Clinical trial NCT04680117: Defining the Severe Paediatric Asthma Endotype
Official title: Defining the Severe Paediatric Asthma Endotype: an Integrated Approach Combining Phenotypic Analyses Related to Immune, Metabolomics and Microbial Features
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Severe Asthma
Keywords: Asthma
Severe
Immunologic
Metabolomic
Microbiologic profil
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-12-22
Enrollment: 150
Sex: ALL
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: The primary objective of this project is to extensively characterize the endotypes of pre-schoolers (0 to 6 years) and school-age children (6 to 12 years) with SA using an integrated approach, combining a description of their phenotype (asthma symptoms, atopy, and lung function) associated with histological (airway inflammation and remodelling), immune (innate and adaptive immunity), metabolomics, and microbiota analyses. This goal shall be achieved by an unsupervised in-depth analysis of patients requiring bronchial endoscopy, with bronchial alveolar lavage (BAL) and bronchial biopsy, as part of their clinical assessment.

Detailed description: Asthma is a chronic disease affecting approximately 235 million people worldwide, and the number is rising. Asthma is not just a public health problem for developed countries; its incidence is also elevated in developing countries. Asthma concerns all age groups, but often starts in childhood. SA in children is infrequent, affecting 2-5% of the asthmatic paediatric population. Children with SA experience frequent SA attacks and have a reduced quality of life . They account for approximately half of the asthma healthcare costs. Asthma has long been thought to be a single disease but is now considered to encompass various conditions characterized by the same symptoms (wheeze, cough, shortness of breath, chest tightness), variable degrees of airflow limitation, and different pattern of inflammation. Recent studies highlighted the heterogeneity of asthma, and the potential influence of various pathogenic mechanisms, including airway inflammation, remodelling, and immune and metabolic pathways in a specific microbial environment. However, there is very little data concerning the pathological process, especially in children. Most of the data describing different asthma endotypes in children are derived from large observational prospective cohorts. Although very informative, these studies were designed to analyse a small number of easily measured parameters, mainly lung function and atopy. The complexity of asthma pathogenesis was therefore underestimated and the individuals' specificities only partially considered. In clinical practice, children with SA require an endoscopy, with broncho-alveolar lavage fluids (BALF) collection and bronchial biopsies to exclude a differential diagnosis and assess airway inflammation and remodelling. This approach also underestimates other components of the endotypes and results in "one size fits all" management based on high doses of inhaled steroids and the use of expensive biotherapy, such as anti-IgE therapy. Thus, although hospital admission and mortality ratesfor asthma decreased until the early 2000's, they have remained stable over the past 10 years. It is therefore imperative to develop new approaches that incorporate relevant parameters analysed in the airways. This project proposes an in-depth analysis, not only of clinical and functional parameters, but also of immune cells, metabolomic compounds, and microbiota present in the airways of asthmatic children.

The primary objective of the project is to extensively characterize the endotypes of pre-schoolers (0 to 6 years) and school-age children (6 to 12 years) with SA using an integrated approach, combining a description of their phenotype (asthma symptoms, atopy, and lung function) associated with histological (airway inflammation and remodelling), immune (innate and adaptive immunity), metabolomics, and microbiota analyses.

This goal shall be achieved by an unsupervised in-depth analysis of patients requiring bronchial endoscopy, with bronchial alveolar lavage (BAL) and bronchial biopsy, as part of their clinical assessment. The main hypothesis is that the complementarity of those approaches will allow investigators to delineate the immune and metabolic pathways and microbiota involved in children with SA. The secondary objectives are to: (1) cluster all data obtained to define new patient groups and develop biomarkers that summarise the different clusters; (2) determine the immune, metabolomic, and microbiota profile of these children to aid future fundamental research that will focus on dissecting new mechanisms involved in paediatric asthma; (3) determine whether pre-schoolers and school-age children with SA share common endotypic features; and (4) establish the basis for the prospective follow-up of patients to identify endotypes that predict asthma persistence throughout childhood, severity, and response to treatment.

Eligibility criteria: Patient Inclusion Criteria:

* Minors aged 0 to 6 years or 6 to 12 years, hospitalized for assessment of Severe Asthma
* Minors need with his follow-up an bronchial endoscopy with realization of LBA and biopsies of bronchial mucosa
* Social insurance affiliation, except AME
* Parents or legal guardians signed the Informed consent form

Control Inclusion Criteria:

* Minors aged 0 to 6 years or 6 to 12 years, hospitalized for assessment of severe respiratory syndrome except severe asthma
* Minors need with his follow-up an bronchial endoscopy with realization of LBA and biopsies of bronchial mucosa
* Social insurance affiliation, except AME
* Parents or legal guardians signed the Informed consent form

Patient Exclusion Criteria

* Prematurity (\<37 weeks gestation)
* Broncho-pulmonary dysplasia, immune deficits, non-Severe Asthma bronchopathies, cystic fibrosis, heart disease, ongoing biotherapy

Primary outcomes:
measure: Description of the environment and smoke exposure
timeFrame: 1 day
measure: Description of family atopy status
timeFrame: 1 day
measure: Description of Demographics
timeFrame: 1 day
measure: Description of Asthma history in the past year
timeFrame: 1 day
measure: Description of Lung function
timeFrame: 1 day
measure: Description of Asthma therapy
timeFrame: 1 day
measure: Description of Airway remodeling
timeFrame: 1 day
measure: Description of inflammatory and histological features in bronchoalveolar lavages (BAL)
timeFrame: 1 day
measure: Description of inflammatory and histological features in bronchial mucosa
timeFrame: 1 day
measure: Bronchial mucosa analysis
timeFrame: 1 day
measure: BAL analysis
timeFrame: 1 day
measure: Blood analysis
timeFrame: 1 day
measure: Metabolomic signature
timeFrame: 1 day
measure: Microbiota analysis
timeFrame: 1 day
Secondary outcomes:
measure: Cluster analysis
timeFrame: 1 year
measure: Number of severe exacerbations in the 12 months following the inclusion
timeFrame: 1 year
measure: Asthma Control Test (ACT) score 12 months after inclusion
timeFrame: 1 year
measure: Asthma control 12 months after inclusion
timeFrame: 1 year
measure: Description of lung function 12 months after the inclusion
timeFrame: 1 year
measure: Number of severe exacerbations during the 1 year follow up
timeFrame: 1 year
measure: Number of emergency department visits for acute asthma during the 1 year follow up
timeFrame: 1 year
measure: Number of cumulated days of oral steroids for asthma exacerbations during the 1 year follow up
timeFrame: 1 year
measure: Number of hospital admissions for acute asthma during the 1 year follow up
timeFrame: 1 year
Other outcomes:
Locations:
city: Paris
country: France
facility: Name: Hôpital Necker-Enfants Malades
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Guillaume Lezmi, Doctor (PHU)
role: PRINCIPAL_INVESTIGATOR
References: