Radiation-free and injection-free imaging of the paediatric chest using a magnetic resonance imaging protocol including zero time echo sequence (3D-ZTE).

Computed tomography (CT) is commonly used for paediatric thoracic diseases but involves radiation exposure and often requires intravenous contrast. We evaluated the performance of a magnetic resonance imaging (MRI) protocol including a 3D zero echo time (3D-ZTE) sequence for radiation-free and contrast-free imaging of the paediatric chest. In this prospective, single-centre study, children aged 6-16 years underwent chest CT and MRI within 48 h. CT and MRI exams were independently assessed by two paediatric radiologists. The primary outcome was the image quality of the 3D-ZTE sequence using a scoring system based on the acceptability of the images obtained and visibility of bronchial structures, vessels and fissures. Secondary outcomes included radiologists' ability to detect lung lesions on 3D-ZTE MRI images compared with CT images. Seventy-two children were included. Overall, the image quality achieved with the 3D-ZTE MRI sequence was inferior to that of CT for visualising pulmonary structures, with satisfactory lung image quality observed for 81.9% (59/72) and 100% (72/72) of patients, respectively. However, MRI sensitivity was excellent (above 90%) for the detection of certain lesions such as lung consolidation, proximal mucoid impactions, pulmonary cysts, ground glass opacities and honeycombing. Intermodality agreement (MRI versus CT) was consistently higher for the senior reader compared to the junior reader. CONCLUSION: Despite its overall lower image quality compared to CT, and the additional years of experience required for accurate interpretation, the 3D-ZTE MRI sequence demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications. WHAT IS KNOWN: • Chest radiography and CT are the main imaging modalities for paediatric thoracic diseases but involve radiation exposure and CT often requires IV contrast. • MRI is promising for radiation-free lung imaging in children but faces challenges of low signal-to-noise ratio and motion artefacts. WHAT IS NEW: • An MRI protocol including a 3D zero echo time (ZTE) sequence allows satisfactory visualisation of lung parenchyma in 82% of children. • Despite overall inferior image quality compared to CT, MRI demonstrated excellent sensitivity for several lesions, making it an appropriate imaging method in certain indications.

Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

Long-term evolution of neuroendocrine cell hyperplasia of infancy: the FRENCHI findings.

Only few studies report long-term evolution of patients with neuroendocrine cell hyperplasia of infancy (NEHI). We report data from a 54-patient cohort followed up in the French network for rare respiratory diseases (RespiRare). Demographic characteristics and respiratory and nutritional evolution were collected at the time of the patient's last scheduled visit. The mean duration of follow-up was 68 months (5 months to 18 years). Fifteen patients (27.8%) were considered clinically cured. During follow-up, hospitalizations for wheezy exacerbations were reported in 35 patients (55%), and asthma diagnosed in 20 (37%). Chest CT scan improvement was noted in 25/44 (56.8%). Spirometry showed a persistent obstructive syndrome in 8/27 (29.6%). A sleep disorder was rare (2/36, 5.5%). Oxygen weaning occurred in 28 of the 45 patients initially treated (62.2%) and was age-dependent (35.7% under 2 years, 70.5% between 2 and 6 years, and 100% after 7 years). Oxygen duration was linked to a biopsy-proven diagnosis (p = 0.02) and to the use of a nutritional support (p = 0.003). Corticosteroids were largely prescribed at diagnosis, with no evident respiratory or nutritional effect during follow-up. Among 23 patients with an initial failure to thrive, 12 (52.2%) had no weight recovery. Initial enteral feeding (17/54, 31.5%) was stopped at a mean age of 43 months (3 to 120), with no effect on cure and oxygen liberation at the last visit.  Conclusion: Our results show that NEHI has a globally positive, but unequal, improvement over time. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI. What is Known: • Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose long-term outcome is considered positive from very few studies including heterogeneous populations. What is New: • The 68-month follow-up of our 54-patient cohort showed respiratory/nutritional symptom persistence in 72.2%, oxygen requiring in 34%, and asthma in 37%. When controlled, radiological or functional improvement was noted in 56.8 and 40.7%. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI.

Retrospective evaluation of clinical and molecular data of 148 cases of esophageal atresia.

Developmental abnormalities provide a unique opportunity to seek for the molecular mechanisms underlying human organogenesis. Esophageal development remains incompletely understood and elucidating causes for esophageal atresia (EA) in humans would contribute to achieve a better comprehension. Prenatal detection, syndromic classification, molecular diagnosis, and prognostic factors in EA are challenging. Some syndromes have been described to frequently include EA, such as CHARGE, EFTUD2-mandibulofacial dysostosis, Feingold syndrome, trisomy 18, and Fanconi anemia. However, no molecular diagnosis is made in most cases, including frequent associations, such as Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL). This study evaluates the clinical and genetic test results of 139 neonates and 9 fetuses followed-up at the Necker-Enfants Malades Hospital over a 10-years period. Overall, 52 cases were isolated EA (35%), and 96 were associated with other anomalies (65%). The latter group is divided into three subgroups: EA with a known genomic cause (9/148, 6%); EA with Vertebral-Anal-Cardiac-Tracheo-Esophageal-Renal-Limb defects (VACTERL) or VACTERL/Oculo-Auriculo-Vertebral Dysplasia (VACTERL/OAV) (22/148, 14%); EA with associated malformations including congenital heart defects, duodenal atresia, and diaphragmatic hernia without known associations or syndromes yet described (65/148, 44%). Altogether, the molecular diagnostic rate remains very low and may underlie frequent non-Mendelian genetic models.

French national cohort of neuroendocrine cell hyperplasia of infancy (FRENCHI) study: diagnosis and initial management.

Early diagnosis of neuroendocrine cell hyperplasia of infancy (NEHI) is crucial as, conversely to the other causes of intersititial lung disease, corticosteroids are not recommended. Diagnosis is historically based on lung biopsy (NEHI), but in current practice, a clinical and radiological approach is more and more preferred (NEHI syndrome). This national study aimed to address diagnosis and initial management of patients followed up for a NEHI pattern in pediatric centers for rare lung diseases (RespiRare, France). Data on neonatal and familial events, symptoms at diagnosis, explorations performed and results, and therapeutic management were collected by questionnaire. Fifty-four children were included (boys 63%). The mean onset of symptoms was 3.8 ± 2.6 months. The most frequent symptoms at diagnosis were tachypnea (100%), retraction (79.6%), crackles (66.7%), and hypoxemia (59.3%). The mean NEHI clinical score, evocative when ≥ 7/10, was 7.9 ± 1.4 (76% with a score ≥ 7). All chest CT-scans showed ground glass opacities evolving at least the middle lobe and the lingula. Lung biopsy was performed in 38.9% of the cases and was typical of NEHI in only 52.4%, even when the clinical presentation was typical. Initial treatments were oxygen (83.6%) and more curiously intravenous pulses of steroids (83.3%) and azithromycin (70.2%). CONCLUSION: This national cohort of patients underlines diagnosis difficulties of NEHI. A composite clinical and radiological score should help clinicians for limiting the use of anti-inflammatory drugs. WHAT IS KNOWN: •Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy. WHAT IS NEW: •In this national cohort of 54 patients with a NEHI pattern, diagnosis is mainly based on clinical symptoms and chest CT-scan results. The newly proposed clinical score and, when performed, the lung biopsies are faulted in 25 and 50% of the cases, respectively. •Corticosteroids are widely used. Such results plead for a new composite score to formally diagnose NEHI.

Genome-wide association study of resistance to Mycobacterium tuberculosis infection identifies a locus at 10q26.2 in three distinct populations.

The natural history of tuberculosis (TB) is characterized by a large inter-individual outcome variability after exposure to Mycobacterium tuberculosis. Specifically, some highly exposed individuals remain resistant to M. tuberculosis infection, as inferred by tuberculin skin test (TST) or interferon-gamma release assays (IGRAs). We performed a genome-wide association study of resistance to M. tuberculosis infection in an endemic region of Southern Vietnam. We enrolled household contacts (HHC) of pulmonary TB cases and compared subjects who were negative for both TST and IGRA (n = 185) with infected individuals (n = 353) who were either positive for both TST and IGRA or had a diagnosis of TB. We found a genome-wide significant locus on chromosome 10q26.2 with a cluster of variants associated with strong protection against M. tuberculosis infection (OR = 0.42, 95%CI 0.35-0.49, P = 3.71×10-8, for the genotyped variant rs17155120). The locus was replicated in a French multi-ethnic HHC cohort and a familial admixed cohort from a hyper-endemic area of South Africa, with an overall OR for rs17155120 estimated at 0.50 (95%CI 0.45-0.55, P = 1.26×10-9). The variants are located in intronic regions and upstream of C10orf90, a tumor suppressor gene which encodes an ubiquitin ligase activating the transcription factor p53. In silico analysis showed that the protective alleles were associated with a decreased expression in monocytes of the nearby gene ADAM12 which could lead to an enhanced response of Th17 lymphocytes. Our results reveal a novel locus controlling resistance to M. tuberculosis infection across different populations.

Thoracoscopic surgery for congenital lung malformations: Does previous infection really matter?

BACKGROUND/ PURPOSE: Elective resection of congenital lung malformations (CLMs) is still debatable. The two main risks are malignant transformation and recurrent pulmonary infections. Our study aimed to assess the effect of previous pulmonary infection on the intraoperative and postoperative courses of thoracoscopic surgery for CLMs. METHODS: This is a retrospective study including all thoracoscopic lung resections for CLMs between 2010 and 2019. Ninety patients were included. There was a history of previous pulmonary infection in 28 patients (group A) and no such history in 62 patients (group B). RESULTS: The median age at operation for group A was 20.4 months (IQR:14.9-41.4) versus 15.1 months (IQR:9.7-20.8) in group B (p = 0.006). There were 10 conversions (35.7%) in group A and 8 (12.9%) in group B (p = 0.02). The operative time was significantly shorter in group B (p<0.002). In group A, 32.1% of patients experienced postoperative fever versus 11.3% of group B (p = 0.03), with higher antibiotics requirement (28.6% versus 6.5% respectively, p = 0.007). However, no significant differences were found in terms of postoperative complications (p = 0.99). CONCLUSION: Earlier intervention for CLMs before the development of pulmonary infection carries higher chances for the success of the thoracoscopic approach with shorter operative time and more uneventful postoperative courses.

Geleophysic and acromicric dysplasias: natural history, genotype-phenotype correlations, and management guidelines from 38 cases.

PURPOSE: Geleophysic dysplasia (GD) and acromicric dysplasia (AD) are characterized by short stature, short extremities, and progressive joint limitation. In GD, cardiorespiratory involvement can result in poor prognosis. Dominant variants in the FBN1 and LTBP3 genes are responsible for AD or GD, whereas recessive variants in the ADAMTSL2 gene are responsible for GD only. The aim of this study was to define the natural history of these disorders and to establish genotype-phenotype correlations. METHODS: This monocentric retrospective study was conducted between January 2008 and December 2018 in a pediatric tertiary care center and included patients with AD or GD with identified variants (FBN1, LTBP3, or ADAMTSL2). RESULTS: Twenty-two patients with GD (12 ADAMTSL2, 8 FBN1, 2 LTBP3) and 16 patients with AD (15 FBN1, 1 LTBP3) were included. Early death occurred in eight GD and one AD. Among GD patients, 68% presented with heart valve disease and 25% developed upper airway obstruction. No AD patient developed life-threatening cardiorespiratory issues. A greater proportion of patients with either a FBN1 cysteine variant or ADAMTSL2 variants had a poor outcome. CONCLUSION: GD and AD are progressive multisystemic disorders with life-threatening complications associated with specific genotype. A careful multidisciplinary follow-up is needed.

Robotic lobectomy in children with severe bronchiectasis: A worthwhile new technology.

BACKGROUND/PURPOSE: Lobectomy is required in children affected by non-responsive, symptomatic, localized bronchiectasis, but inflammation makes thoracoscopy challenging. We present the first published series of robotic-assisted pulmonary lobectomy in children with bronchiectasis. METHODS: Retrospective analysis of all consecutive patients who underwent pulmonary lobectomy for severe localized bronchiectasis (2014-2019) via thoracoscopic versus robotic lobectomy. Four 5 mm ports were used for thoracoscopy; a four-arm approach was used for robotic surgery (Da Vinci Surgical Xi System, Intuitive Surgical, California). RESULTS: Eighteen children were operated (robotic resection, n = 7; thoracoscopy, n = 11) with infected congenital pulmonary malformation, primary ciliary dyskinesia, and post-viral infection. There were no conversions to open surgery with robotic surgery, but five with thoracoscopy. Total operative time was significantly longer with robotic versus thoracoscopic surgery (mean 247 ± 50 versus 152 ± 57 min, p = 0.008). There were no significant differences in perioperative complications, length of thoracic drainage, or total length of stay (mean 7 ± 2 versus 8 ± 3 days, respectively). No blood transfusions were required. Two thoracoscopic patients had a type-3 postoperative complication. CONCLUSIONS: Pediatric robotic lung lobectomy is feasible and safe, with excellent visualization and bi-manual hand-wrist dissection - useful properties in difficult cases of infectious pathologies. However, instrumentation dimensions limit use in smaller thoraxes.

Ultrasound detected prenatal hyperechoic lung lesions and concordance with postnatal findings: A common aspect for multiple diagnoses.

OBJECTIVE: Hyperechoic lung lesions are largely detected prenatally but their underlying etiology is still poorly defined. The aim of the study was to determine the concordance between pre and postnatal diagnosis of hyperechoic lung lesions. METHODS: Prenatal ultrasound (US) evaluation was performed by a fetal medicine specialist. Postnatal diagnosis was based on CT-scan. Pre- and postnatal features were retrieved from medical charts. RESULTS: Seventy five patients were included from January 2009 to December 2018. Main prenatal diagnoses were bronchopulmonary sequestrations (BPS) (n = 24%-32%), pulmonary cystic malformations (PCM) (n = 19%-25%), congenital lobar emphysemas (CLE) (n = 15%-20%). Mediastinal shift was observed in 18 cases (24%). The prenatal detection of a systemic arterial supply had a diagnostic accuracy of 90%, while the prenatal detection of a cystic component had a diagnostic accuracy of 76.5%. All 16 neonates with prenatal isolated mediastinal shift were asymptomatic at birth. Seven neonates showed respiratory distress that was not predicted prenatally. CONCLUSIONS: Hyperechoic lung malformations reflect a heterogeneous group of lesions with a good concordance for bronchopulmonary sequestration, but not a satisfying prediction for cystic lesions.

Intravenous pulses of methylprednisolone for infants with severe bronchopulmonary dysplasia and respiratory support after 3 months of age.

INTRODUCTION: There are few published data on the efficacy of systemic corticosteroids in preterm infants with very severe forms of bronchopulmonary dysplasia (BPD), requiring respiratory support after 3 months of age. The aim of this study was to report the use of pulses of methylprednisolone in this population and its consequences on the level of respiratory support. METHODS: This retrospective monocentre study included infants over 3 months of age with severe BPD who received at least one pulse of methylprednisolone (300 mg/m2 /day intravenous [IV] over 3 days). The primary outcome was the evolution of the pulmonary severity score (PSS) during the 3 months preceding and the 5 months following the first pulse. The evolution of the median PSS over time was analyzed using linear segmented regression for interrupted time series. RESULTS: Ten infants were included. During the 3 months preceding the first pulse, a significant increase in the median PSS was observed (p = .01), followed by a progressive decrease during the 5 months after administration of the first pulse (p < .01). Greater effects were observed in more severe infants requiring mechanical or noninvasive ventilation than in those receiving supplemental oxygen through nasal cannula. CONCLUSION: High-dose IV pulses of methylprednisolone were associated with a decrease in the level of respiratory support required by infants with very severe forms of BPD, with a greater effect in those on mechanical or noninvasive ventilation. Further studies are warranted to confirm these preliminary results and assess the long-term safety of this therapy.

Respiratory polygraphy in subjects with bronchopulmonary dysplasia: a retrospective study.

BACKGROUND: Periodic assessment of the need for oxygen supplementation and/or mechanical ventilation in children with severe bronchopulmonary dysplasia (BPD) is crucial. The aim of the study was to analyze the indications and results of respiratory polygraphies (RP) performed in preterm infants with BPD followed at a tertiary university hospital. METHODS: All subjects < 5-year-old with BPD who had a RP between September and February 2018 were included. The indications and results of RP and consequent medical management were analyzed. RESULTS: Fourteen infants (9 females, mean gestational age 27.6±3.3 weeks) underwent a RP at mean age of 26.4±19.4 months. Five subjects were evaluated for the need of long-term respiratory support (RS), 3 started continuous positive airway pressure (CPAP), 2 were weaned from RS. Four subjects underwent RP for suspected obstructive sleep apnea (OSA), one started on CPAP. Central apnea syndrome (CSA) was confirmed in 2 subjects and one was started on non-invasive ventilation. RP allowed safe tracheostomy decannulation in 2 subjects. Finally, RP was normal in one patient who had a brief resolved unexplained event (BRUE). CONCLUSIONS: RP represents an important tool for the evaluation of children with BPD and leads to important therapeutic decisions.

Deletion of Yy1 in mouse lung epithelium unveils molecular mechanisms governing pleuropulmonary blastoma pathogenesis.

Pleuropulmonary blastoma (PPB) is a very rare pediatric lung disease. It can progress from abnormal epithelial cysts to an aggressive sarcoma with poor survival. PPB is difficult to diagnose as it can be confounded with other cystic lung disorders, such as congenital pulmonary airway malformation (CPAM). PPB is associated with mutations in DICER1 that perturb the microRNA (miRNA) profile in lung. How DICER1 and miRNAs act during PPB pathogenesis remains unsolved. Lung epithelial deletion of the Yin Yang1 (Yy1) gene in mice causes a phenotype mimicking the cystic form of PPB and affects the expression of key regulators of lung development. Similar changes in expression were observed in PPB but not in CPAM lung biopsies, revealing a distinctive PPB molecular signature. Deregulation of molecules promoting epithelial-mesenchymal transition (EMT) was detected in PPB specimens, suggesting that EMT might participate in tumor progression. Changes in miRNA expression also occurred in PPB lung biopsies. miR-125a-3p, a candidate to regulate YY1 expression and lung branching, was abnormally highly expressed in PPB samples. Together, these findings support the concept that reduced expression of YY1, due to the abnormal miRNA profile resulting from DICER1 mutations, contributes to PPB development via its impact on the expression of key lung developmental genes.This article has an associated First Person interview with the joint first authors of the paper.

Alveolar proteinosis of genetic origins.

Pulmonary alveolar proteinosis (PAP) is a rare form of chronic interstitial lung disease, characterised by the intra-alveolar accumulation of lipoproteinaceous material. Numerous conditions can lead to its development. Whereas the autoimmune type is the main cause in adults, genetic defects account for a large part of cases in infants and children. Even if associated extra-respiratory signs may guide the clinician during diagnostic work-up, next-generation sequencing panels represent an efficient diagnostic tool. Exome sequencing also allowed the discovery of new variants and genes involved in PAP. The aim of this article is to summarise our current knowledge of genetic causes of PAP.

Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia.

SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 2 (SPOCK2) was previously associated with genetic susceptibility to bronchopulmonary dysplasia in a French population of very preterm neonates. Its expression increases during lung development and is increased after exposure of rat pups to hyperoxia compared with controls bred in room air. To further investigate the role of SPOCK2 during lung development, we designed two mouse models, one that uses a specific anti-Spock2 antibody and one that reproduces the hyperoxia-induced Spock2 expression with a transgenic mouse model resulting in a conditional and lung-targeted overexpression of Spock2. When mice were bred under hyperoxic conditions, treatment with anti-Spock2 antibodies significantly improved alveolarization. Lung overexpression of Spock2 altered alveolar development in pups bred in room air and worsened hyperoxia-induced lesions. Neither treatment with anti-Spock2 antibody nor overexpression of Spock2 was associated with abnormal activation of matrix metalloproteinase-2. These two models did not alter the expression of known players in alveolar development. This study brings strong arguments for the deleterious role of SPOCK2 on lung alveolar development especially after lung injury, suggesting its role in bronchopulmonary dysplasia susceptibility. These effects are not mediated by a deregulation in metalloproteases activity and in expression of factors essential to normal alveolarization. The balance between types 1 and 2 epithelial alveolar cells may be involved.

Congenital cystic adenomatoid malformations of the lung: an epithelial transcriptomic approach.

BACKGROUND: The pathophysiology of congenital cystic adenomatoid malformations (CCAM) of the lung remains poorly understood. AIM: This study aimed to identify more precisely the molecular mechanisms limited to a compartment of lung tissue, through a transcriptomic analysis of the epithelium of macrocystic forms. METHODS: Tissue fragments displaying CCAM were obtained during planned surgical resections. Epithelial mRNA was obtained from cystic and normal areas after laser capture microdissection (LCM). Transcriptomic analyses were performed and the results were confirmed by RT-PCR and immunohistochemistry in independent samples. RESULTS: After controlling for RNA quality, we analysed the transcriptomes of six cystic areas and five control areas. In total, 393 transcripts were differentially expressed in the epithelium, between CCAM and control areas. The most highly redundant genes involved in biological functions and signalling pathways differentially expressed between CCAM and control epithelium included TGFB2, TGFBR1, and MAP 2 K1. These genes were considered particularly relevant as they have been implicated in branching morphogenesis. RT-qPCR analysis confirmed in independent samples that TGFBR1 was more strongly expressed in CCAM than in control tissues (p < 0.03). Immunohistochemistry analysis showed TGFBR1 (p = 0.0007) and TGFB2 (p < 0.02) levels to be significantly higher in the epithelium of CCAM than in that of control tissues. CONCLUSIONS: This compartmentalised transcriptomic analysis of the epithelium of macrocystic lung malformations identified a dysregulation of TGFB signalling at the mRNA and protein levels, suggesting a possible role of this pathway in CCAM pathogenesis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01732185.

Exome sequencing of extreme phenotypes in bronchopulmonary dysplasia.

Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants with growing evidence that genetic factors contribute largely to moderate and severe cases. We assessed by exome sequencing if rare genetic variants could account for extremely severe phenotypes. We selected 6 infants born very preterm with severe bronchopulmonary dysplasia and 8 very preterm born controls for exome sequencing. We filtered whole exome sequencing results to include only rare variants and selected variants and/or genes with variants that were present in at least 2 cases and absent in controls. We selected variants, all heterozygous, in 9 candidate genes, 7 with a putative role in lung development and 2 that displayed 3 variations in 3 different cases, independently of their potential role in lung development. Sequencing of 5 other severe cases for these variants did not replicate our results.Conclusion: In selected preterm born infants with severe bronchopulmonary dysplasia and controls, we failed to find any rare variant shared by several infants with an extremely severe phenotype. Our results are not consistent with the role of rare causative variants in bronchopulmonary dysplasia's development and argue for the highly polygenic nature of susceptibility of this disorder.What is Known:• Bronchopulmonary dysplasia is a multifactorial disease resulting from complex environmental and genetic interactions occurring in an immature lung.• It is not known whether rare genetic variants in coding regions could account for extreme phenotypes of the disease.What is New:• In a group of infants with an extreme phenotype of bronchopulmonary dysplasia and in comparison to controls, no common genetic variants were found, nor did variants that were select in other exome studies in this setting.• These results argue for the highly polygenic nature of susceptibility of bronchopulmonary dysplasia.

Educational and health outcomes associated with bronchopulmonary dysplasia in 15-year-olds born preterm.

INTRODUCTION: To evaluate the consequences of bronchopulmonary dysplasia (BPD) on academic outcomes and healthcare use in adolescents born very preterm. METHODS: This cohort study included 15-year-old adolescents born very preterm (< 32 weeks) between 2011 and 2013, with and without BPD, and controls born full term. Data regarding academic performance, current medical follow-up, and family characteristics were collected. Multivariate logistic regression was used to quantify relationships between academic outcomes and BPD. RESULTS: From the 1341 children included in the initial cohort, 985 adolescents were eligible and 351 included (55 preterms with a history of BPD, 249 without, and 47 controls). Among adolescents born very preterm, a history of BPD was associated with a higher risk to attend a school for children with special needs (p < 0.05) and to have repeated a grade (p = 0.01). It was also associated with an increased number of medical and paramedical consultations. A history of BPD was not associated with the parents' employment status, family structure, or the presence of younger siblings. CONCLUSION: This study highlights that a history of BPD is associated with poorer academic outcomes and high healthcare use in adolescence.

Isolation of Nontuberculous Mycobacteria in Southeast Asian and African Human Immunodeficiency Virus-infected Children With Suspected Tuberculosis.

We enrolled 427 human immunodeficiency virus-infected children (median age, 7.3 years), 59.2% severely immunodeficient, with suspected tuberculosis in Southeast Asian and African settings. Nontuberculous mycobacteria were isolated in 46 children (10.8%); 45.7% of isolates were Mycobacterium avium complex. Southeast Asian origin, age 5-9 years, and severe immunodeficiency were independently associated with nontuberculous mycobacteria isolation. CLINICAL TRIALS REGISTRATION: NCT01331811.