood Interstitial Lung Disease and Pediatric Pulmonary Fibrosis.

Childhood interstitial lung disease (chILD) comprises a spectrum of rare diffuse lung disorders. chILD is heterogeneous in origin, with different disease manifestations occurring in the context of ongoing lung development. The large number of disorders in chILD, in combination with the rarity of each diagnosis, has hampered scientific and clinical progress within the field. Epidemiologic and natural history data are limited. The prognosis varies depending on the etiology, with some forms progressing to lung transplant or death. There are limited treatment options for patients with chILD. Although U.S. Food and Drug Administration-approved treatments are now available for adult patients with idiopathic pulmonary fibrosis, no clinical trials have been conducted in a pediatric population using agents designed to treat lung fibrosis. This review will focus on progressive chILD disorders and on the urgent need for meaningful objective outcome measures to define, detect, and monitor fibrosis in children.

Transnasal Endoscopy in Unsedated Children With Eosinophilic Esophagitis Using Virtual Reality Video Goggles.

BACKGROUND & AIMS: Evaluation and treatment of children with eosinophilic esophagitis (EoE) requires serial endoscopic, visual, and histologic assessment by sedated esophagogastroduodenoscopy (EGD). Unsedated transnasal endoscopy (TNE) was reported to be successful in a pilot study of children. We evaluated video goggle and virtual reality-based unsedated TNE in children with EoE, collecting data on rates of completion, adverse events, and adequacy of visual and histologic findings. METHODS: We performed a retrospective study of 190 children and young adults (age, 3-22 y) who underwent video goggle or virtual reality-based unsedated TNE from January 2015 through February 2018. We analyzed data on patient demographics, procedure completion, endoscope type, adverse events, visual and histologic findings, estimated costs, and duration in the facility. Esophageal biopsies from the first 173 subjects who underwent TNE were compared with those from previous EGD evaluations. RESULTS: During 300 attempts, 294 TNEs were performed (98% rate of success). Fifty-four patients (age, 6-18 y) underwent multiple TNEs for dietary or medical management of EoE. There were no significant adverse events. Visual and histologic findings were adequate for assessment of EoE. TNE reduced costs by 53.4% compared with EGD (TNE $4393.00 vs EGD $9444.33). TNE was used increasingly from 2015 through 2017, comprising 31.8% of endoscopies performed for EoE. The total time spent in the clinic (front desk check-in to check-out) in 2018 was 71 minutes. CONCLUSIONS: In a retrospective study of 190 children and young adults (age, 3-22 y) who underwent video goggle or virtual reality-based unsedated TNE, TNE was safe and effective and reduced costs of EoE monitoring. Advantages of TNE include reduced risk and cost associated with anesthesia as well as decreased in-office time, which is of particular relevance for patients with EoE, who require serial EGDs.

Unsedated In-office Transgastrostomy Esophagoscopy to Monitor Therapy in Pediatric Esophageal Disease.

Monitoring therapy in esophageal inflammatory disorders such as eosinophilic esophagitis and reflux esophagitis often requires frequent endoscopic evaluation. We recently reported the effective use of unsedated in-office transnasal esophagoscopy that significantly decreased costs and anesthetic exposure associated with pediatric esophagoscopy in eosinophilic esophagitis. Here we report a series of pediatric patients with esophagitis with gastrostomy tubes who underwent unsedated transgastrostomy esophagoscopy (TGE) in an office setting. Nine patients (ages 16 months-21 years) tolerated TGE without significant adverse events. Biopsy specimens were adequate for evaluation. This series confirms that unsedated in-office TGE can be used to successfully obtain mucosal biopsies to monitor esophageal inflammatory conditions in children without the use of sedation.

Pediatric tracheomalacia and the perioperative anesthetic management of thoracoscopic posterior tracheopexy.

Tracheomalacia is a broad term used to describe an abnormally compliant trachea that can lead to exaggerated collapse and obstruction with expiration. We describe the perioperative management of a complex pediatric patient undergoing a posterior tracheopexy which is a relatively new surgical treatment, with a novel surgical approach-thoracoscopy. This procedure has competing surgical and anesthetic needs and presents unique challenges to the physicians involved in caring for these patients. We also review the current literature on pediatric tracheomalacia and examine the newest treatment options to highlight the potential anesthetic challenges and pitfalls associated with management.

Lung and airway shape in neuroendocrine cell hyperplasia of infancy.

BACKGROUND: Neuroendocrine cell hyperplasia of infancy (NEHI) is a rare lung disease associated with significant air trapping. Although chest CT is crucial in establishing a diagnosis, CT and biopsy findings do not reveal airway abnormalities to explain the air trapping. OBJECTIVE: We compared lung and airway morphology obtained from chest CT scans in children with NEHI and control children. In the children with NEHI, we explored relationships between lung and airway shape and lung function. MATERIALS AND METHODS: We performed a retrospective review of children with NEHI who underwent clinical chest CT. We identified control children of similar size and age. We created lung masks and airway skeletons using semi-automated software and compared them using statistical shape modeling methods. Then we calculated a logistic regression model using lung and airway shape to differentiate NEHI from controls, and we compared shape model parameters to lung function measurements. RESULTS: Airway and lung shapes were statistically different between children with NEHI and controls. We noted a broad lung apex in the children with NEHI and a significantly increased apical anterior-posterior lung diameter. A logistic regression model including lung shape was 90% accurate in differentiating children with NEHI from controls. Correlation coefficients were significant between lung function values and lung and airway shape. CONCLUSION: Lung and airway shapes were different between children with NEHI and control children in this cohort. Children with NEHI had an increased anteroposterior diameter of their lungs that might be useful in the diagnostic criteria.

Clinical potential for imaging in patients with asthma and other lung disorders.

The ability of lung imaging to phenotype patients, determine prognosis, and predict response to treatment is expanding in clinical and translational research. The purpose of this perspective is to describe current imaging modalities that might be useful clinical tools in patients with asthma and other lung disorders and to explore some of the new developments in imaging modalities of the lung. These imaging modalities include chest radiography, computed tomography, lung magnetic resonance imaging, electrical impedance tomography, bronchoscopy, and others.

Unsedated transnasal esophagoscopy for monitoring therapy in pediatric eosinophilic esophagitis.

BACKGROUND AND AIMS: Unsedated transnasal endoscopy (TNE) is safer and less costly than sedated EGD. The aim of this study was to evaluate the performance of TNE with biopsies in monitoring the esophageal mucosa of pediatric patients with eosinophilic esophagitis. METHODS: Patients between 8 and 17 years of age with eosinophilic esophagitis and their parents were enrolled. Unsedated TNE was performed. A 2.8-mm (1.2-mm channel) or a 4-mm flexible bronchoscope (2-mm channel) was used, and esophageal biopsy specimens were obtained. Biopsy specimen analysis, duration, adverse events, and billing charges of TNE were assessed. Immediately after TNE and a minimum of 2 weeks later, a modified Group Health Association of America 9 survey and a preference questionnaire were completed, respectively. RESULTS: Twenty-one of 22 enrolled patients underwent TNE. TNE was performed with no serious adverse events. Histopathological analysis revealed 0 eosinophils per high-power field (n = 12), fewer than 15 eosinophils per high-power field (n = 4), and more than 15 eosinophils per high-power field (n = 5). The total epithelial surface area of mucosal biopsy samples from either TNE Forceps (1.2 mm or 2 mm biopsy channel forceps) compared with those obtained during the subject's previous EGD by using standard endoscopic forceps was not statistically different (P = .308 [1.2 mm]/P = .492 [2 mm]). All parents and 76.2% of subjects would undergo the TNE again. TNE was preferred over EGD by 85.7% of parents and 52.4% of subjects. The modified Group Health Association of America 9 survey revealed a high degree of satisfaction (average, 43.19 ± 2.6; maximum score, 45). Charges associated with TNE were 60.1% lower than for previous EGDs. CONCLUSIONS: Unsedated TNE is an effective, lower-cost procedure for monitoring the esophageal mucosa of children with eosinophilic esophagitis.

Cardiopulmonary Phenotypes and Protein Signatures in Children With Down Syndrome.

Pulmonary disease, lower respiratory tract infection, and pneumonia are the largest causes of morbidity and mortality in individuals with Down syndrome (DS), but whether pulmonary diagnoses in children with DS are common and occur independently of cardiac disease and pulmonary hypertension (PH) is unknown. Cardiopulmonary phenotypes were examined in a cohort of 1248 children with DS. Aptamer-based proteomic analysis of blood was performed in a subset (n = 120) of these children. By the age of 10 years, half of the patients in this cohort (n = 634, 50.8%) had co-occurring pulmonary diagnoses. That proteins and related pathways were distinct between children with pulmonary diagnoses and those with cardiac disease and/or PH may indicate that pulmonary diagnoses appear to occur independently of cardiac disease and PH. Heparin sulfate-glycosaminoglycandegradation, nicotinate metabolism, and elastic fiber formation were ranked highest in the group with pulmonary diagnoses.

Imaging of pulmonary fibrosis in children: A review, with proposed diagnostic criteria.

Computed tomography (CT) imaging findings of pulmonary fibrosis are well established for adults and have been shown to correlate with prognosis and outcome. Recognition of fibrotic CT findings in children is more limited. With approved treatments for adult pulmonary fibrosis, it has become critical to define CT criteria for fibrosis in children, to identify patients in need of treatment and those eligible for clinical trials. Understanding how pediatric fibrosis compares with idiopathic pulmonary fibrosis and other causes of fibrosis in adults is increasingly important as these patients transition to adult care teams. Here, we review what is known regarding the features of pulmonary fibrosis in children compared with adults. Pulmonary fibrosis in children may be associated with genetic surfactant dysfunction disorders, autoimmune systemic disorders, and complications after radiation, chemotherapy, transplantation, and other exposures. Rather than a basal-predominant usual interstitial pneumonia pattern with honeycombing, pediatric fibrosis is primarily characterized by reticulation, traction bronchiectasis, architectural distortion, or cystic lucencies/abnormalities. Ground-glass opacities are more frequent in children with fibrotic interstitial lung disease than adults, and disease distribution appears more diffuse, without clearly defined axial or craniocaudal predominance. Following discussion and consensus amongst a panel of expert radiologists, pathologists and physicians, distinctive disease features were integrated to develop criteria for the first global Phase III trial in children with pulmonary fibrosis.

Initiatives to improve lung and sleep health in children: Delphi consensus from the pediatrics, pulmonary, and sleep conference.

BACKGROUND AND OBJECTIVES: The lung and sleep health of adults is heavily influenced by early factors, both genetic and environmental; therefore, optimizing respiratory health begins in childhood. Multiple barriers impede improvements in lung and sleep health for children. First, the traditional siloing between general pediatric care in the community, pediatric pulmonary and sleep subspecialty care, and the research community limits the translation of knowledge into practice. Additionally, identifying and addressing health disparities remains a challenge. The 2021 NHLBI-sponsored workshop "Defining and Promoting Pediatric Pulmonary Health (DAP3H)" was a first step in defining critical gaps in our current healthcare system in identifying and optimizing lung and sleep health in children. The workshop identified key opportunities including measuring pulmonary function in young children, sleep-focused outcomes, developing biomarkers, and longitudinal research cohorts. To expand on the work of DAP3H and continue initiatives to improve childhood lung and sleep health, the Pediatrics & Pulmonary Network: Improving Health Together conference was held in 2023. STUDY DESIGN: A modified Delphi process was applied to form consensus surrounding gaps, barriers, and action items, with the goal of identifying the most urgent opportnities for improving childhood lung and sleep health. RESULTS: Cross-cutting foundational principles were identified as: (1) Authentic Stakeholder Collaboration & Engagement, (2) Reach & Implementation in Real World Settings, (3) Understanding Current Landscape & Resources and (4) Purposeful Diversity, Equity, & Inclusion Initiatives. CONCLUSIONS: To improve lung and sleep health in children, these principles should be the foundation for research design, development, and implementation.

Estimating the effect of nintedanib on forced vital capacity in children and adolescents with fibrosing interstitial lung disease using a Bayesian dynamic borrowing approach.

BACKGROUND: The rarity of childhood interstitial lung disease (chILD) makes it challenging to conduct powered trials. In the InPedILD trial, among 39 children and adolescents with fibrosing ILD, there was a numerical benefit of nintedanib versus placebo on change in forced vital capacity (FVC) over 24 weeks (difference in mean change in FVC % predicted of 1.21 [95% confidence interval: -3.40, 5.81]). Nintedanib has shown a consistent effect on FVC across populations of adults with different diagnoses of fibrosing ILD. METHODS: In a Bayesian dynamic borrowing analysis, prespecified before data unblinding, we incorporated data on the effect of nintedanib in adults and the data from the InPedILD trial to estimate the effect of nintedanib on FVC in children and adolescents with fibrosing ILD. The data from adults were represented as a meta-analytic predictive (MAP) prior distribution with mean 1.69 (95% credible interval: 0.49, 3.08). The adult data were weighted according to expert judgment on their relevance to the efficacy of nintedanib in chILD, obtained in a formal elicitation exercise. RESULTS: Combined data from the MAP prior and InPedILD trial analyzed within the Bayesian framework resulted in a median difference between nintedanib and placebo in change in FVC % predicted at Week 24 of 1.63 (95% credible interval: -0.69, 3.40). The posterior probability for superiority of nintedanib versus placebo was 95.5%, reaching the predefined success criterion of at least 90%. CONCLUSION: These findings, together with the safety data from the InPedILD trial, support the use of nintedanib in children and adolescents with fibrosing ILDs.

Advancements in imaging in ChILD.

Interstitial and diffuse lung diseases in children constitute a range of congenital and acquired disorders. These disorders present with signs and symptoms of respiratory disease accompanied by diffuse radiographic changes. In many cases, radiographic findings are nonspecific, while in other disorders, chest computed tomography (CT) is diagnostic in the appropriate context. Regardless, chest imaging remains central in the evaluation of the patient with suspected childhood interstitial lung disease (chILD). Several newly described chILD entities, spanning both genetic and acquired etiologies, have imaging that aid in their diagnoses. Advances in CT scanning technology and CT analysis techniques continue to improve scan quality as well as expand use of chest CT as a research tool. Finally, ongoing research is expanding use of imaging modalities without ionizing radiation. Magnetic resonance imaging is being applied to investigate pulmonary structure and function, and ultrasound of the lung and pleura is a novel technique with an emerging role in chILD disorders. This review describes the current state of imaging in chILD including recently described diagnoses, advances in conventional imaging techniques and applications, and evolving new imaging modalities that expand the clinical and research roles for imaging in these disorders.

Social support moderates the relationship between burnout and job satisfaction in aerodigestive team members.

OBJECTIVES: Burnout among healthcare workers is a public health crisis. Burnout is associated with elevated cynicism, emotional exhaustion, and low job satisfaction. Methods to combat burnout have been challenging to identify. Based on positive experiences of pediatric aerodigestive team members, we hypothesized that social support in multidisciplinary aerodigestive teams moderates the effects of burnout on job satisfaction. METHODS: Using a survey of the Aerodigestive Society, members of Aerodigestive teams (N = 119) completed demographics, the Maslach Burnout Inventory, and measures of job satisfaction, emotional, and instrumental social support. In addition to assessing relationships between components of burnout and job satisfaction, six tests were conducted using PROCESS to ascertain the degree to which social support moderated these relationships. RESULTS: Similar to US healthcare base rates, burnout scores in this sample suggest that a third-to-half felt Emotionally Exhausted and Burned Out from work "A few times a month"-to-"Every Day." Simultaneously, however, the majority in sample (60.6%) noted feeling that they "positively impact others' lives" with 33.3% endorsing "Every Day." Job satisfaction was strikingly high at 89%, with most reporting Aerodigestive team affiliation related to higher job satisfaction. Both Emotional and Instrumental social support moderated the effect of Cynicism and Emotional Exhaustion on Job Satisfaction, with higher Job Satisfaction scores in conditions of high support. CONCLUSIONS: These results support the hypothesis that social support from a multidisciplinary aerodigestive team moderates the effect of burnout in its team members. Further work is needed to understand if membership in other interprofessional healthcare teams can help combat the negative effects of burnout.