Defining the Severe Paediatric Asthma Endotype

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.