Diagnosis of Post-Hematopoietic Stem Cell Transplantation Bronchiolitis Obliterans Syndrome in Children: Time for a Rethink?

Hematopoietic stem cell transplantation (HSCT) is undertaken in children with the aim of curing a range of malignant and nonmalignant conditions. Unfortunately, pulmonary complications, especially bronchiolitis obliterans syndrome (BOS), are significant sources of morbidity and mortality post-HSCT. Currently, criteria developed by a National Institutes of Health (NIH) working group are used to diagnose BOS in children post-HSCT. Unfortunately, during the development of a recent American Thoracic Society (ATS) Clinical Practice Guideline on this topic, it became apparent that the NIH criteria have significant limitations in the pediatric population, leading to late diagnosis of BOS. Specific limitations include use of an outdated pulmonary function testing reference equation, a reliance on spirometry, use of a fixed forced expiratory volume in 1 second (FEV1) threshold, focus on obstructive defects defined by FEV1/vital capacity, and failure to acknowledge that BOS and infection can coexist. In this review, we summarize the evidence regarding the limitations of the current criteria. We also suggest potential evidence-based ideas for improving these criteria. Finally, we highlight a new proposed criteria for post-HSCT BOS in children that were developed by the authors of the recently published ATS clinical practice guideline, along with a pathway forward for improving timely diagnosis of BOS in children post-HSCT.

Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: Many children undergo allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for the treatment of malignant and non-malignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common non-infectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent National Institutes of Health workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children. METHODS: A multinational, multidisciplinary panel of experts identified six questions regarding surveillance for, and evaluation of post-HSCT BOS in children. Systematic review of the literature was undertaken to answer each question. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to rate the quality of evidence and the strength of recommendations. RESULTS: The panel members considered the strength of each recommendation and evaluated the benefits and risks of applying the intervention. In formulating the recommendations, the panel considered patient and caregiver values, the cost of care, and feasibility. Recommendations addressing the role of screening pulmonary function testing and diagnostic tests in children with suspected post-HSCT BOS were made. Following a Delphi process, new diagnostic criteria for pediatric post-HSCT BOS were also proposed. CONCLUSIONS: This document provides an evidence-based approach to detection of post-HSCT BOS in children, while also highlighting considerations for implementation of each recommendation. Further, the document describes important areas for future research.

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.

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.

Computed tomographic findings in TBX4 mutation: a common cause of severe pulmonary artery hypertension in children.

BACKGROUND: Mutations in the T-Box 4 (TBX4) gene are a lesser-known cause of heritable pulmonary arterial hypertension (PAH). Patients with heritable PAH typically have worse outcomes when compared with patients with idiopathic PAH, yet little is known about the phenotypical presentation of this mutation. OBJECTIVE: This article reviews the pattern of chest CT findings in pediatric patients with PAH and TBX4 mutations and compares their radiographic presentation with those of age-matched patients with PAH but without TBX4 mutations. MATERIALS AND METHODS: A retrospective chart review of the pulmonary arterial hypertension database was performed. Pediatric patients with PAH-confirmed TBX4 mutations and an available high CT were included. Fifteen (9 females) patients met the inclusion criteria. Fourteen (8 females) age-matched controls with diagnosed PAH but without TBX4 mutations were also evaluated. The median age at diagnosis was 7.4 years (range: 0.1-16.4 years). Demographic information and clinical outcomes were collected. CTs of the chest were reviewed for multiple airway, parenchymal, and structural abnormalities (16 imaging findings in total). Chi-square tests were used to compare the prevalence of each imaging finding in the TBX4 cohort compared to the control group. RESULTS: Patients with TBX-4 mutations had increased presence of peripheral or subpleural irregularity (73% vs 0%, P < 0.01), cystic lucencies (67% vs 7%, P < 0.01), and linear or reticular opacity (53% vs 0%, P < 0.01) compared to the control group. Ground glass opacities, bronchiectasis, and centrilobular nodules were not significantly different between the two patient groups (P > 0.05). CONCLUSION: TBX4 mutations have distinct imaging phenotypes in pediatric patients with PAH. Compared to patients without this mutation, patients with TBX-4 genes typically present with peripheral or subpleural irregularity, cystic lucencies, and linear or reticular opacity.

Autophagy-associated immune dysregulation and hyperplasia in a patient with compound heterozygous mutations in ATG9A.

ABBREVIATIONS: 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.

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.

Chest computed tomography findings of ground-glass nodules with enhancing central vessel/nodule in pediatric patients with BMPR2 mutations and plexogenic arteriopathy.

BACKGROUND: 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. OBJECTIVE: To correlate the clinical presentation, pathology and chest CT findings in pediatric patients with pulmonary hypertension caused by mutations in the BMPR2 gene. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Ground glass and fibrotic change in children with surfactant protein C dysfunction mutations.

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.

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.

Emergent high fatality lung disease in systemic juvenile arthritis.

OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD 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. CONCLUSIONS: A 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.

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.

Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance.

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.

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.

An SFTPC BRICHOS mutant links epithelial ER stress and spontaneous lung fibrosis.

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. SftpcC121G expression during fetal development resulted in a toxic gain-of-function causing fatal postnatal respiratory failure from disrupted lung morphogenesis. Induced SftpcC121G expression in adult mice resulted in an ER-retained pro-protein causing AT2 cell ER stress. SftpcC121G 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, SftpcC121G 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.

Novel Application of Aptamer Proteomic Analysis in Cystic Fibrosis Bronchoalveolar Lavage Fluid.

PURPOSE: Biomarkers are needed in cystic fibrosis (CF) to understand disease progression, assess response to therapy, and enrich enrollment for clinical trials. Aptamer-based proteomics have proven useful in blood samples. The aim is to evaluate proteins in bronchoalveolar lavage fluid (BALF) in CF children compared to controls and identify endotypes during CF exacerbations. EXPERIMENTAL DESIGN: BALF is collected clinically from 50 patients with CF and nine disease controls, processed, and stored per protocol. BALF supernatants are analyzed for 1129 proteins by aptamer approach (SOMAscan proteomics platform). Proteins are compared across groups and used for pathway analysis. Endotypes are identified within the CF group. RESULTS: CF BALF has increased concentrations of neutrophil elastase, myeloperoxidase, and decreased concentration of protein folding and host defense proteins. Pathways that distinguished CF subjects included interferon gamma signaling, membrane trafficking, and phospholipid metabolism. In the CF group, unbiased analysis of proteins identified two distinct endotypes that differed based on BALF white blood cell and neutrophil counts and detection of CF pathogens. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic analysis of the CF airway demonstrates a complex environment of proteins and pathways. This work provides evidence that aptamer-based proteomics can differentiate between groups and can determine endotypes within CF.

Pulmonary interstitial glycogenosis: Diagnostic evaluation and clinical course.

OBJECTIVES: We sought to describe the phenotype for patients with P.I.G. including presentation, evaluation, cardiac co-morbidities, high resolution computed tomography findings, and outcomes. METHODS: With institutional review board approval, we performed a retrospective review of patients with biopsy-proven P.I.G. Biopsies, high resolution chest computed tomography, and cardiac evaluations were reviewed and characterized by experts in each field. RESULTS: Sixty-two percent of the patients were male. The median gestational age was 37 weeks (range 27-40). The median age at biopsy was 1.6 months (range 0.3-6 months). Structural heart disease was present in 63% of patients. Pulmonary hypertension (diagnosed by echocardiogram and/or cardiac catheterization) was noted in 38% of patients. Alveolar simplification was present in 79% of patients. Fifty percent of available biopsies revealed patchy disease. An increase in age at biopsy was associated with patchy (vs diffuse) disease. Ninety-two percent of patients were treated with systemic corticosteroids. Median age at last follow-up was 1234 days with a range of 37 days to 15 years. At the time of last follow-up, 12 patients were off all support, eight were on supplemental oxygen, two were mechanically ventilated, one underwent lung transplantation, and one died. CT findings commonly included ground glass opacities (86%) and cystic change (50%). CONCLUSIONS: The P.I.G. phenotype has not been comprehensively described, and poor recognition and misconceptions about P.I.G. persist. P.I.G. is a disease that presents in early infancy, requires significant medical intervention, and frequently is seen in association with alveolar simplification and/or cardiovascular disease. CT findings include ground glass opacities and cysts. Patients should be monitored for pulmonary hypertension. Without life-threatening comorbidities, many patients do well over time, although respiratory symptoms may persist into adolescence.

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.