Detection of Bronchiolitis Obliterans Syndrome after 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 nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH 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. A 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 the detection of post-HSCT BOS in children while also highlighting considerations for the implementation of each recommendation. Further, the document describes important areas for future research.

Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease.

BACKGROUND: Childhood interstitial lung disease (chILD) encompasses a group of rare heterogeneous respiratory conditions associated with significant morbidity and mortality. Reports suggest that many patients diagnosed with chILD continue to have potentially progressive or fibrosing disease into adulthood. Over the last decade, the spectrum of conditions within chILD has widened substantially, with the discovery of novel entities through advanced genetic testing. However, most evidence is often limited to small case series, with reports disseminated across an array of subspecialty, clinical and molecular journals. In particular, the frequency, management and outcome of paediatric pulmonary fibrosis is not well characterised, unlike in adults, where clear diagnosis and treatment guidelines are available. METHODS AND RESULTS: This review assesses the current understanding of pulmonary fibrosis in chILD. Based on registry data, we have provisionally estimated the occurrence of fibrosis in various manifestations of chILD, with 47 different potentially fibrotic chILD entities identified. Published evidence for fibrosis in the spectrum of chILD entities is assessed, and current and future issues in management of pulmonary fibrosis in childhood, continuing into adulthood, are considered. CONCLUSIONS: There is a need for improved knowledge of chILD among pulmonologists to optimise the transition of care from paediatric to adult facilities. Updated evidence-based guidelines are needed that incorporate recommendations for the diagnosis and management of immune-mediated disorders, as well as chILD in older children approaching adulthood.

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.

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.

Stevens-Johnson Syndrome in Children: Consider Monitoring for Bronchiolitis Obliterans.

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.

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

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

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

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

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.

High-resolution computed tomography findings of thyroid transcription factor 1 deficiency (NKX2-1 mutations).

BACKGROUND: 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. OBJECTIVE: To summarize the clinical presentations, pathology and HRCT imaging findings of children with NKX2-1 mutations. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A Comparative Analysis of Pulmonary and Critical Care Medicine Guideline Development Methodologies.

RATIONALE: The Institute of Medicine (IOM) standards for guideline development have had unintended negative consequences. A more efficient approach is desirable. OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: 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). CONCLUSIONS: 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.