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.

How we approach pediatric congenital chylous effusions and ascites.

Congenital lymphatic leak may develop in patients with maldeveloped lymphatics and result in life-threatening fluid and electrolyte imbalance, protein deficiency, and immunodeficiency. Rapid diagnosis and therapy are necessary to prevent these complications; however, the field lacks clinical trials to support standardized diagnostic treatment guidelines. We present our current multidisciplinary approach to the diagnosis and management of congenital lymphatic leak including chylous pleural effusions and ascites. Depending on the rate of lymphatic leak, therapy can range from observation with nutritional modifications to surgical and interventional procedures aimed to reduce lymphatic drainage. Modalities to image central and peripheral lymphatics have advanced considerably. Genetic variants and subsequent targets that drive lymphatic maldevelopment have expanded the repertoire of possible pharmacotherapeutic options.

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.

Relationships between Physiologic and Neuropsychologic Functioning after Fontan.

OBJECTIVE: To investigate potential relationships between neuropsychologic functioning and cardiac, gastroenterologic/hepatologic, and pulmonary complications in the single ventricle heart disease (SVHD) post-Fontan population. STUDY DESIGN: Following the initiation of a Fontan Multidisciplinary Clinic, patients with SVHD were evaluated systematically according to a clinical care pathway, and data from multiple subspecialty evaluations were collected prospectively from 2016 to 2019. Biomarkers of cardiology, pulmonary, and hepatology/gastroenterology functioning were abstracted, along with neuropsychologic testing results. Bivariate correlations and regression analyses examined cross-sectional relationships between physiologic predictors and neuropsychologic outcomes. RESULTS: The sample included a cohort of 68 youth with SVHD age 3-19 years, after Fontan palliation. Sleep-disordered breathing was related to poorer visual-motor integration skills (r = -0.33; P < .05) and marginally related to poorer executive functioning (r = -0.33; P = .05). Lower arterial blood oxygen content was related to poorer executive functioning (r = .45; P < .05). Greater atrioventricular valve regurgitation was related to lower parent-rated adaptive functioning (ρ = -0.34; P < .01). These results were maintained in regression analyses controlling for history of stroke and/or seizures. CONCLUSIONS: We demonstrated associations between neuropsychologic functioning and potentially modifiable aspects of physiologic functioning in a prospectively evaluated cohort of patients with SVHD with Fontan physiology. Our findings emphasize the importance of multidisciplinary screening and care after a Fontan procedure and suggest avenues for intervention that may improve patient outcomes and quality of life.

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.

High Altitude Pulmonary Edema in Children: A Single Referral Center Evaluation.

OBJECTIVE: To describe the clinical features of children who presented to Children's Hospital Colorado (CHCO) with high-altitude pulmonary edema (HAPE). STUDY DESIGN: We performed a retrospective chart review in children discharged from CHCO (an elevation of 1668 m) with a clinical diagnosis of HAPE and a chest radiograph consistent with noncardiogenic pulmonary edema. Descriptive statistics were used to describe the demographics, presentations, and treatment strategies. RESULTS: From 2004 to 2014, 50 children presented to CHCO who were found to have a clinical diagnosis of HAPE and a chest radiograph consistent with noncardiogenic pulmonary edema. Most (72%) patients were male, and most (60%) of the children in the study were diagnosed with classic HAPE, 38% with re-entry HAPE, and 2% with high altitude resident pulmonary edema. Elevation at symptom presentation ranged from 1840 to 3536 m. Patients were treated with a variety of medications, including diuretics, steroids, and antibiotics. Four patients were newly diagnosed with structural heart findings: 2 patients with patent foramen ovale and 2 with atrial septal defects. Eleven patients had findings consistent with pulmonary hypertension at the time of echocardiography. CONCLUSIONS: HAPE symptoms may develop below 2500 m, so providers should not rule out HAPE based on elevation alone. Structural heart findings and pulmonary hypertension are associated with HAPE susceptibility and their presence may inform treatment. Inappropriate use of antibiotics and diuretics in children with HAPE suggest that further education of providers is warranted.

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.

Pulmonary toxicity in paediatric patients with relapsed or refractory Hodgkin lymphoma receiving brentuximab vedotin.

Brentuximab vedotin (Bv) is becoming increasingly important in the treatment of Hodgkin lymphoma (HL), with improved outcomes and an overall favourable toxicity profile. However, Bv is associated with severe pulmonary toxicity when combined with bleomycin, suggesting that additive toxicity may be an important consideration. Furthermore, little has been published on tolerability in paediatric patients. We retrospectively evaluated the occurrence of pulmonary toxicity of Bv in 19 paediatric and young adult patients with relapsed or refractory HL. Patient characteristics, baseline health status, treatment regimens including cumulative doses of Bv, bleomycin, gemcitabine, radiation and carmustine, and the occurrence of pulmonary toxicity were collected. Seven (36·8%) of the 19 patients were treated with Bv. The odds of pulmonary toxicity were 4·0-fold higher (95% confidence interval 0·55-29·18) in patients exposed to Bv compared to unexposed patients in univariate analysis (P = 0·17). Similar results were found in multivariable analysis. Pulmonary toxicity occurred frequently in our cohort and was more common in patients who received Bv than in patients who did not receive Bv, although this was not statistically significant. Because patients with HL are exposed to a myriad of therapies with potential for pulmonary toxicity, continuing to evaluate the risk associated with Bv is critical.

Pulmonary Screening in Subjects after the Fontan Procedure.

OBJECTIVES: To review the pulmonary findings of the first 51 patients who presented to our interdisciplinary single-ventricle clinic after undergoing the Fontan procedure. STUDY DESIGN: We performed an Institutional Review Board-approved retrospective review of 51 patients evaluated following the Fontan procedure. Evaluation included history, physical examination, pulmonary function testing, and 6-minute walk. Descriptive statistics were used to describe the population and testing data. RESULTS: Sixty-one percent of the patients had a pulmonary concern raised during the visit. Three patients had plastic bronchitis. Abnormal lung function testing was present in 46% of patients. Two-thirds (66%) of the patients had significant desaturation during the 6-minute walk test. Patients who underwent a fenestrated Fontan procedure and those who underwent unfenestrated Fontan were compared in terms of saturation and 6-minute walk test results. Sleep concerns were present in 45% of the patients. CONCLUSIONS: Pulmonary morbidities are common in patients after Fontan surgery and include plastic bronchitis, abnormal lung function, desaturations with walking, and sleep concerns. Abnormal lung function and obstructive sleep apnea may stress the Fontan circuit and may have implications for cognitive and emotional functioning. A pulmonologist involved in the care of patients after Fontan surgery can assist in screening for comorbidities and recommend interventions.

High-resolution CT findings of pulmonary interstitial glycogenosis.

BACKGROUND: 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. OBJECTIVE: 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. MATERIALS AND METHODS: A 10-year retrospective review was performed to identify pediatric patients <18 years who underwent biopsy and CT within the last 10 years at our institution. The inclusion criteria include patients who had a CT within 3 months of biopsy and pathology-proven pulmonary interstitial glycogenosis CTs that were evaluated by three radiologists using a standardized scoring system. RESULTS: Fifteen patients met inclusion criteria (9 male, 6 female). At the time of initial pre-biopsy CT, ages ranged from 2 weeks to 5 months. Pulmonary symptoms presented at birth in the majority of patients (n=13). Two patients presented in early infancy at 3 months (n=1) and 5 months (n=1). Ground glass opacities were the most common CT finding (n=14), which varied from diffuse to scattered. Cystic lucencies (n=11) were noted in the majority of patients as well. Interlobular septal thickening (n=10) and architectural distortion (n=8) were less common findings. CONCLUSION: The most common CT findings of pulmonary interstitial glycogenosis are ground glass opacities with cystic lucencies. While the imaging findings are distinct from the typical presentation of neuroendocrine hyperplasia of infancy, there is significant overlap of these findings with surfactant dysfunction mutations, entities that also present with respiratory distress in the neonatal period. Therefore, imaging findings in pulmonary interstitial glycogenosis are helpful in guiding the need for genetic testing and/or biopsy.

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.

HRCT findings of childhood follicular bronchiolitis.

BACKGROUND: Follicular bronchiolitis is a lymphoproliferative form of interstitial lung disease (ILD) defined by the presence of peribronchial lymphoid follicles. Follicular bronchiolitis has been associated with viral infection, autoimmune disease and immunodeficiency. The most common clinical manifestation is respiratory distress in infancy followed by a prolonged course with gradual improvement. We found no reports of systematic review of high-resolution computed tomography (HRCT) findings in pediatric follicular bronchiolitis. OBJECTIVE: The purpose of this study was to describe the HRCT findings of follicular bronchiolitis in children and correlate these imaging findings with histopathology. MATERIALS AND METHODS: A 5-year retrospective review of all pathology-proven cases of follicular bronchiolitis was performed. Inclusion criteria were age <18 years and an HRCT within 6 months of lung biopsy. HRCTs were reviewed by three observers and scored using the system previously described by Brody et al. RESULTS: Six patients met the inclusion criteria with age range at HRCT of 7-82 months (median: 39.5 months). Pulmonary nodules (n=6) were the most common HRCT finding followed by focal consolidation (n=5), bronchiectasis (n=4) and lymphadenopathy (n=3). Tree and bud opacities and nodules on CT correlated with interstitial lymphocytic infiltrates and discrete lymphoid follicles on pathology. CONCLUSION: The salient HRCT findings of childhood follicular bronchiolitis are bilateral, lower lung zone predominant pulmonary nodules and bronchiectasis with infantile onset of symptoms. These characteristic HRCT findings help differentiate follicular bronchiolitis from other forms of infantile onset ILD.

Pediatric Pulmonology 2023 year in review: Rare and diffuse lung disease.

The field of pediatric rare and diffuse lung disease continues its maturation as research advances the understanding of diagnosis and treatment of children's interstitial lung disease, noncystic fibrosis bronchiectasis, and primary ciliary dyskinesia. The rarity and breadth of these conditions make them challenging to study, yet we continue to make progress in our understanding of pathophysiology, genotype/phenotype relationships, and treatment. Papers published on these topics in Pediatric Pulmonology and other journals in 2023 describe the power of multicenter cooperation and patient registries, enhance our understanding of pathophysiology and genotype/phenotype relationships, and report progress in treatments. In this review, we hope to increase awareness and knowledge of these conditions and to inspire future research.

Improved tracheostomy-dependent patient outcomes after implementation of the Pediatric Resident Education in Pulmonary (PREP) Boot Camp.

INTRODUCTION: Children with tracheostomies are high risk for morbidity and mortality. Pediatric resident physicians are not routinely taught skills to care for this vulnerable patient population. Few reports link educational interventions to improved patient outcomes. This study evaluates the impact of an intensive educational training program on pediatric residents' observed skills and tracheostomy-dependent patient outcomes. METHODS: Pediatric post-graduate year 2 (PGY2) resident physicians rotating through the inpatient pediatric pulmonology month at Children's Hospital Colorado July 2018-2019 participated in the Pediatric Resident Education in Pulmonary (PREP) Boot Camp, an intensive educational program with an interactive lecture and simulation experience on patients with tracheostomy-dependence. PGY2s who partook in PREP and PGY3s who rotated before PREP initiation were invited to be studied. Primary outcomes included: (1) resident skills assessed by direct observation during simulation encounters and (2) rates of intensive care unit (ICU) transfers in tracheostomy-dependent patients following acute events before and after introduction of PREP. We hypothesized that increased education would enhance resident skills and improve patient outcomes by decreasing the rate of ICU transfers. RESULTS: PGY2 residents retained skills learned during PREP up to 11 months following initial participation, and significantly outperformed their PGY3 counterparts. There was a significant decrease in ICU transfer rate in patients with tracheostomies admitted to the pulmonary team during the 19 months following initiation of PREP. CONCLUSIONS: Enhanced early education may improve resident physicians' ability to care for complex patients with tracheostomies and could improve outcomes in this high-risk population.

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.

Pediatric pulmonology 2021 year in review: Rare and diffuse lung disease.

The field of rare and diffuse pediatric lung disease is experiencing rapid progress as diagnostic and therapeutic options continue to expand. In this annual review, we discuss manuscripts published in Pediatric Pulmonology in 2021 in (1) children's interstitial and diffuse lung disease, (2) congenital airway and lung malformations, and (3) noncystic fibrosis bronchiectasis including primary ciliary dyskinesia. These include case reports, descriptive cohorts, trials of therapies, animal model studies, and review articles. The results are put into the context of other literature in the field. Each furthers the field in important ways, while also highlighting the continued need for further studies.