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We reviewed patients with Stevens-Johnson syndrome (SJS) evaluated at Children's Hospital Colorado and investigated the occurrence of bronchiolitis obliterans (BO). Approximately 9% of patients with SJS developed BO. Pediatricians should consider monitoring patients with SJS for BO, especially those with recurrent SJS and patients treated with mechanical ventilation.

Frequent blood pressure monitoring is the key to diagnosis and treatments of many severe diseases. However, the conventional ambulatory methods require patients to carry a blood pressure (BP) monitoring device for 24 h and conduct the measurement every 10--15 min. Despite their extensive usage, wearing the wrist/arm-based BP monitoring device for a long time has a significant impact on users' daily activities. To address the problem, we developed eBP to measure blood pressure (BP) from inside user's ear aiming to minimize the measurement's impact on users' normal activities although maximizing its comfort level. The key novelty of eBP includes (1) a light-based inflatable pulse sensor which goes inside the ear, (2) a digital air pump with a fine controller, and (3) BP estimation algorithms that eliminate the need of blocking the blood flow inside the ear. Through the comparative study of 35 subjects, eBP can achieve the average error of 1.8 mmHg for systolic (high-pressure value) and -3.1 mmHg for diastolic (low-pressure value) with the standard deviation error of 7.2 mmHg and 7.9 mmHg, respectively. These results satisfy the FDA's AAMI standard, which requires a mean error of less than 5 mmHg and a standard deviation of less than 8 mmHg.

BCL2: BCL2 apoptosis regulator; BCL10: BCL10 immune signaling adaptor; CARD11: caspase recruitment domain family member 11; CBM: CARD11-BCL10-MALT1; CR2: complement C3d receptor 2; EBNA: Epstein Barr nuclear antigen; EBV: Epstein-Barr virus; FCGR3A; Fc gamma receptor IIIa; GLILD: granulomatous-lymphocytic interstitial lung disease; HV: healthy volunteer; IKBKB/IKB kinase: inhibitor of nuclear factor kappa B kinase subunit beta; IL2RA: interleukin 2 receptor subunit alpha; MALT1: MALT1 paracaspase; MS4A1: membrane spanning 4-domain A1; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH: transcription factor; NCAM1: neural cell adhesion molecule 1; NFKB: nuclear factor kappa B; NIAID: National Institute of Allergy and Infectious Diseases; NK: natural killer; PTPRC: protein tyrosine phosphatase receptor type C; SELL: selectin L; PBMCs: peripheral blood mononuclear cells; TR: T cell receptor; Tregs: regulatory T cells; WT: wild-type.

INTRODUCTION Therapeutics exist to treat fibrotic lung disease in adults, but these have not been investigated in children. Defining biomarkers for pediatric fibrotic lung disease in children is crucial for clinical trials. Children with surfactant protein C (SFTPC) dysfunction mutations develop fibrotic lung disease over time. We evaluated chest computed tomography (CT) changes over time in children with SFTPC dysfunction mutations. METHODS We performed an institutional review board-approved retrospective review of children with SFTPC dysfunction mutations. We collected demographic and clinical information. Chest CT scans were evaluated using visual and computerized scores. Chest CT scores and pulmonary function tests were reviewed. RESULTS Eleven children were included. All children presented in infancy and four children suffered from respiratory failure requiring mechanical ventilation. Those who performed pulmonary function tests had stable forced vital capacities over time by percent predicted, but increased forced vital capacity in liters. CT findings evolved over time in most patients with earlier CT scans demonstrating ground glass opacities and later CT scans with more fibrotic features. In a pilot analysis, data-driven textural analysis software identified fibrotic features in children with SFTPC dysfunction that increased over time and correlated with visual CT scores. DISCUSSION We describe 11 children with SFTPC dysfunction mutations. Increases in forced vital capacity over time suggest that these children experience lung growth and that therapeutic intervention may maximize lung growth. Ground glass opacities are the primary early imaging findings while fibrotic features dominate later. CT findings suggest the development of and increases in fibrotic features that may serve as potential biomarkers for antifibrotic therapeutic trials.

Children's interstitial and diffuse lung diseases are a diverse group of rare lung disorders that present in childhood with diffuse pulmonary infiltrates and respiratory signs and symptoms. Children with these disorders face high morbidity and mortality and their families must cope with overwhelming uncertainty. Physicians caring for these patients are challenged by a paucity of directed therapies, or even understanding of natural history. Through the establishment of the Children's Interstitial Lung Disease Foundation Research Network and the Children's Interstitial Lung Disease Foundation significant progress has been made through collaboration and research. This review outlines the past and current successes in the new and rapidly growing field of Children's Interstitial and Diffuse Lung Disease.

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.

Diagnosing hypertension or hemodialysis requires patients to carry a blood pressure (BP) monitoring device for 24 hours. Th erefore, wearing the wrist/arm-based BP monitoring device, in this case, has a signifi cant impact on users' daily activities. To address the problem, we developed eBP, an ear-worn device that measures blood pressure from inside the ear. Th rough the evaluation of 35 subjects, eBP can achieve the average error of 1.8 mmHg for systolic BP and -3.1 mmHg for diastolic BP with the standard deviation error of 7.2 mmHg and 7.9 mmHg, respectively.

Patients with respiratory diseases require frequent and accurate blood oxygen level monitoring. Existing techniques, however, either need a dedicated hardware or fail to predict low saturation levels. To fill in this gap, we propose a phone-based oxygen level estimation system, called PhO 2 , using camera and flashlight functions that are readily available on today’s off-the-shelf smartphones. Since the phone’s camera and flashlight were not made for this purpose, utilizing them for oxygen level estimation poses many difficulties. We introduce a cost-effective add-on together with a set of algorithms for spatial and spectral optical signal modulation to amplify the optical signal of interest while minimizing noise. A near-field-based pressure detection and feedback mechanism are also proposed to mitigate the negative impacts of user’s behavior during the measurement. We also derive a non-linear referencing model with an outlier removal technique that allows PhO 2 to accurately estimate the oxygen level from color intensity ratios produced by the smartphone’s camera. An evaluation on COTS smartphone with six subjects shows that PhO 2 can estimate the oxygen saturation within 3.5% error rate comparing to FDA-approved gold standard pulse oximetry. In addition, our evaluation in hospitals presents high correlation with ground-truth qualified by the 0.83/1.0 Kendall τ coefficient.

Autophagy involving core machinery proteins such as ATG9A is part of a cytoprotective process whose dysregulation is associated with carcinogenesis, neurodegeneration and autoimmunity, but few examples exist of monogenic diseases to further insights into human disease. In the present studies, we report a patient with novel compound heterozygous mutations in ATG9A after patient and parental DNA were subjected to whole exome sequencing. The patient developed hyperplastic proliferations of T and B cells in lung and brain and exhibited defects in lymphocyte memory cell populations after developing an infection with Epstein-Barr virus (EBV). Peripheral blood leukocytes from the patient exhibited defects in autophagic activity and EBV-transformed cells redemonstrated this defect which was also associated with defective NFKB (nuclear factor kappa B) signaling and accumulation of the pro-proliferative protein MYC (MYC proto-oncogene, bHLH transcription factor) and anti-apoptotic protein BCL2 (BCL2 apoptosis regulator), leading to increased proliferative capacity. Defects were corrected after transformation with plasmids expressing ATG9A and after treatment of cells as well as the patient with the MTOR (mechanistic target of rapamycin kinase) inhibitor, autophagy-inducing immunosuppressant rapamycin. These results point to a novel role of ATG9A and autophagy in human cellular signaling associated with hyperplasia and lymphocyte biology and provide an example how genetic studies may suggest effective specific therapeutic interventions. BCL2: BCL2 apoptosis regulator; BCL10: BCL10 immune signaling adaptor; CARD11: caspase recruitment domain family member 11; CBM: CARD11-BCL10-MALT1; CR2: complement C3d receptor 2; EBNA: Epstein Barr nuclear antigen; EBV: Epstein-Barr virus; FCGR3A; Fc gamma receptor IIIa; GLILD: granulomatous-lymphocytic interstitial lung disease; HV: healthy volunteer; IKBKB/IKB kinase: inhibitor of nuclear factor kappa B kinase subunit beta; IL2RA: interleukin 2 receptor subunit alpha; MALT1: MALT1 paracaspase; MS4A1: membrane spanning 4-domain A1; MTOR: mechanistic target of rapamycin kinase; MYC: MYC proto-oncogene, bHLH: transcription factor; NCAM1: neural cell adhesion molecule 1; NFKB: nuclear factor kappa B; NIAID: National Institute of Allergy and Infectious Diseases; NK: natural killer; PTPRC: protein tyrosine phosphatase receptor type C; SELL: selectin L; PBMCs: peripheral blood mononuclear cells; TR: T cell receptor; Tregs: regulatory T cells; WT: wild-type

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 pathogen...

Germline mutation in bone morphogenetic protein type II (BMPR2) is the most common cause of idiopathic/heritable pulmonary hypertension in pediatric patients. Despite the discovery of this gene there are no known descriptions of the CT or CT angiography findings in these children.To correlate the clinical presentation, pathology and chest CT findings in pediatric patients with pulmonary hypertension caused by mutations in the BMPR2 gene.We performed a search to identify pediatric patients with a BMPR2 mutation and CT or CT angiography with the clinical history of pulmonary hypertension. Three pediatric radiologists reviewed the children's CT imaging findings and ranked the dominant findings in order of prevalence via consensus.We identified three children with pulmonary hypertension and confirmed germline BMPR2 mutations, two of whom had undergone lung biopsy. We then correlated the imaging findings with histopathology and clinical course.All of our patients with BMPR2 mutations demonstrated a distinct CT pattern of ground-glass nodules with a prominent central enhancing vessel/nodule. These findings correlated well with the pathological findings of plexogenic arteriopathy.

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.

OBJECTIVES Manual clinical scoring systems are the current standard used for acute asthma clinical care pathways. No automated system exists that assesses disease severity, time course, and treatment impact in pediatric acute severe asthma exacerbations. WORKING HYPOTHESIS machine learning applied to continuous vital sign data could provide a novel pediatric-automated asthma respiratory score (pARS) by using the manual pediatric asthma score (PAS) as the clinical care standard. METHODS Continuous vital sign monitoring data (heart rate, respiratory rate, and pulse oximetry) were merged with the health record data including a provider-determined PAS in children between 2 and 18 years of age admitted to the pediatric intensive care unit (PICU) for status asthmaticus. A cascaded artificial neural network (ANN) was applied to create an automated respiratory score and validated by two approaches. The ANN was compared with the Normal and Poisson regression models. RESULTS Out of an initial group of 186 patients, 128 patients met inclusion criteria. Merging physiologic data with clinical data yielded >37 000 data points for model training. The pARS score had good predictive accuracy, with 80% of the pARS values within ±2 points of the provider-determined PAS, especially over the mid-range of PASs (6-9). The Poisson and Normal distribution regressions yielded a smaller overall median absolute error. CONCLUSIONS The pARS reproduced the manually recorded PAS. Once validated and studied prospectively as a tool for research and for physician decision support, this methodology can be implemented in the PICU to objectively guide treatment decisions.

The expression of the NKX2–1 gene and its encoded protein, thyroid transcription factor 1 (TTF-1), plays a role in pulmonary surfactant homeostasis and lung development. NKX2–1 mutations have been associated with neonatal respiratory distress, hypotonia, choreoathetosis and congenital hypothyroidism. These clinical findings have been coined brain–lung–thyroid syndrome, although not all three organs are always involved. While many of these children develop interstitial lung disease, no systematic review of chest high-resolution CT (HRCT) findings has been reported. To summarize the clinical presentations, pathology and HRCT imaging findings of children with NKX2–1 mutations. We identified six children with NKX2–1 mutations, deletions or duplications confirmed via genetic testing at our institution. Three pediatric radiologists reviewed the children’s HRCT imaging findings and ranked the dominant findings in order of prevalence via consensus. We then correlated the imaging findings with histopathology and clinical course. All children in the study were heterozygous for NKX2–1 mutations, deletions or duplications. Ground-glass opacities were the most common imaging feature, present in all but one child. Consolidation was also a prevalent finding in 4/6 of the children. Architectural distortion was less common. HRCT findings of TTF-1 deficiency are heterogeneous and evolve over time. There is significant overlap between the HRCT findings of TTF-1 deficiency, other surfactant dysfunction mutations, and pulmonary interstitial glycogenosis. TTF-1 deficiency should be considered in term infants presenting with interstitial lung disease, especially if hypotonia or hypothyroidism is present.

OBJECTIVES/HYPOTHESIS The Aerodigestive Program (the Aero Program) at Children's Hospital Colorado is a multidisciplinary program focused on airway, digestive, and lung disorders in complex children, involving collaboration between gastroenterology, pulmonology, anesthesiology, and otolaryngology in clinic and operating room. These programs have proliferated as institutions focus on providing greater care coordination and family satisfaction. However, few cost, charge, and satisfaction data exist to support these resource-intensive programs. The goal of this study was to investigate the value of combined triple endoscopy delivered by the Aero Program through analysis of institutional charges, direct costs, operating room efficiency metrics, and parent satisfaction. STUDY DESIGN Program evaluation. METHODS Finance, satisfaction, efficiency, and quality-of-care metrics were evaluated within and outside of the Aero Program through retrospective queries of electronic health records, administrative databases, and parent surveys at our institution. RESULTS Mean anesthesia time in the Aero Program was 54 minutes (49-60; 95% confidence interval), which was significantly less (P

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.

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6–17 years (≥30; including ≥20 adolescents aged 12–17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects., We describe the design of #InPedILD, a study of 24 weeks’ nintedanib or placebo on top of standard of care, followed by variable-duration open-label nintedanib in children with interstitial lung disease (ClinicalTrials.gov NCT04093024) #PedILD https://bit.ly/3tC1a7P

Coronavirus Disease 2019 (COVID-19) has been an unprecedented and continuously evolving healthcare crisis. SARS-CoV-2 spread rapidly and initially little was known about the virus or the clinical course for infected children. In the United States of America, the medical response has been regionalized, based on variation in community transmission of the virus and localized outbreaks. Pediatric pulmonary and sleep divisions evolved in response to the administrative and clinical challenges. As the workforce transitioned to working remotely, video conferencing technology and multicenter collaborative efforts were implemented to create clinical protocols. The COVID-19 pandemic challenges the framework of current medical practice but also highlights the dynamic and cooperative nature of pediatric pulmonology and sleep medicine. Our response to this pandemic has laid the groundwork for future challenges. This article is protected by copyright. All rights reserved.

Objective To improve understanding of the interrelatedness of airway and esophageal diagnoses by evaluating the yield of procedural and radiographic testing of the gastrointestinal tract in children with airway conditions by their referring diagnoses in a pediatric aerodigestive clinic. Methods A retrospective chart review of all 325 patients seen in the aerodigestive program from 2010 to 2013 was performed in a single academic medical center. Demographics and results from esophagogastroduodenoscopies with biopsies (EGD), upper gastrointestinal fluoroscopy studies (UGI), and pH multichannel intraluminal impedance probe (pH-MII) performed within 30 days of the clinic visit were evaluated according to presenting diagnoses. Results Mean patient age was 3.15 years (range 0.15-24 years) and 41.2% were born premature. 189/325 (58.1%) were on acid suppression. A total of 295 EGD, 193 pH-MII, and 54 UGI were performed. The most common diagnosis with an abnormal pH-MII was asthma. The most common diagnoses with an abnormal EGD were feeding difficulty and tracheal esophageal fistula/ esophageal atresia (TEF/EA). EGDs were normal in 188/295 (63.7%), while 39/295 (13.2%) demonstrated esophagitis, and 22/295 (7.5%) had >15 esophageal eosinophils per high power field. The majority of pH-MII (144/193 [74.6%]) and UGI (47/54 [87%]) were normal. Conclusions Children with feeding difficulty, TEF/EA, and asthma were the mostly likely to have a histologic abnormality on EGD or an abnormal pH-MII. The majority of children were previously prescribed acid suppression medication and had a referring diagnosis of gastroesophageal reflux disease but were subsequently found to have normal evaluation. Prospective studies are needed to optimize care of this population.

INTRODUCTION Training in pediatric flexible bronchoscopy (FB) is predominantly completed on patients. Early trainees are less accurate and slower than experienced bronchoscopists. This report describes the development of a three-dimensional printed airway model and describes how the model was used to teach learners basic FB skills. METHODS Postgraduate year two (PGY2) pediatric residents completing a 1-month pediatric pulmonology rotation with minimal previous exposure to FB were randomized into a simulation trainee group (n = 18) or a control resident group (n = 9). The simulation group received four 15-minute practice sessions (3 self-directed, 1 with feedback). Participants completed a bronchoscopy assessment on the model at prestudy, poststudy, and delayed (at least 2 months after the rotation) time points. Outcomes were identification of markers located in the six lung areas and completion time. RESULTS There was no difference in prestudy scores between groups. In the poststudy assessment, the simulation participants correctly identified more lung area markers (median = 6 vs 1.5, P < 0.001) and were faster (median = 102 vs 600 seconds, P < 0.001). In the delayed assessment, correct marker identification trended toward improvement in the simulation group compared with controls (median = 4 vs 2, P = 0.077). CONCLUSIONS With 1 hour of practice time, requiring 15 minutes of direct teaching, novice resident bronchoscopists are able to more accurately identify and visualize the five lung lobes and lingula via FB and are able to do so in less time than control residents. This anatomically accurate model could be used to train basic FB skills at a low cost compared with other models.

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. 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. 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. 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. 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.

Objectives Neuroendocrine cell hyperplasia of infancy (NEHI) is a children's interstitial and diffuse lung disease of unknown etiology that presents in infancy with characteristic findings of tachypnea, retractions, crackles, and hypoxemia. At the present, the mainstay of treatment is oxygen supplementation to normalize oxygen saturations and decrease work of breathing. There are characteristic pulmonary function, radiographic, and histologic findings, but polysomnography (PSG) data has not been reported. We sought to report PSG data and implications for management and treatment of NEHI patients. Methods A retrospective chart review was performed under a Colorado Institutional Review Board approved protocol for which consent was waived. Informatics for Integrating Biology and the Bedside was used to query the electronic medical record at Children's Hospital Colorado for patients with both a diagnosis of NEHI and a PSG. PSG was performed for clinical reasons. Routine sleep quality and respiratory parameters were recorded and analyzed. Results Of our 77 patients with NEHI, 14 (19%) children underwent PSG during the study period. Eight children met criteria for OSA and three met criteria for CSA. Ten patients had low oxygen saturations during a study, six had low sleep efficiency, and three had periodic limb movement disorder. Conclusions Patients with NEHI may have sleep related breathing disorders that contribute to disrupted sleep, including obstructive and central sleep apnea, hypoxemia, decreased sleep efficiency, and increased periodic limb movement disorder. PSG should be considered as part of NEHI management, as it may lead to recognition of clinically significant sleep-disordered breathing.

The Institute of Medicine (IOM) standards for guideline development have had unintended negative consequences. A more efficient approach is desirable.To determine whether a modified Delphi process early during guideline development discriminates recommendations that should be informed by a systematic review from those that can be based upon expert consensus.The same questions addressed by IOM-compliant pulmonary or critical care guidelines were addressed by expert panels using a modified Delphi process, termed the Convergence of Opinion on Recommendations and Evidence (CORE) process. The resulting recommendations were compared. Concordance of the course of action, strength of recommendation, and quality of evidence, as well as the duration of recommendation development, were measured.When 50% agreement was required to make a recommendation, all questions yielded recommendations, and the recommended courses of action were 89.6% concordant. When 70% agreement was required, 17.9% of questions did not yield recommendations, but for those that did, the recommended courses of action were 98.2% concordant. The time to completion was shorter for the CORE process (median, 19.3 vs. 1,309.0 d; P = 0.0002).We propose the CORE process as an early step in guideline creation. Questions for which 70% agreement on a recommendation cannot be achieved should go through an IOM-compliant process; however, questions for which 70% agreement on a recommendation can be achieved can be accepted, avoiding a lengthy systematic review.

Frequent blood pressure (BP) assessment is key to the diagnosis and treatment of many severe diseases, such as heart failure, kidney failure, hypertension, and hemodialysis. Current "gold-standard'' BP measurement techniques require the complete blockage of blood flow, which causes discomfort and disruption to normal activity when the assessment is done repetitively and frequently. Unfortunately, patients with hypertension or hemodialysis often have to get their BP measured every 15 minutes for a duration of 4-5 hours or more. The discomfort of wearing a cumbersome and limited mobility device affects their normal activities. In this work, we propose a device called eBP to measure BP from inside the user's ear aiming to minimize the measurement's impact on users' normal activities while maximizing its comfort level. eBP has 3 key components: (1) a light-based pulse sensor attached on an inflatable pipe that goes inside the ear, (2) a digital air pump with a fine controller, and (3) a BP estimation algorithm. In contrast to existing devices, eBP introduces a novel technique that eliminates the need to block the blood flow inside the ear, which alleviates the user's discomfort. We prototyped eBP custom hardware and software and evaluated the system through a comparative study on 35 subjects. The study shows that eBP obtains the average error of 1.8 mmHg and -3.1 mmHg and a standard deviation error of 7.2 mmHg and 7.9 mmHg for systolic (high-pressure value) and diastolic (low-pressure value), respectively. These errors are around the acceptable margins regulated by the FDA's AAMI protocol, which allows mean errors of up to 5 mmHg and a standard deviation of up to 8 mmHg.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by AIRE mutations, presents with several autoimmune diseases. Among these, endocrine organ failure is widely recognized, but the prevalence, immunopathogenesis, and treatment of non-endocrine manifestations such as pneumonitis remain poorly characterized. We enrolled 50 patients with APECED in a prospective observational study and comprehensively examined their clinical and radiographic findings, performed pulmonary function tests, and analyzed immunological characteristics in blood, bronchoalveolar lavage fluid, and endobronchial and lung biopsies. Pneumonitis was found in >40% of our patients, presented early in life, was misdiagnosed despite chronic respiratory symptoms and accompanying radiographic and pulmonary function abnormalities, and caused hypoxemic respiratory failure and death. Autoantibodies against BPIFB1 and KCNRG and the homozygous c.967_979del13 AIRE mutation are associated with pneumonitis development. APECED pneumonitis features compartmentalized immunopathology, with accumulation of activated neutrophils in the airways and lymphocytic infiltration in intraepithelial, submucosal, peribronchiolar, and interstitial areas. Beyond APECED, we extend these observations to lung disease seen in other conditions with secondary AIRE deficiency (thymoma and RAG deficiency). Aire-deficient mice had similar compartmentalized cellular immune responses in the airways and lung tissue, which was ameliorated by deficiency of T and B lymphocytes. Accordingly, T and B lymphocyte-directed immunomodulation controlled symptoms and radiographic abnormalities and improved pulmonary function in patients with APECED pneumonitis. Collectively, our findings unveil lung autoimmunity as a common, early, and unrecognized manifestation of APECED and provide insights into the immunopathogenesis and treatment of pulmonary autoimmunity associated with impaired central immune tolerance.

Introduction Children with repaired congenital esophageal atresia/tracheoesophageal fistula (EA/TEF) are at high risk of aerodigestive morbidity. We hypothesized that age and coexisting pulmonary diagnoses are associated with dysphagia in this population. Methods Retrospective review of children with EA/TEF seen in the aerodigestive program between 2011 and 2015 was carried out and comorbidities, video fluoroscopic swallow studies (VFSS), chest CT, and bronchoscopy results were reviewed. VFSS was considered abnormal if there was aspiration, deep laryngeal penetration, significant residue, or delayed initiation. Mann–Whitney U test was used to examine VFSS results by age. Fisher's exact test was used to assess the relationship between VFSS result and comorbidities. Results Ninety VFSS were performed on 44 children with EA/TEF (median 2 studies per patient, range: 0–7). Fifty three percent (23/39) children had at least one abnormal VFSS. Seventeen children had VFSS change between normal and abnormal over time, with 11 normal on their most recent VFSS. Younger children (Mdn = 1.57 years) were more likely to have an abnormal test result than older children (Mdn = 3.55 years) (p = 0.001). Children with severe tracheomalacia (>90% tracheal collapse visualized on flexible bronchoscopy) had a higher incidence of abnormal VFSS (14/20; 70%) than the other children with EA/TEF (9/24; 38%) (P = 0.04). Children with other pulmonary and airway comorbidities, including gestation age Discussion Dysphagia was prevalent in this cohort and related to age and severe tracheomalacia. This reinforces the need for a multidisciplinary evaluation including feeding and swallowing evaluation. In this rare disease, we must collaborate between sites to improve our understanding of aerodigestive diagnoses and disease outcomes.

Alveolar type 2 (AT2) cell endoplasmic reticulum (ER) stress is a prominent feature in adult and pediatric interstitial lung disease (ILD and ChILD), but in vivo models linking AT2 cell ER stress to ILD have been elusive. Based on a clinical ChILD case, we identified a critical cysteine residue in the surfactant protein C gene (SFTPC) BRICHOS domain whose mutation induced ER stress in vitro. To model this in vivo, we generated a knockin mouse model expressing a cysteine-to-glycine substitution at codon 121 (C121G) in the Sftpc gene. Sftpc(C121G) expression during fetal development resulted in a toxic gain-of-function causing fatal postnatal respiratory failure from disrupted lung morphogenesis. Induced Sftpc(C121G) expression in adult mice resulted in an ER-retained pro-protein causing AT2 cell ER stress. Sftpc(C121G) AT2 cells were a source of cytokines expressed in concert with development of polycellular alveolitis. These cytokines were subsequently found in a high-dimensional proteomic screen of bronchoalveolar lavage fluid from ChILD patients with the same class of SFTPC mutations. Following alveolitis resolution, Sftpc(C121G) mice developed spontaneous pulmonary fibrosis and restrictive lung impairment. This model provides proof of concept linking AT2 cell ER stress to fibrotic lung disease coupled with translationally relevant biomarkers.

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.

ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

Neuroendocrine cell Hyperplasia of Infancy (NEHI) presents with tachypnea, retractions, hypoxemia, and often failure to thrive. The radiologic and physiologic findings in infants with NEHI have been well described with a distinct geographic pattern of ground-glass opacities on chest computerized tomography imaging and profound air-trapping on infant pulmonary function testing. Despite gradual improvement over time, unexplained exacerbation has been observed but not well characterized. We present physiological and radiological changes of increased air-trapping during acute exacerbations in two older children with NEHI who had previously experienced significant clinical improvement. These cases illustrate previously undescribed manifestations of NEHI in older children.

Introduction: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare pulmonary disorders. Our objectives are to advance knowledge on clinical features, management, and outcomes of this population. Methods: The Children’s Interstitial and Diffuse Lung Disease Research Network (ChILDRN) established a longitudinal observational study in 2016 using a national platform for single IRB reliance agreements with 13 participating sites across the United States. Results: 254 subjects have been enrolled to date. Specific chILD diagnoses and clinical characteristics are summarized in Table 1. Overall mean age at study enrollment was 101±73 months. Identified morbidity included home oxygen supplementation in 71% at any time and 44% with ongoing requirement. Failure to thrive was noted in 53%. 46% of subjects had undergone lung biopsy; genetic studies were used in diagnosis for 23%. Pulmonary function abnormalities varied based on disease subgroup. Conclusions: The first multicenter prospective study of chILD in the U.S. indicates substantial morbidity with variable phenotypes in different forms of chILD. This cohort provides a framework for future longitudinal studies focused on elucidation of the genetic and molecular underpinnings of these disorders, development of targeted therapies, and optimization of supportive care.

OBJECTIVE Lung function monitoring by spirometry plays a critical role in the clinical care of pediatric cystic fibrosis (CF) patients, but many young children are unable to perform spirometry, and the outputs are often normal even in the presence of lung disease. Measures derived from electrical impedance tomography (EIT) images were studied for their utility as potential surrogates for spirometry in CF patients and to assess response to intravenous antibiotic treatment for acute pulmonary exacerbations (PEx) in a subset of patients. APPROACH EIT data were collected on 35 subjects (21 with CF, 14 healthy controls, 8 CF patients pre- and post-treatment for an acute PEx) ages 2 to 20 years during tidal breathing and also concurrently with spirometry on subjects over age 8. EIT-derived measures of FEV1, FVC, and FEV1/FVC were computed globally and regionally from dynamic EIT images. MAIN RESULTS Global EIT-derived FEV1/FVC showed good correlation with spirometry FEV1/FVC values (r = 0.54, p = 0.01), and were able to distinguish between the groups (p = 0.01). Lung heterogeneity was assessed through the spatial coefficient of variation (CV) of EIT difference images between key time points, and the CVs for EIT-derived FEV1 and FVC showed significant correlation with the CV for tidal breathing (r = 0.47, p = 0.01 and r = 0.50, p = 0.01, respectively). Global EIT-derived FEV1/FVC was better able to distinguish between groups than spirometry FEV1 (F-values 776.5 and 146.3, respectively, p

Pulmonary interstitial glycogenosis is a form of childhood interstitial lung disease characterized by the histological finding of abundant glycogen-laden mesenchymal cells within the pulmonary interstitium. Patients present in the neonatal period with disproportionate respiratory distress. Often, pulmonary interstitial glycogenosis is accompanied by alveolar simplification complicating recognition and diagnosis. Despite the recognition of pulmonary interstitial glycogenosis as a distinct entity, only a few case reports describing imaging findings are found in the literature, with no published systematic review available. The purpose of this review is to provide a review of CT findings of pulmonary interstitial glycogenosis with histological correlation to aid in early diagnosis and management. A 10-year retrospective review was performed to identify pediatric patients