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Background/Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP) poses significant therapeutic challenges. The introduction of Mepolizumab, an anti-interleukin-5 monoclonal antibody, offers a new therapeutic option for patients with severe, uncontrolled CRSwNP. This prospective observational study aims to assess the efficacy and safety of Mepolizumab for treating severe CRSwNP in Italy. Methods: A single-center prospective observational study conducted in real-life settings with the patients of our center. Prior to enrollment, each patient underwent an interdisciplinary evaluation involving a pulmonologist and an allergologist if deemed necessary. All patients who were referred for treatment with Mepolizumab in compliance with the AIFA guidelines and the EPOS/EUFOREA update were included in the study population: (1) subjects who were over the age of 18, (2) who had severe CRSwNP, (3) whose condition was not successfully managed with standard therapies alone, and (4) whose blood eosinophil counts were greater than 150 cells/mL. Mepolizumab was administered subcutaneously through a 100 mg injection once every four weeks in addition to the standard-of-care therapy. Results: At the end of the enrollment process, 20 patients with severe CRSwNP were enrolled. Significant improvements were observed in Nasal Polyp Score, quality of life (SNOT-22; p < 0.05), and nasal obstruction and rhinorrhea (p < 0.05), while no significant improvements were seen in olfactory function (p < 0.05). Eosinophil levels also significantly decreased (p < 0.05). Conclusions: Mepolizumab effectively manages severe CRSwNP, showing improvements in symptom control and quality of life with an acceptable safety profile. Full article