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. Severe asthma (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. 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 rates for 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. Our project proposes an in-depth analysis, not only of clinical and functional parameters, but also of inflammation and remodelling, immune cells, metabolomic compounds, and microbiota present in the airways of children with SA. The project, scheduled for 4 years, is divided into five Tasks that will be performed by the following three teams: M. Leite-de-Moraes and G. Lezmi (Partner 1 and coordinator), K. Adel-Patient (Partner 2) and M. Thomas (Partner 3). Ethical approval has already been obtained for the project allowing the consortium to obtain preliminary data confirming the feasibility of the project.