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Severe asthma is associated with increased morbidity, mortality, healthcare costs and impaired quality of life. Asthma is no longer considered as a single entity but as a heterogeneous disease with different clinical presentations (phenotypes) and variable underlying mechanistic biological pathways (endotypes). Two different endotypes are based on the inflammatory Type 2 T-helper response: T2-high and T2-low. The understanding of these endotypes has revolutionised the management of severe asthma. Recent guidelines from the 2019 European Respiratory Society/American Thoracic Society (ERS/ATS) and Global Initiative for Asthma (GINA) 2021 specifically address the diagnosis and the management of severe asthma in adults, but less evidence exists for the paediatric population. Presently, five biologics for the treatment of severe asthma are approved, i.e., omalizumab (anti-IgE antibody), mepolizumab and reslizumab (anti-IL-5 antibody), benralizumab (anti-IL-5 receptor antibody) and dupilumab (anti-IL-4 receptor alpha antibody). This article reviews the pathological mechanisms of severe asthma, clinical biomarkers related to the T2-high endotype, and their use for the prediction of the severity of the disease and response to biological therapy. Furthermore, future developments of biologics for severe asthma are presented.

BackgroundWheezing disorders in childhood vary widely in clinical presentation and disease course. During the last years, several ways to classify wheezing children into different disease phenotypes have been proposed and are increasingly used for clinical guidance, but validation of these hypothetical entities is difficult.Methodology/principal findingsThe aim of this study was to develop a testable disease model which reflects the full spectrum of wheezing illness in preschool children. We performed a qualitative study among a panel of 7 experienced clinicians from 4 European countries working in primary, secondary and tertiary paediatric care. In a series of questionnaire surveys and structured discussions, we found a general consensus that preschool wheezing disorders consist of several phenotypes, with a great heterogeneity of specific disease concepts between clinicians. Initially, 24 disease entities were described among the 7 physicians. In structured discussions, these could be narrowed down to three entities which were linked to proposed mechanisms: a) allergic wheeze, b) non-allergic wheeze due to structural airway narrowing and c) non-allergic wheeze due to increased immune response to viral infections. This disease model will serve to create an artificial dataset that allows the validation of data-driven multidimensional methods, such as cluster analysis, which have been proposed for identification of wheezing phenotypes in children.Conclusions/significanceWhile there appears to be wide agreement among clinicians that wheezing disorders consist of several diseases, there is less agreement regarding their number and nature. A great diversity of disease concepts exist but a unified phenotype classification reflecting underlying disease mechanisms is lacking. We propose a disease model which may help guide future research so that proposed mechanisms are measured at the right time and their role in disease heterogeneity can be studied.