BenRalizumab Effect on Airway Remodeling in Severe asTHma

Interleukin (IL)-5 is the main cytokine responsible for the activation of eosinophils, hence therapeutic strategies have been investigated and developed for clinical use. Biologics targeting IL-5 and its receptor have been recently approved and used as add-on therapy for severe eosinophilic asthma resulting in a reduction in the circulating eosinophil count, improvement in lung function and exacerbation reduction in patients with severe asthma. Response to biologic therapies in severe asthma is variable, with patients being either non-responders, responders or super-responders. There is currently no explanation for this broad variation in response. It is important to examine whether these patients have distinct characteristics that could help the treating physician in making the correct diagnosis in clinical practice. Aim of this clinical study is to evaluate the efficacy of benralizumab, a humanized an anti-interleukin 5 receptor α monoclonal antibody in patients with severe eosinophilic asthma and to evaluate airway remodeling before and after benralizumab treatment. Every patient will be a control to himself by comparing baseline's biomarker measurements of each patient to the following timepoint's measurements. However, we have added 10 severe asthmatics with no intervention, receiving standard of care as control groups to make more comparisons. Several methods are used to investigate airway inflammation: direct measurements (like bronchial biopsies or bronchoalveolar lavages) and indirect methods (like symptom assessment, blood sample analysis and lung function tests). The direct techniques have the advantage of reliably assessing the airway inflammation, but they are invasive and not feasible at large scale because of patient discomfort and the risk incurred. As for the indirect methods, they poorly correlate with the direct assessment of airway inflammation. In this study, among patients' clinical characteristics spirometry, biomarkers of inflammation such as blood eosinophils, Fractional Exhaled Nitric Oxide (FeNO), immunoglobulin E (IgE) levels), and airway remodeling via bronchoscopy will be evaluated. The precise effects of increased airway smooth muscle area on airway narrowing are not known and may vary with disease severity. In addition, biomarkers of inflammation will also be evaluated before and after 52-week of benralizumab treatment in biological fluids (serum and bronchial samples). Biomarkers of inflammation are very important to identify treatment response. Besides, asthmatic disease is characterized by a chronic mucosal inflammatory process, which results in irreversible changes of the bronchial wall, known today as "bronchial remodeling". Glandular and smooth muscle fibers hyperplasia and/or hypertrophy, goblet cells hyperplasia, and variable thickening of basement membrane (BM) present under the respiratory epithelium are part of these morphological changes. the changes generated at the epithelium-connective interface account for an "adaptive response" to inflammatory stress and sporadic bronchoconstriction. However, current data on BM reactivity in asthmatic patient are still incomplete for an accurate assessment of its involvement in pathogenesis and specifically in bronchial wall remodeling, mainly as collagen deposits in lamina reticularis are not correlated to the degree of disease severity. Moreover, it is increasingly evident that severe asthma is not a single disease, as evidenced by the variety of clinical presentations, physiologic characteristics, and outcomes seen in patients with asthma. To better understand this heterogeneity, the concept of asthma phenotyping and endotyping has emerged. Phenotyping integrates both biological and clinical features, from molecular, cellular, morphologic, and functional to patient-oriented characteristics with the goal to improve therapy. Ultimately, these phenotypes evolve into asthma "endotypes," which combine clinical characteristics with identifiable mechanistic pathways. Biomarkers, defined as characteristics that can be objectively measured and serve as an indicator of underlying biological processes or pathogenesis, are crucial in defining phenotypes and endotypes. In asthma, genetic polymorphisms, measures of airway physiology, and levels of inflammatory mediators in urine, blood, sputum, tissue, exhaled gas, and breath condensate have all been studied as potential markers to improve and objectify asthma diagnosis and management. Developing such tools will allow us to phenotype and endotype the various clinical patterns described in asthma, with the ultimate goal of tailoring therapy based on a specific biomarker profile. Biomarkers can then be used to help better understand the pharmacologic response to an intervention and adjust therapy accordingly. Biomarkers have been critical for studies of disease pathogenesis and the development of new therapies in severe asthma. In particular, biomarkers of type 2 inflammation have proven valuable for endotyping and targeting new biological agents. Because of these successes in understanding and marking type 2 inflammation, lack of knowledge regarding non-type 2 inflammatory mechanisms in asthma will soon be the major obstacle to the development of new treatments and management strategies in severe asthma. Other potential biomarkers include innate lymphoid cells, IL-33 or thymic stromal lymphopoietin.