Asthma is a chronic, heterogeneous inflammatory disease of the lower respiratory tract that affects over 300 million people worldwide with 5-10% of patients having severe disease that is difficult to manage. While the definition of severe asthma is based on corticosteroid responsiveness and clinical symptoms, we are learning more and more about the underlying cellular and molecular mechanisms (asthma endotypes) responsible for both severe disease as well as asthma, in general. Asthma classically has been associated with type 2 (T2) inflammation, the thought being that T helper 2 cells are the predominant source of the cytokines responsible for disease pathology. However, it is now appreciated that asthma involves more than the adaptive arm of the immune response with other cell types, including innate lymphoid cells and epithelial cells playing critical roles as well. Alarmin signals, such as IL-33 and TSLP, produced by epithelial cells, activate innate lymphoid cells to produce a variety of inflammatory cytokines, independent of T helper 2 cell activation. This non-T2 inflammation is now known to be the important driver of disease pathogenesis in a number of patients with severe disease and it is often these patients who are most resistant to current treatment modalities.

In addition to inhaled and oral corticosteroids and long-acting beta agonists, there are several biologics available for the treatment of severe asthma. However, all of the current biologics are directed towards patients with T2 asthma, those with either allergic or eosinophilic phenotypes. To date, there are no approved biologic treatments for patients with T2 low asthma. However, there are new therapies on the horizon, one of which is directed at thymic stromal lymphopoietin (TSLP), one of the epithelial alarmins that, due to its upstream positioning, plays a putative pathogenic role in several asthma pathways.

TSLP has been found to be markedly elevated in the bronchoalveolar lavage fluid of patients with severe asthma and elevated concentrations have been shown to inversely correlate with lung function. Anti-TSLP or tezepelumab has been shown to, not only significantly reduce annualized rates of asthma exacerbations and improve lung function in patients with severe asthma, but also this biologic has been shown to reduce type 2 inflammatory biomarkers in patients across the disease spectrum, those with both T2 high and T2 low inflammation. Thus, this new biologic, indeed may be a game changer in that, because of its putative effects across the many heterogenous severe asthma endotypes, it may be the answer for those patients with severe corticosteroid-resistant disease that remains poorly controlled on currently-available treatment modalities.