COBRAPed cohort: Do sensitization patterns differentiate children with severe asthma from those with a milder disease?

BACKGROUND: It is unclear whether sensitization patterns differentiate children with severe recurrent wheeze (SRW)/severe asthma (SA) from those with non-severe recurrent wheeze (NSRW)/non-severe asthma (NSA). Our objective was to determine whether sensitization patterns can discriminate between children from the French COBRAPed cohort with NSRW/NSA and those with SRW/SA. METHODS: IgE to 112 components (c-sIgE) (ImmunoCAP® ISAC) were analyzed in 125 preschools (3-6 years) and 170 school-age children (7-12 years). Supervised analyses and clustering methods were applied to identify patterns of sensitization among children with positive c-sIgE. RESULTS: We observed c-sIgE sensitization in 51% of preschool and 75% of school-age children. Sensitization to house dust mite (HDM) components was more frequent among NSRW than SRW (53% vs. 24%, p < .01). Sensitization to non-specific lipid transfer protein (nsLTP) components was more frequent among SA than NSA (16% vs. 4%, p < .01) and associated with an FEV1/FVC < -1.64 z-score. Among sensitized children, seven clusters with varying patterns were identified. The two broader clusters identified in each age group were characterized by "few sensitizations, mainly to HDM." One cluster (n = 4) with "multiple sensitizations, mainly to grass pollen, HDM, PR-10, and nsLTP" was associated with SA in school-age children. CONCLUSIONS: Although children with wheeze/asthma display frequent occurrences and high levels of sensitization, sensitization patterns did not provide strong signals to discriminate children with severe disease from those with milder disease. These results suggest that the severity of wheeze/asthma may depend on both IgE- and non-IgE-mediated mechanisms.

Untargeted metabolomic profiling in children identifies novel pathways in asthma and atopy.

BACKGROUND: Asthma and other atopic disorders can present with varying clinical phenotypes marked by differential metabolomic manifestations and enriched biological pathways. OBJECTIVE: We sought to identify these unique metabolomic profiles in atopy and asthma. METHODS: We analyzed baseline nonfasted plasma samples from a large multisite pediatric population of 470 children aged <13 years from 3 different sites in the United States and France. Atopy positivity (At+) was defined as skin prick test result of ≥3 mm and/or specific IgE ≥ 0.35 IU/mL and/or total IgE ≥ 173 IU/mL. Asthma positivity (As+) was based on physician diagnosis. The cohort was divided into 4 groups of varying combinations of asthma and atopy, and 6 pairwise analyses were conducted to best assess the differential metabolomic profiles between groups. RESULTS: Two hundred ten children were classified as At-As-, 42 as At+As-, 74 as At-As+, and 144 as At+As+. Untargeted global metabolomic profiles were generated through ultra-high-performance liquid chromatography-tandem mass spectroscopy. We applied 2 independent machine learning classifiers and short-listed 362 metabolites as discriminant features. Our analysis showed the most diverse metabolomic profile in the At+As+/At-As- comparison, followed by the At-As+/At-As- comparison, indicating that asthma is the most discriminant condition associated with metabolomic changes. At+As+ metabolomic profiles were characterized by higher levels of bile acids, sphingolipids, and phospholipids, and lower levels of polyamine, tryptophan, and gamma-glutamyl amino acids. CONCLUSION: The At+As+ phenotype displays a distinct metabolomic profile suggesting underlying mechanisms such as modulation of host-pathogen and gut microbiota interactions, epigenetic changes in T-cell differentiation, and lower antioxidant properties of the airway epithelium.

Fetal Lung Volume Appears to Predict Respiratory Morbidity in Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and respiratory morbidity. To assess whether respiratory morbidity during the first 2 years of life in infants with left-sided CDH is associated with fetal lung volume (FLV) evaluated by the observed-to-expected FLV ratio (o/e FLV) on antenatal magnetic resonance imaging (MRI). In this retrospective study, o/e FLV measures were collected. Respiratory morbidity in the first 2 years of life was studied according to two endpoints: treatment with inhaled corticosteroids for >3 consecutive months and hospitalization for any acute respiratory disease. The primary outcome was a favorable progression defined by the absence of either endpoint. Forty-seven patients were included. The median o/e FLV was 39% (interquartile range, 33-49). Sixteen (34%) infants were treated with inhaled corticosteroids and 13 (28%) were hospitalized. The most efficient threshold for a favorable outcome was an o/e FLV ≥ 44% with a sensitivity of 57%, specificity of 79%, negative predictive value of 56%, and positive predictive value of 80%. An o/e FLV ≥ 44% was associated with a favorable outcome in 80% of cases. These data suggest that lung volume measurement on fetal MRI may help to identify children at lower respiratory risk and improve information during pregnancy, patient characterization, decisions about treatment strategy and research, and personalized follow-up.

Primary ciliary dyskinesia and fungal infections: Two cases of allergic bronchopulmonary aspergillosis in children.

Primary ciliary dyskinesia (PCD) is a rare inherited disease that affects the movement of the respiratory cilia. The main clinical manifestations are chronic upper and lower respiratory symptoms and recurrent lung infections, particularly bacterial and viral infections. Fungal infections are not usually associated with PCD. Allergic bronchopulmonary aspergillosis (ABPA) is a rare complex immune hypersensitivity reaction to Aspergillus fumigatus reported in patients with asthma and cystic fibrosis. Only three cases of ABPA associated with adult PCD have been described in the literature. Herein, we reported on two cases of ABPA in two boys aged 10 and 13 years with PCD. Both had severe lung disease and chronic Pseudomonas aeruginosa infections. One patient was diagnosed according to the typical clinical features of ABPA, while the other was diagnosed during a scheduled visit with no clinical changes but worsening pulmonary function and radiologic anomalies. The diagnosis of ABPA was confirmed in the two patients who then improved after receiving specific treatment. These two cases were the first to describe the occurrence of ABPA in children with PCD. We recommend that physicians involved in the management of children with PCD be aware of this potential complication.

Esophageal Atresia and Respiratory Morbidity.

BACKGROUND AND OBJECTIVES: Respiratory diseases are common in children with esophageal atresia (EA), leading to increased morbidity and mortality in the first year. The primary study objective was to identify the factors associated with readmissions for respiratory causes in the first year in EA children. METHODS: A population-based study. We included all children born between 2008 and 2016 with available data and analyzed factors at birth and 1 year follow-up. Factors with a P value <.10 in univariate analyses were retained in logistic regression models. RESULTS: Among 1460 patients born with EA, 97 (7%) were deceased before the age of 1 year, and follow-up data were available for 1287 patients, who constituted our study population. EAs were Ladd classification type III or IV in 89%, preterm birth was observed in 38%, and associated malformations were observed in 52%. Collectively, 61% were readmitted after initial discharge in the first year, 31% for a respiratory cause. Among these, respiratory infections occurred in 64%, and 35% received a respiratory treatment. In logistic regression models, factors associated with readmission for a respiratory cause were recurrence of tracheoesophageal fistula, aortopexy, antireflux surgery, and tube feeding; factors associated with respiratory treatment were male sex and laryngeal cleft. CONCLUSIONS: Respiratory morbidity in the first year after EA repair is frequent, accounting for >50% of readmissions. Identifying high risk groups of EA patients (ie, those with chronic aspiration, anomalies of the respiratory tract, and need for tube feeding) may guide follow-up strategies.

Food Allergies: An Example of Translational Research.

Food allergies have been rising in prevalence since the 1990s, imposing substantial physical, psychosocial, and economic burdens on affected patients and their families. Until recently, the only therapy for food allergy was strict avoidance of the allergenic food. Recent advances in translational studies, however, have led to insights into allergic sensitization and tolerance. This article provides an overview of cutting-edge research into food allergy and immune tolerance mechanisms utilizing mouse models, human studies, and systems biology approaches. This research is being translated and implemented in the clinical setting to improve diagnosis and reduce food allergy's public health burden.

Factors Associated with Asthma Severity in Children: Data from the French COBRAPed Cohort.

BACKGROUND: Severe asthma (SA) in children is a complex, heterogeneous disease, associated with a considerable burden. However, factors influencing asthma severity are poorly described and may differ according to age. OBJECTIVE: To determine whether factors associated with asthma severity differ between preschoolers with severe recurrent wheeze (SRW) and school-age children with SA. METHODS: Data from the French multicenter prospective observational cohort of preschool (3-6 years) children with SRW and nonsevere recurrent wheeze (NSRW) and school-age (7-11 years) children with SA and nonsevere asthma (NSA) (Pediatric Cohort of Bronchial Obstruction and Asthma) were analyzed. RESULTS: A total of 131 preschool children (92 SRW and 49 NSRW) and 207 school-age children (92 SA and 115 NSA) were included. In both univariable and multivariable analysis, SRW was associated with second-hand smoke exposure (multivariable analysis: odds ratio [95% CI], 29.8 [3.57-3910]) and exposure to mold/dampness at home (multivariable analysis: odds ratio [95% CI], 4.22 [1.25-18.2]) compared with NSRW. At school-age, history of atopic dermatitis and food allergy was more frequent in children with SA than in those with NSA. Multivariable analysis confirmed that SA was associated with a history of food allergy (odds ratio [95% CI], 5.01 [2.23-11.9]). CONCLUSIONS: Our data suggest that factors influencing asthma severity may differ according to age. In preschool children with SRW, second-hand smoke and exposure to mold are predominant, whereas associated allergic disorders are mainly involved in SA at school-age.

Quality of life was similar in children with congenital diaphragmatic hernia and oesophageal atresia and related to respiratory morbidity.

AIM: To assess quality of life (QoL) in children with congenital diaphragmatic hernia (CDH) and to compare it with oesophageal atresia (OA). METHODS: A cross-sectional study in CDH children (≥7 years) was conducted in Lille University Hospital, France, from January 2013 to April 2014. History, lung function (rest, exercise) and Pediatric Quality of Life Inventory questionnaires (PedsQoL 4.0) were collected. Data of OA children were previously published. RESULTS: Fifty-four CDH patients (male: 53%, median age: 11 years, IQR 9-14) were compared to 54 OA patients (male: 61%, median age: 13 years, IQR: 11-15). CDH children had significantly more frequent history of pneumonia (30% vs 13%), exercise limitation (54% vs 35%) and chest deformity (39% vs 11%); 46% had an obstructive pattern and 66% an abnormal cardiopulmonary exercise test. The median PedsQoL total score in children was 81 (IQR 73-90) in CDH and 81 (IQR 72-91) in OA (P = .8). In CDH, duration of neonatal oxygen therapy, hospitalisation for respiratory disease, exercise limitation, inhaled corticosteroids treatment, chest deformity, abnormal cardiopulmonary exercise test and lower forced expiratory volume in one second were significantly associated with lower QoL scores. CONCLUSION: PedsQoL scores remained satisfactory in CDH children with CDH, with no difference compared to OA. Patients with respiratory morbidity and lung function impairment, who displayed lower scores, should be identified in order to optimise their management in reference centres.

Childhood asthma heterogeneity at the era of precision medicine: Modulating the immune response or the microbiota for the management of asthma attack.

Exacerbations are a main characteristic of asthma. In childhood, the risk is increasing with severity. Exacerbations are a strong phenotypic marker, particularly of severe and therapy-resistant asthma. These early-life events may influence the evolution and be involved in lung function decline. In children, asthma attacks are facilitated by exposure to allergens and pollutants, but are mainly triggered by microbial agents. Multiple studies have assessed immune responses to viruses, and to a lesser extend bacteria, during asthma exacerbation. Research has identified impairment of innate immune responses in children, related to altered pathogen recognition, interferon release, or anti-viral response. Influence of this host-microbiota dialog on the adaptive immune response may be crucial, leading to the development of biased T helper (Th)2 inflammation. These dynamic interactions may impact the presentations of asthma attacks, and have long-term consequences. The aim of this review is to synthesize studies exploring immune mechanisms impairment against viruses and bacteria promoting asthma attacks in children. The potential influence of the nature of infectious agents and/or preexisting microbiota on the development of exacerbation is also addressed. We then discuss our understanding of how these diverse host-microbiota interactions in children may account for the heterogeneity of endotypes and clinical presentations. Finally, improving the knowledge of the pathophysiological processes induced by infections has led to offer new opportunities for the development of preventive or curative therapeutics for acute asthma. A better definition of asthma endotypes associated with precision medicine might lead to substantial progress in the management of severe childhood asthma.

Severe preschool asthmatics have altered cytokine and anti-viral responses during exacerbation.

BACKGROUND: Preschool asthma/recurrent wheeze is a heterogeneous condition. Different clinical phenotypes have been described, including episodic viral wheeze (EVW), severe intermittent wheeze (SIW), and multiple-trigger wheeze (MTW). OBJECTIVE: To compare clinical, viral, and inflammatory/immune profiling at exacerbation between MTW, SIW, and EVW phenotypes. METHODS: Multicenter, prospective, observational cohort (VIRASTHMA-2). Children (1-5 years) with preschool asthma were enrolled during hospitalization for a severe exacerbation. History and anamnestic data, plasma, and nasal samples were collected at exacerbation (T1) and at steady state, 8 weeks later (T2), and sputum samples were collected at T1. RESULTS: A total of 147 children were enrolled, 37 (25%) had SIW, 18 (12.2%) EVW, and 92 (63%) MTW. They were atopic (47%), exposed to mold (22%) and cigarette smoke (50%), and prone to exacerbations (≥2 in the previous year in 70%). At exacerbation, at least one virus was isolated in 94% and rhinovirus in 75%, with no difference between phenotypes. Children with MTW and SIW phenotypes displayed lower plasma concentrations of IFN-γ (P = .002), IL-5 (P = .020), TNF-α (P = .038), IL-10 (P = .002), IFN-ß (P = .036), and CXCL10 (P = .006) and lower levels of IFN-γ (P = .047) in sputum at exacerbation than children with EVW. At T2, they also displayed lower plasma levels of IFN-γ (P = .045) and CXCL10 (P = .013). CONCLUSION: Among preschool asthmatic children, MTW and SIW, prone to exacerbations, display lower systemic levels of Th1, Th2 cytokines, pro- and anti-inflammatory cytokines, and antiviral responses during severe virus-induced exacerbation.

Bronchopulmonary and vascular anomalies are frequent in children with oesophageal atresia.

AIM: Oesophageal atresia is frequently associated with other malformations, and our aim was to use computed tomography (CT) to explore intrathoracic malformations in patients with this condition. METHOD: This was retrospective study of children aged 0-16 with oesophageal atresia who were born in 1996-2013 and followed up at the French reference centre for rare oesophageal diseases at the University of Lille. Computed tomography scans were available for 48 of the 234 patients during follow-up visits, and these were reviewed by a thoracic radiologist. RESULTS: More than two-thirds of the scans were performed to explore persistent respiratory symptoms. We found that six patients had a pulmonary malformations: four lobar agenesis, one right pulmonary aplasia and one congenital cystic adenomatoid malformation. Computed tomography enabled us to diagnose unexpected thoracic malformations in 16 patients: four lobar agenesis, six arteria lusoria, five persistent left superior vena cava and one partial anomalous pulmonary venous return. It also confirmed the diagnoses of suspected malformations in five patients: one congenital cystic adenomatoid malformation, one pulmonary hypoplasia, two right-sided aortic arches and one communicating bronchopulmonary foregut malformation. CONCLUSION: Intrathoracic anomalies were frequently associated with oesophageal atresia, and contrast-enhanced chest CT scans should be performed on patients with persistent respiratory symptoms.