Asthma is a complex, multifactorial inflammatory disorder of the airways, characterized by recurrent symptoms and variable airflow obstruction. So far, two main asthma endotypes have been identified, type 2 (T2)-high or T2-low, based on the underlying immunological mechanisms. Recently, extracellular vesicles (EVs), particularly exosomes, have gained increasing attention due to their pivotal role in intercellular communication and distal signaling modulation. In the context of asthma pathobiology, an increasing amount of experimental evidence suggests that EVs secreted by eosinophils, mast cells, dendritic cells, T cells, neutrophils, macrophages, and epithelial cells contribute to disease modulation. This review explores the role of EVs in profiling the molecular signatures of T2-high and T2-low asthma, offering novel perspectives on disease mechanisms and potential therapeutic targets.

Background: The anti-IL-5 monoclonal antibody, mepolizumab, has shown clinical efficacy and safety for the treatment of severe eosinophilic asthma (SEA), chronic rhinosinusitis with nasal polyps (CRwNP) and eosinophilic granulomatosis with polyangiitis (EGPA). We aimed to investigate the trajectories of the inflammatory cytokines at the systemic level during mepolizumab treatment, in SEA, SEA with CRwNP, and EGPA. Material and Methods: Treatment response was explored within a real-life observational prospective study. Clinical, functional and inflammatory outcomes as well as serum T2 (IL-4, IL-5 and IL-13) and non-T2 cytokine trends (including IL-5, IL-6, IL-13, IL-10) were evaluated at baseline and 6–12 months after mepolizumab initiation. Results: Overall, 45 patients were consecutively enrolled (SEA: 18; SEA with CRwNP: 9; EGPA: 18), including 27 females, with an average cohort age 60.65 years. Clinical parameters (FEV1, FeNO, SNOT 22, ACT, blood eosinophil count) improved in the different subgroups regardless of coexisting determinants of potential higher disease burden, including CRwNP and previous EGPA history. Cytokine analysis revealed heterogeneous profiles at baseline and statistically significant changes in IL-5 and IL-10 concentrations within the same disease subgroup at different time points. Conclusions: Our observations suggest the ability of mepolizumab to modulate both T2 and non-T2 immune pathways and highlight the persistence of slightly different molecular profile in different severe asthma patients depending on concomitant conditions, which is relevant for the long-term follow-up and potential association therapy combining options which address different targets. More research and larger studies are needed.