The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Pulmonary Complications in Patients With Fontan Circulation: JACC Review Topic of the Week.

The Fontan operation has resulted in significant improvement in survival of patients with single ventricle physiology. As a result, there is a growing population of individuals with Fontan physiology reaching adolescence and adulthood. Despite the improved survival, there are long-term morbidities associated with the Fontan operation. Pulmonary complications are common and may contribute to both circulatory and pulmonary insufficiency, leading ultimately to Fontan failure. These complications include restrictive lung disease, sleep abnormalities, plastic bronchitis, and cyanosis. Cyanosis post-Fontan procedure can be attributed to multiple causes including systemic to pulmonary venous collateral channels and pulmonary arteriovenous malformations. This review presents the unique cardiopulmonary interactions in the Fontan circulation. Understanding the cardiopulmonary interactions along with improved recognition and treatment of pulmonary abnormalities may improve the long-term outcomes in this growing patient population. Interventions focused on improving pulmonary function including inspiratory muscle training and endurance training have shown a promising effect post-Fontan procedure.

The lung in inborn errors of immunity: From clinical disease patterns to molecular pathogenesis.

In addition to being a vital organ for gas exchange, the lung is a crucial immune organ continuously exposed to the external environment. Genetic defects that impair immune function, called inborn errors of immunity (IEI), often have lung disease as the initial and/or primary manifestation. Common types of lung disease seen in IEI include infectious complications and a diverse group of diffuse interstitial lung diseases. Although lung damage in IEI has been historically ascribed to recurrent infections, contributions from potentially targetable autoimmune and inflammatory pathways are now increasingly recognized. This article provides a practical guide to identifying the diverse pulmonary disease patterns in IEI based on lung imaging and respiratory manifestations, and integrates this clinical information with molecular mechanisms of disease and diagnostic assessments in IEI. We cover the entire IEI spectrum, including immunodeficiencies and immune dysregulation with monogenic autoimmunity and autoinflammation, as well as recently described IEI with pulmonary manifestations. Although the pulmonary manifestations of IEI are highly relevant for all age groups, special emphasis is placed on the pediatric population, because initial presentations often occur during childhood. We also highlight the pivotal role of genetic testing in the diagnosis of IEI involving the lungs and the critical need to develop multidisciplinary teams for the challenging evaluation of these rare but potentially life-threatening disorders.

Neuroendocrine Cell Hyperplasia of Infancy. Clinical Score and Comorbidities.

Rationale: Neuroendocrine cell hyperplasia of infancy (NEHI) is an important form of children's interstitial and diffuse lung disease for which the diagnostic strategy has evolved. The prevalence of comorbidities in NEHI that may influence treatment has not been previously assessed.Objectives: To evaluate a previously unpublished NEHI clinical score for assistance in diagnosis of NEHI and to assess comorbidities in NEHI.Methods: We performed a retrospective chart review of 199 deidentified patients with NEHI from 11 centers. Data were collected in a centralized Research Electronic Data Capture registry and we performed descriptive statistics.Results: The majority of patients with NEHI were male (66%). The sensitivity of the NEHI Clinical Score was 87% (95% confidence interval [CI], 0.82-0.91) for all patients from included centers and 93% (95% CI, 0.86-0.97) for those with complete scores (e.g., no missing data). Findings were similar when we limited the population to the 75 patients diagnosed by lung biopsy (87%; 95% CI, 0.77-0.93). Of those patients evaluated for comorbidities, 51% had gastroesophageal reflux, 35% had aspiration or were at risk for aspiration, and 17% had evidence of immune system abnormalities.Conclusions: The NEHI Clinical Score is a sensitive tool for clinically evaluating NEHI; however, its specificity has not yet been addressed. Clinicians should consider evaluating patients with NEHI for comorbidities, including gastroesophageal reflux, aspiration, and immune system abnormalities, because these can contribute to the child's clinical picture and may influence clinical course and treatment.

Postinfectious Bronchiolitis Obliterans in Children: Diagnostic Workup and Therapeutic Options: A Workshop Report.

Bronchiolitis obliterans (BO) is a rare, chronic form of obstructive lung disease, often initiated with injury of the bronchiolar epithelium followed by an inflammatory response and progressive fibrosis of small airways resulting in nonuniform luminal obliteration or narrowing. The term BO comprises a group of diseases with different underlying etiologies, courses, and characteristics. Among the better recognized inciting stimuli leading to BO are airway pathogens such as adenovirus and mycoplasma, which, in a small percentage of infected children, will result in progressive fixed airflow obstruction, an entity referred to as postinfectious bronchiolitis obliterans (PIBO). The present knowledge on BO in general is reasonably well developed, in part because of the relatively high incidence in patients who have undergone lung transplantation or bone marrow transplant recipients who have had graft-versus-host disease in the posttransplant period. The cellular and molecular pathways involved in PIBO, while assumed to be similar, have not been adequately elucidated. Since 2016, an international consortium of experts with an interest in PIBO assembles on a regular basis in Geisenheim, Germany, to discuss key areas in PIBO which include diagnostic workup, treatment strategies, and research fields.

Home Oxygen Therapy for Children. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Home oxygen therapy is often required in children with chronic respiratory conditions. This document provides an evidence-based clinical practice guideline on the implementation, monitoring, and discontinuation of home oxygen therapy for the pediatric population. METHODS: A multidisciplinary panel identified pertinent questions regarding home oxygen therapy in children, conducted systematic reviews of the relevant literature, and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach to rate the quality of evidence and strength of clinical recommendations. RESULTS: After considering the panel's confidence in the estimated effects, the balance of desirable (benefits) and undesirable (harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were developed for or against home oxygen therapy specific to pediatric lung and pulmonary vascular diseases. CONCLUSIONS: Although home oxygen therapy is commonly required in the care of children, there is a striking lack of empirical evidence regarding implementation, monitoring, and discontinuation of supplemental oxygen therapy. The panel formulated and provided the rationale for clinical recommendations for home oxygen therapy based on scant empirical evidence, expert opinion, and clinical experience to aid clinicians in the management of these complex pediatric patients and identified important areas for future research.

Perception of Pulmonary Function in Children with Asthma and Cystic Fibrosis.

Background: Under-perception of pulmonary dysfunction may delay appropriate treatment, while over-perception may result in unnecessary treatments. Objectives: To evaluate the ability of patients with asthma or cystic fibrosis and their subspecialty caregivers to assess changes in lung function based on their subjective clinical impressions. Methods: Patients were asked to qualitatively describe how they felt compared to their prior visit (same/better/worse) and to quantitatively estimate their forced expiratory volume in 1 s (FEV1) after being reminded of their FEV1 at the prior visit. Providers made similar estimates based on history and physical examination and knowledge of prior FEV1. After adjusting for relevant clinical covariates, lung function estimates were categorized as accurate (±5% of measured FEV1), overestimated (>5% above measured), and underestimated (>5% below measured). Results: One hundred nine patients estimated FEV1 on 179 occasions. Concordance between patient qualitative assessment and FEV1-based categories was low (κ = 0.08); 44% of patients reported feeling better than the FEV1-based category showed. Quantitatively, 56% of patient estimates were accurate, 18% were underestimated, and 26% overestimated; accuracy improved with age (odds ratio = 1.16, P = 0.01). Concordance between provider qualitative assessments and FEV1-based category was moderate (κ = 0.35); about 19% said their patient looked better than the FEV1-based category showed. Quantitatively, 65% of provider estimates were accurate, 16% were underestimated, and 19% were overestimated; accuracy improved with years of experience. Conclusions: Patients' and providers' perceptions of lung function were low to moderately accurate. Relying on subjective impression may place patients at risk for unnecessary treatments or increased morbidity. These findings highlight the importance of objective lung function assessment.

Airway microbiota across age and disease spectrum in cystic fibrosis.

Our objectives were to characterise the microbiota in cystic fibrosis (CF) bronchoalveolar lavage fluid (BALF), and determine its relationship to inflammation and disease status.BALF from paediatric and adult CF patients and paediatric disease controls undergoing clinically indicated bronchoscopy was analysed for total bacterial load and for microbiota by 16S rDNA sequencing.We examined 191 BALF samples (146 CF and 45 disease controls) from 13 CF centres. In CF patients aged <2 years, nontraditional taxa (e.gStreptococcus, Prevotella and Veillonella) constituted ∼50% of the microbiota, whereas in CF patients aged ≥6 years, traditional CF taxa (e.gPseudomonas, Staphylococcus and Stenotrophomonas) predominated. Sequencing detected a dominant taxon not traditionally associated with CF (e.gStreptococcus or Prevotella) in 20% of CF BALF and identified bacteria in 24% of culture-negative BALF. Microbial diversity and relative abundance of Streptococcus, Prevotella and Veillonella were inversely associated with airway inflammation. Microbiota communities were distinct in CF compared with disease controls, but did not differ based on pulmonary exacerbation status in CF.The CF microbiota detected in BALF differs with age. In CF patients aged <2 years, Streptococcus predominates, whereas classic CF pathogens predominate in most older children and adults.

A novel surfactant protein C gene mutation associated with progressive respiratory failure in infancy.

Mutations of the Surfactant Protein C (SPC) gene (SFTPC) have been associated with childhood interstitial lung disease (chILD) with variable age of onset, severity of lung disease, and outcomes. We report a novel mutation in SFTPC [c.435G->A, p.(Gln145)] that was associated with onset of symptoms in early infancy, progressive respiratory failure with need for prolonged mechanical ventilatory support, and eventual lung transplant at 1 year of age. While the mutation was not predicted to alter the amino acid sequence of the SP-C precursor protein, analysis of SP-C transcripts demonstrated skipping of exon 4. Because of limited data about the outcomes of infants with SFTPC mutations, we conducted a systematic review of all the SFTPC mutations reported in the literature in order to define their presenting features, clinical and radiologic features, and outcomes. Further advances in our understanding of chILD and creation of an international registry will help to track these patients and their outcomes. Pediatr Pulmonol. 2017;52:57-68. © 2016 Wiley Periodicals, Inc.

Obesity and Airway Dysanapsis in Children with and without Asthma.

RATIONALE: For unclear reasons, obese children with asthma have higher morbidity and reduced response to inhaled corticosteroids. OBJECTIVES: To assess whether childhood obesity is associated with airway dysanapsis (an incongruence between the growth of the lungs and the airways) and whether dysanapsis is associated with asthma morbidity. METHODS: We examined the relationship between obesity and dysanapsis in six cohorts of children with and without asthma, as well as the relationship between dysanapsis and clinical outcomes in children with asthma. Adjusted odds ratios (ORs) were calculated for each cohort and in a combined analysis of all cohorts; longitudinal analyses were also performed for cohorts with available data. Hazard ratios (HRs) for clinical outcomes were calculated for children with asthma in the Childhood Asthma Management Program. MEASUREMENTS AND MAIN RESULTS: Being overweight or obese was associated with dysanapsis in both the cross-sectional (OR, 1.95; 95% confidence interval [CI], 1.62-2.35 [for overweight/obese compared with normal weight children]) and the longitudinal (OR, 4.31; 95% CI, 2.99-6.22 [for children who were overweight/obese at all visits compared with normal weight children]) analyses. Dysanapsis was associated with greater lung volumes (FVC, vital capacity, and total lung capacity) and lesser flows (FEV1 and forced expiratory flow, midexpiratory phase), and with indicators of ventilation inhomogeneity and anisotropic lung and airway growth. Among overweight/obese children with asthma, dysanapsis was associated with severe disease exacerbations (HR, 1.95; 95% CI, 1.38-2.75) and use of systemic steroids (HR, 3.22; 95% CI, 2.02-5.14). CONCLUSIONS: Obesity is associated with airway dysanapsis in children. Dysanapsis is associated with increased morbidity among obese children with asthma and may partly explain their reduced response to inhaled corticosteroids.

Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation.

Significant morbidity in cystic fibrosis (CF) results from chronic lung inflammation, most commonly due to Pseudomonas aeruginosa infection. Recent data suggest that IL-17 contributes to pathological inflammation in the setting of abnormal mucosal immunity, and type 17 immunity-driven inflammatory responses may represent a target to block aberrant inflammation in CF. Indeed, transcriptomic analysis of the airway epithelium from CF patients undergoing clinical bronchoscopy revealed upregulation of IL-17 downstream signature genes, implicating a substantial contribution of IL-17-mediated immunity in CF lungs. Bromodomain and extraterminal domain (BET) chromatin modulators can regulate T cell responses, specifically Th17-mediated inflammation, by mechanisms that include bromodomain-dependent inhibition of acetylated histones at the IL17 locus. Here, we show that, in vitro, BET inhibition potently suppressed Th17 cell responses in explanted CF tissue and inhibited IL-17-driven chemokine production in human bronchial epithelial cells. In an acute P. aeruginosa lung infection murine model, BET inhibition decreased inflammation, without exacerbating infection, suggesting that BET inhibition may be a potential therapeutic target in patients with CF.

Site of Bronchoalveolar Lavage Via Flexible Bronchoscopy and Fluid Return in Children.

BACKGROUND: Despite its widespread use as a diagnostic tool, the procedure for bronchoalveolar lavage (BAL) via flexible bronchoscopy is not standardized in children. Our objective was to examine the dissimilarities in fluid return between the different lobes in children undergoing flexible bronchoscopies with BAL. METHODS: We conducted a review of all pediatric flexible bronchoscopies with BAL conducted at a single institution over a 2-year period. Our predictor of interest was the site of the BAL. Our outcome of interest was the percent of fluid return. We used 1-way analysis of variance with subsequent pairwise comparisons for unadjusted analyses and multivariable linear regression for adjusted analyses. RESULTS: We identified 529 procedures that met prespecified criteria. The mean (SD) percent of fluid return was 52.1 (14.4) for the right middle lobe, 50.7 (16.0) for the lingula (LIN), 50.5 (18.6) for the right or left upper lobes other than LIN (R/L-UL), and 42.2 (18.7) for the right or left lower lobes (R/L-LL). The R/L-LL had significantly lower fluid return when compared with each of the other lobes (P<0.05 for all pairwise comparisons); in contrast, there was no significant difference in fluid return between the other lobes. In our main analysis adjusting for potential confounders, performing the BAL in the right middle lobe, LIN, or R/L-UL increased the fluid return by 11.1% [95% confidence interval (CI), 6.2-16.1], 9.5% (95% CI, 3.2-15.8), and 8.7% (95% CI, 0.9-16.5%), respectively, when compared with the R/L-LL. CONCLUSION: Our results suggest that the lower lobes provide the lowest BAL fluid return in children, whereas the other lobes seem to perform similarly.

Subjective and Objective Assessments of Flow-Volume Curve Configuration in Children and Young Adults.

RATIONALE: Analysis of maximal expiratory flow-volume curves (MEFVCs) allows for determination of airway obstruction, but quantitative methods to describe these curves are not commonly used. OBJECTIVES: We sought to determine the variability in MEFVC concavity assessment by pulmonary physicians, whether objective indices of concavity can be substituted for subjective expert impression, and whether MEFVC concavity correlates with clinical outcomes. METHODS: A survey of 37 MEFVCs (plus 3 duplicates) was sent to pulmonologists for quantitative assessment of MEFVC concavity. Objective indices (ß-angle, ratio forced expiratory flow at 50% of total lung volume to peak expiratory flow rate [FEF50/PEFR], ratio of maximum mid-expiratory flow to FVC [MMEF/FVC], kmax, and averaged flow-volume second derivatives) were calculated for each MEFVC and were correlated with the mean expert score. Both the mean expert scores and the best-performing index were then correlated with hospitalizations. MEASUREMENTS AND MAIN RESULTS: Ninety-two respondents provided usable data. There was substantial variability in concavity scores between subjects, but strong intrasubject reliability. Mean expert score did not differ by physician years of experience. Several indices (ß-angle, FEF50/PEFR, FEV1/FVC, MMEF/FVC, FEF50, and forced expiratory flow between 25 and 75% of total lung volume) correlated strongly with mean expert scores. A new variable (ß-MMEF) was constructed using coefficients from stepwise linear regression and accurately predicted the mean expert score (R(2) = 0.96). Mean expert score and ß-MMEF showed similar odds ratios for hospitalization (2.13 and 2.32, respectively) with identical positive (∼71%) and negative (87%) predictive values. The ß-MMEF was also associated with hospitalizations in two independent cohorts of children with asthma and cystic fibrosis. CONCLUSIONS: The ß-MMEF is an objective measure of maximal expiratory flow-volume curve concavity and highly correlates with expert impression. Both the mean expert score for expiratory curve concavity and the ß-MMEF were associated with increased risk of subsequent hospitalization. The ß-MMEF may be a useful biomarker for disease severity in asthma and cystic fibrosis.

Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme.

RATIONALE: Children's Interstitial and Diffuse Lung Disease (chILD) is a heterogeneous group of disorders that is challenging to categorize. In previous study, a classification scheme was successfully applied to children 0 to 2 years of age who underwent lung biopsies for chILD. This classification scheme has not been evaluated in children 2 to 18 years of age. OBJECTIVES: This multicenter interdisciplinary study sought to describe the spectrum of biopsy-proven chILD in North America and to apply a previously reported classification scheme in children 2 to 18 years of age. Mortality and risk factors for mortality were also assessed. METHODS: Patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease from 12 North American institutions were included. Demographic and clinical data were collected and described. The lung biopsies were reviewed by pediatric lung pathologists with expertise in diffuse lung disease and were classified by the chILD classification scheme. Logistic regression was used to determine risk factors for mortality. MEASUREMENTS AND MAIN RESULTS: A total of 191 cases were included in the final analysis. Number of biopsies varied by center (5-49 biopsies; mean, 15.8) and by age (2-18 yr; mean, 10.6 yr). The most common classification category in this cohort was Disorders of the Immunocompromised Host (40.8%), and the least common was Disorders of Infancy (4.7%). Immunocompromised patients suffered the highest mortality (52.8%). Additional associations with mortality included mechanical ventilation, worse clinical status at time of biopsy, tachypnea, hemoptysis, and crackles. Pulmonary hypertension was found to be a risk factor for mortality but only in the immunocompetent patients. CONCLUSIONS: In patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease, there were far fewer diagnoses prevalent in infancy and more overlap with adult diagnoses. Immunocompromised patients with diffuse lung disease who underwent lung biopsies had less than 50% survival at time of last follow-up.

Surfactant Administration During Pediatric Extracorporeal Membrane Oxygenation.

Administering surfactant during pediatric extracorporeal membrane oxygenation (ECMO) may influence important clinical variables but has been insufficiently described. Ninety-six courses of ECMO from our center were retrospectively assessed, and 89 surfactant doses were identified during 37 ECMO courses. Surfactant administration was associated with a respiratory indication for ECMO and increased durations of ECMO and positive pressure ventilation. Hospital survival was 64.9% (24) in surfactant-treated ECMO courses and 72.9% (43) otherwise (p = 0.41). Dynamic compliance of the respiratory system (Cdyn; shown as least squares mean [standard error] in ml/cm H2O/kg by mixed-effects modeling) increased significantly from 0.34 (0.03) before surfactant to 0.40 (0.03) within 12 hours (p = 0.023) and to 0.45 (0.03) within 24 hours (p < 0.001) of surfactant administration. Other mechanical ventilator parameters, ECMO settings, and arterial blood gas results did not differ significantly after surfactant administration. Among surfactant recipients, significantly increased Cdyn was observed in the nonsurgical group (n = 20) but not in the cardiac surgery group (n = 17). In conclusion, respiratory system compliance is increased after surfactant administration and noncardiac surgical patients may preferentially benefit from this therapy. Surfactant administration was associated with longer durations of mechanical support, but not with unfavorable mortality.

Official American Thoracic Society technical standards: flexible airway endoscopy in children.

BACKGROUND: Flexible airway endoscopy (FAE) is an accepted and frequently performed procedure in the evaluation of children with known or suspected airway and lung parenchymal disorders. However, published technical standards on how to perform FAE in children are lacking. METHODS: The American Thoracic Society (ATS) approved the formation of a multidisciplinary committee to delineate technical standards for performing FAE in children. The committee completed a pragmatic synthesis of the evidence and used the evidence synthesis to answer clinically relevant questions. RESULTS: There is a paucity of randomized controlled trials in pediatric FAE. The committee developed recommendations based predominantly on the collective clinical experience of our committee members highlighting the importance of FAE-specific airway management techniques and anesthesia, establishing suggested competencies for the bronchoscopist in training, and defining areas deserving further investigation. CONCLUSIONS: These ATS-sponsored technical standards describe the equipment, personnel, competencies, and special procedures associated with FAE in children.

Dexmedetomidine for infant pulmonary function testing.

For the last thirty years, oral chloral hydrate has been used for sedation of infants for lung function testing. Recently, however, availability of chloral hydrate became severely limited in the United States after two manufacturers discontinued manufacturing in 2012. Due to these limitations and the recent and ongoing shortage of chloral hydrate, other medications have been proposed for lung function testing, including midazolam and propofol. Herein, we describe our limited experience using intravenous dexmedetomedine (DMED), a medication thus far described as having minimal effect on pulmonary function or respiratory drive.