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.

Long-term outcomes of congenital diaphragmatic hernia: A single institution experience.

BACKGROUND/PURPOSE: As survival rates for patients with congenital diaphragmatic hernia (CDH) increase, long-term sequelae become increasingly prevalent. We present the outcomes of patients who underwent CDH repair at our institution and discuss standardization of follow-up care in our long-term multidisciplinary follow-up clinic. METHODS: A retrospective review of patients followed in multidisciplinary clinic after CDH repair at our institution from January 1, 2005 to December 1, 2020. RESULTS: A total of 193 patients met inclusion criteria, 73 females (37.8%) and 120 males (62.2%). Left-sided defects were most common (75.7%), followed by right-sided defects (20.7%). Median age at repair was 4 days (IQR 3-6) and 59.6% of all defects required patch repair. Median length of stay was 29 days (IQR 16.8-50.0). Median length of follow up was 49 months (IQR 17.8-95.3) with 25 patients followed for more than 12 years. Long-term outcomes included gastroesophageal reflux disease (42.0%), diaphragmatic hernia recurrence (10.9%), asthma (23.6%), neurodevelopmental delay (28.6%), attention deficit hyperactivity disorder (7.3%), autism (1.6%), chest wall deformity (15.5%), scoliosis (11.4%), and inguinal hernia (6.7%). CONCLUSION: As survival of patients with CDH improves, long-term care must be continuously studied and fine-tuned to ensure appropriate surveillance and optimization of long-term outcomes.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Validation of a Questionnaire to Identify Respiratory Tract Infections in Children With Sickle Cell Disease.

BACKGROUND: No validated questionnaires have been published that are specific for identifying respiratory infections in children with sickle cell disease (SCD). METHODS: A questionnaire was developed that included 6 respiratory symptoms (difficulty breathing, wheezing, fever, cough, runny or stuffy nose, and sore throat) to identify respiratory events for a clinical trial. The questionnaire results were compared with identification of viral respiratory pathogens from nasal samples by reverse transcriptase polymerase chain reaction. RESULTS: Eighty questionnaire responses (40 with symptom/s and 40 without) paired with isolation of viral respiratory pathogen from nasal samples were obtained from 53 children with SCD, ages 4 to 18 years over 2 separate periods in different seasons. The questionnaire yielded a sensitivity of 82%, specificity of 72% with an overall accuracy of 76%. The kappa value was 0.53, indicating moderate agreement, and the Fleiss' kappa test statistic was 4.77 with P<0.001, indicating that agreement between the 2 methods was not by chance. CONCLUSION: These results provide evidence for validity of this 6-symptom respiratory questionnaire in identification of respiratory viral infections for use in SCD-related research.

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.

Airway Inflammation and Lung Function in Sickle Cell Disease.

Rationale: Asthma is a common comorbid condition in sickle cell disease (SCD). However, obstructive lung disease is prevalent in SCD, independent of a diagnosis of asthma. It is speculated that the heightened state of inflammation in SCD, involving pathways distinct from allergic asthma, may underlie the SCD-specific obstructive disease. Objective: The objective of the study was to compare airway and systemic inflammatory markers between SCD patients with pulmonary manifestations and patients with allergic asthma, and correlate the discriminating inflammatory markers with clinical measures of pulmonary disease. Materials and Methods: In a pilot translational study conducted at the Children's Hospital at Montefiore, 15 patients with SCD, and history of asthma, airway obstruction, or airway hyper-reactivity, and 15 control patients with allergic asthma 6-21 years of age were recruited. Inflammatory markers, including peripheral blood T helper cell subsets, serum and exhaled breath condensate (EBC) cytokines and chemokines of the Th-1/Th-17, Th-2, and monocytic pathways, and serum cysteinyl leukotrienes B4 (LTB4), were quantified, compared between the study groups, and correlated with atopic sensitization, pulmonary function tests, and markers of hemolysis. Results: White blood cells (P < 0.05) and monocytes (P < 0.001) were elevated in the SCD group, while atopic characteristics were higher in the control asthma group. Tumor necrosis factor-alpha (P < 0.01), interferon gamma inducible protein (IP)-10 (P < 0.05), and interleukin-4 (P < 0.01) in serum and monocyte chemotactic protein (MCP)-1 in EBC were higher in the SCD group (P ≤ 0.05). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) in patients with SCD inversely correlated with serum IP-10 and LTB4 levels. Conclusions: Compared with atopic asthmatic patients, inflammatory markers involving Th-1, Th-2, and monocytic pathways were higher in the SCD group, among which Th-1 measures correlated with pulmonary function deficits.

Sleep and Breathing the First Night After Adenotonsillectomy in Obese Children With Obstructive Sleep Apnea.

STUDY OBJECTIVES: There are few studies measuring postoperative respiratory complications in obese children with obstructive sleep apnea (OSA) undergoing adenotonsillectomy (AT). These complications are further compounded by perioperative medications. Our objective was to study obese children with OSA for their respiratory characteristics and sleep architecture on the night of AT. METHODS: This was a prospective study at a tertiary pediatric hospital between January 2009-February 2012. Twenty obese children between 8-17 years of age with OSA and adenotonsillar hypertrophy were recruited. Patients underwent baseline polysomnography (PSG) and AT with or without additional debulking procedures, followed by a second PSG on the night of surgery. Demographic and clinical variables, surgical details, perioperative anesthetics and analgesics, and PSG respiratory and sleep architecture parameters were recorded. Statistical tests included Pearson correlation coefficient for correlation between continuous variables and chi-square and Wilcoxon rank-sum tests for differences between groups. RESULTS: Baseline PSG showed OSA with mean obstructive apnea-hypopnea index (oAHI) 27.1 ± 22.9, SpO2 nadir 80.1 ± 7.9%, and sleep fragmentation-arousal index 25.5 ± 22.0. Postoperatively, 85% of patients had abnormal sleep studies similar to baseline, with postoperative oAHI 27.0 ± 34.3 (P = .204), SpO2 nadir, 82.0 ± 8.7% (P = .462), and arousal index, 24.3 ± 24.0 (P = .295). Sleep architecture was abnormal after surgery, showing a significant decrease in REM sleep (P = .003), and a corresponding increase in N2 (P = .017). CONCLUSIONS: Obese children undergoing AT for OSA are at increased risk for residual OSA on the night of surgery. Special considerations should be taken for postoperative monitoring and treatment of these children. COMMENTARY: A commentary on this article appears in this issue on page 775.

Pulmonary Alveolar Proteinosis in Association with Secondary Hemophagocytic Lymphohistiocytosis.

Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease in the pediatric population. There are currently few cases documenting hemophagocytic lymphohistiocytosis as a cause for secondary PAP. We describe an ex-preterm child with secondary hemophagocytic lymphohistiocytosis, complicated by PAP and hypoxemic respiratory failure.

Pilot Feasibility Study of Comprehensive Pulmonary Evaluation Following Lung Radiation Therapy.

BACKGROUND: Symptoms of pulmonary injury following lung irradiation may not manifest clinically in childhood. We performed comprehensive pulmonary evaluation of patients who had received lung irradiation for treatment of cancer. MATERIALS AND METHODS: Patients underwent a focused history and physical examination, computed tomography of the chest, pulmonary function test, and cardiopulmonary exercise stress test (CPET). Health-related Quality of Life was also measured. RESULTS: Fourteen patients were recruited with median age of 16 years (range, 6 to 21 y). Median time from pulmonary radiation to testing was 5 years (range, 2 to 11 y). Five patients reported pulmonary symptoms. Twelve patients (85.7%) had at least 1 pulmonary function test abnormality. Nine patients demonstrated CPET abnormalities; 7 patients had abnormal pulmonary limitation to exercise, and 5 patients had exercise-induced bronchospasm. The pulmonary limitations included abnormal ventilatory response to exercise in 5 patients, and gas exchange abnormalities in 4 patients. Chest computed tomography demonstrated grade 1-2 radiation-induced lung changes in 4 patients, and grade 3 abnormalities in 1 patient. CONCLUSIONS: Significant pulmonary dysfunction was observed in childhood cancer survivors who had received lung irradiation. CPET is feasible in childhood cancer survivors and can be valuable for assessment of pulmonary function and exercise capacity.

Correlation of pulmonary function abnormalities with dose volume histograms in children treated with lung irradiation.

BACKGROUND: There is limited data on pulmonary function test (PFT) abnormalities in children treated with modern irradiation techniques. PFT abnormalities have not been correlated with the dose and volume of irradiation. METHODS: A retrospective chart review of PFTs and clinical outcomes in children who received radiation therapy (RT) at Children's Hospital Los Angeles between 1999 and 2009 was performed. Radiation dose distribution to normal lung tissue was calculated. RESULTS: Forty-nine patients had PFTs available post-RT at a median time of 2.91 years (range, 0.01-8.28) from irradiation. Sixty-seven percent of patients had at least one PFT abnormality on their last available study. The most common abnormality was obstructive lung disease (24%) followed by hyperinflation (20%). Thoracic surgery prior to RT increased the odds of an abnormal FEV1, RV/TLC, and obstructive disease. The sex of the patient, age at the time of irradiation, and time of the PFT after irradiation did not have a significant association with abnormalities. The mean lung dose, maximum lung dose, and prescribed dose of radiation were significantly associated with the development of PFT abnormalities. The odds of developing an abnormal PFT increased with increase in the minimum threshold dose (V(dose)) of radiation, mostly above V(20). CONCLUSION: PFT abnormalities are common even when modern radiation techniques are used. A significant correlation between radiation parameters and PFT abnormalities was noted.

Pulmonary function abnormalities in childhood cancer survivors treated with bleomycin.

BACKGROUND: Bleomycin is associated with pulmonary toxic side effects including pneumonitis and pulmonary fibrosis. We evaluated the prevalence of long-term pulmonary function abnormalities in children receiving bleomycin therapy in the context of current chemotherapeutic regimens. METHODS: A retrospective review of patients who received bleomycin between January 1999 and December 2011 was conducted. Abnormalities in the most recent pulmonary function test (PFT) at least 1 year after diagnosis were analyzed. RESULTS: Two-hundred and seven patients had received bleomycin. The results of PFT performed at least 1 year from diagnosis were available for 80 patients. Median time of follow up was 3.9 years (range 1.1-11.76 years). Median cumulative dose of bleomycin was 65 IU/m(2) (range 10-120). The most common diagnoses were Hodgkin lymphoma and germ cell tumor. At least one pulmonary function abnormality was present in 42 (52.5%) patients. When classified in groups, 22.5% patients had obstructive lung disease, 7.5% had restrictive lung disease, 28.8% had hyperinflation and 14% of patients had non-uniform distribution of ventilation. Non-Hispanic patients (OR 2.81) and children younger than 8 years (OR 4.14) had higher odds of having an abnormal PFT parameter. Very few patients had pulmonary symptoms. CONCLUSIONS: More than half the patients who received bleomycin had subclinical pulmonary dysfunction as evidenced by abnormalities in pulmonary function tests, although the incidence of clinical symptoms was low.

Vallecular cyst as a cause of obstructive sleep apnea in an infant.

A 3-month-old baby was diagnosed with obstructive sleep apnea (OSA) on polysomnography (PSG) with a high apnea hypopnea index (AHI). On further investigations he was found to have a vallecular cyst that was successfully treated. We discuss the clinical presentation of vallecular cysts and the importance of polysomnography in identifying this rare condition.

Isolated renal relapse in acute lymphoblastic leukemia.

Current therapy for acute lymphoblastic leukemia have resulted in cure rates over 80%. Relapses occur most frequently in the bone marrow. We report the unusual case of a young man who presented with an isolated kidney relapse after maintaining remission from acute lymphoblastic leukemia for over 6 years. Sites of extramedullary relapse and a review of the literature are discussed.