Abstract
Asthma is a chronic inflammatory lung disease. Refractory asthma poses a significant challenge in management due to its resistance to standard therapies. Key molecular pathways of refractory asthma include T2 inflammation mediated by Th2 and ILC2 cells, eosinophils, and cytokines including IL-4, IL-5, and IL-13. Additionally, non-T2 mechanisms involving neutrophils, macrophages, IL-1, IL-6, and IL-17 mediate a corticosteroid resistant phenotype. Mediators including alarmins (IL-25, IL-33, TSLP) and OX40L have overlap between T2 and non-T2 inflammation and may signify unique pathways of asthma inflammation. Therapies that target these pathways and mediators have proven to be effective in reducing exacerbations and improving lung function in subsets of severe asthma patients. However, there are patients with severe asthma who do not respond to approved therapies. Small molecule inhibitors, such as JAK-inhibitors, and monoclonal antibodies targeting mast cells, IL-1, IL-6, IL-33, TNFα, and OX40L are under investigation for their potential to modulate inflammation involved in refractory asthma. Understanding refractory asthma heterogeneity and identifying mediators involved are essential in developing therapeutic interventions for patients unresponsive to currently approved biologics. Further investigation is needed to develop personalized treatments based on these molecular insights to potentially offer more effective treatments for this complex disease.