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.

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.

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.

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.

New perspectives of childhood asthma treatment with biologics.

Asthma is no longer considered as a single disease but rather as a syndrome corresponding to different entities and pathophysiologic pathways. A targeted strategy is part of personalized medicine which aims to better define each patient's phenotype and endotype so as to prescribe the most suitable treatment at an individual level. Omalizumab and, more recently, mepolizumab are the first biologics approved for children (6-18 years). Omalizumab is now widely used to treat severe allergic asthma in children and is highly effective for asthma exacerbations and asthma control with a good safety profile. Moreover, several other drugs-lebrikizumab, dupilumab, tezepelumab, mepolizumab, reslizumab, benralizumab-are used or are being studied in both teenagers and adults and could benefit younger children in the near future. We hypothesize that defining the asthma phenotype/endotype regarding the type and intensity of inflammation, association with allergic or non-allergic comorbidities, and airway remodeling should contribute to the choice of a specific biologic. Pediatric specificities have to be addressed and validated by studies in children. Long-term effectiveness and particularly the impact on the natural history of asthma should also be investigated. Severe asthma in children is a complex disease, and patients have to be referred to a specialized pediatric asthma center to confirm diagnosis and initiate the best treatment strategy which could include biologics while taking into account their high cost.

Anaphylaxis admissions in pediatric intensive care units: Follow-up and risk of recurrence.

BACKGROUND: Data about the risk of anaphylaxis recurrence in children are lacking. We assessed anaphylaxis recurrence and medical follow-up in a cohort of children previously hospitalized in a French pediatric intensive care unit (PICU) for anaphylaxis. METHODS: We conducted a telephone survey of 166 children (≤18 years) hospitalized from 2003 to 2013. RESULTS: In all, 106 (64%) completed the survey (boys, 59%; mean age [SD]: 15.3 years [5.5]). The main index triggers were drugs (45%) and foods (37%). The mean duration follow-up was of 7.7 years (SD: 2.4). Thirty-eight (36%) children experienced 399 new allergic reactions during a follow-up period of 282 patient-years (incidence rate: 1.4/100 patients/y; 95% CI: 0.64-2.04). Twelve children experienced 19 anaphylaxis reactions including five requiring PICU admission (anaphylaxis recurrence rate: 0.20/100 patients/y; 95% CI non-calculable). Food was the trigger for 79% of recurrent reactions and drugs for 8%. The food trigger was previously known in 83%, the same as the index trigger in 69%. Overall, 1.5% of the recurrent reactions were treated with adrenaline injection and 8% an emergency hospital admission. Patients with recurrence had more likely a history of food allergy (P < 10-4 ), asthma (P < 0.005), atopic dermatitis (P < 0.05) than those without. 31% of the 50 children with food allergy did not see an allergist, 23% had no adrenaline auto-injector, and 26% lacked a school individual healthcare plan. CONCLUSIONS: Following a PICU admission for anaphylaxis, recurrence is high in children with food allergy compared with drug allergy. Allergic comorbidities increase the risk. Medical follow-up has to be improved for these at-risk children.

Virus-triggered exacerbation in allergic asthmatic children: neutrophilic airway inflammation and alteration of virus sensors characterize a subgroup of patients.

BACKGROUND: Viruses are important triggers of asthma exacerbations. They are also detected outside of exacerbation. Alteration of anti-viral response in asthmatic patients has been shown although the mechanisms responsible for this defect remain unclear. The objective of this study was to compare in virus-infected and not-infected allergic asthmatic children, aged 6 to 16 years, admitted to hospital for a severe exacerbation, the innate immune response and especially the expression of pattern recognition receptor (PRR) and their function. METHODS: Virus identification was performed both during the exacerbation and at steady state (eight weeks later). Data assessed at both periods included clinical features, anti-viral response and inflammation (in sputum and plasma), and PRR expression/function in blood mononuclear cells. RESULTS: Viruses were identified in 46 out of 72 children (median age 8.9 years) during exacerbation, and among them, in 17 at steady state. IFN-ß, IFN-γ and IL-29 levels in sputum and plasma were similar between infected and not infected patients at both times, as well as the expression of TLR3, RIG-I and MDA5 in blood monocytes and dendritic cells. Airway inflammation in infected patients was characterized by significantly higher IL-5 concentration and eosinophil count. Compared to patients only infected at exacerbation, the re-infected children significantly exhibited lower levels of IFN-γ in plasma and sputum at exacerbation associated with modifications in PRR expression and function in blood mononuclear cells. These re-infected patients also presented an airway neutrophilic inflammation at steady state. CONCLUSION: Our results reports in asthmatic children that impaired anti-viral response during virus-induced exacerbation is more pronounced in a subgroup of patients prone to re-infection by virus. This subgroup is characterized by altered PRR function and a different pattern of airway inflammation. TRIAL REGISTRATION: This multicenter prospective study was approved by the regional investigational review board (ref: 08/07).

The dopamine D1 receptor agonist SKF 38393 improves temporal order memory performance in maternally deprived rats.

Previously, we showed that maternal deprivation (MD) (3h/day, postnatal-day 1-14) impaired the performance at adulthood in the object temporal order memory task (TMT) that principally implicates the medial prefrontal cortex (mPFC). Dopamine (DA) transmission in the PFC may play a critical role in the achievement of the TMT. Here, to investigate whether MD could results in dysfunction of the DA system in the mPFC, we assessed in this region the tissue contents and extracellular levels of DA and its metabolites, as the density of D1 receptor. Besides we examined whether an agonist of the DA receptor D1, the SKF38393, could have a beneficial effect on the performance of deprived (D) rats in the TMT. We observed that MD induced a significant reduction of the extracellular level of DOPAC in the mPFC and in the density of the D1 receptor in the anterior cingulate cortex, a sub-region of mPFC. On the other hand, we observed that an acute systemic injection of a D1 receptor agonist, SKF38393, was effective to correct the memory deficiency of D rats in the TMT, when administered before the retrieval phase. We showed that a stress suffered by rats during the perinatal period led to dysfunction of the adult DA system, possibly triggering greater vulnerability to cognitive and mood disorders. Interestingly, an acute administration of a D1 receptor agonist in adulthood was sufficient to improve the deficit in the temporal memory. A better understanding of this phenomenon would permit the development of treatments adapted to patients with a history of early traumatic experiences.