Severe therapy resistant asthma in children: translational approaches to uncover sub-phenotypes

Paediatric severe therapy resistant asthma (STRA) affects a very small proportion of all children with asthma, but results in significant morbidity, has a high risk of mortality and utilises approximately half of all healthcare resources for childhood asthma. children with STRA need add-on 'beyond guidelines' therapies because of poor control despite maximal conventional treatments and optimisation of basic asthma management. however, STRA is heterogeneous with marked phenotypic variation between patients and mechanisms from adult severe asthma cannot be extrapolated to children. Areas covered: This review will cover our current knowledge of paediatric STRA pathophysiology, with examples of translational approaches that have been used to define sub-phenotypes including; 1. pre-clinical age-appropriate models using clinically relevant allergens, 2. in vitro techniques incorporating complex co-cultures of structural and inflammatory cells, and 3. techniques that allow detailed cellular immunophenotyping of small airway samples will be discussed. Studies using these approaches that have demonstrated the importance of the innate mediator IL-33 and vitamin D deficiency in severe steroid resistant disease will also be discussed. Expert commentary: These experimental approaches allow investigation of age and disease specific molecular pathways and the development of personalised therapies that can be stratified and targeted to sub-phenotypes of paediatric STRA.