Mepolizumab Effectiveness in Patients With Chronic Rhinosinusitis, Nasal Polyps and Comorbid Severe Eosinophilic Asthma

The goal of this observational study is to learn about clinical and functional outcomes in patients with Chronic rhinosinusitis with nasal polyps and comorbid Severe Eosinophilic Asthma and patients with Chronic rhinosinusitis with nasal polyps only treated with mepolizumab compared to healthy controls. Participants will be asked to give nasal, blood and sputum samples before mepolizumab administration (T0) and at 3 (T3), 6 (T6) and 12 (T12) months after mepolizumab initiation The main aims are to identify airways microbiota modifications and differential gene expression after mepolizumab initiation. Researchers will compare: * Patients with Chronic rhinosinusitis with nasal polyps and comorbid Severe Eosinophilic Asthma * Patients with Chronic rhinosinusitis with nasal polyps only * Healthy subjects The research will address the following questions: 1. What are the prospective clinical and functional outcomes of mepolizumab treatment 2. What is the impact of mepolizumab therapy on the airways microbiota and how this may relate to a potentially reduced need for steroids 3. What are the host differential gene expression patterns and the immune/inflammatory (cytokines/chemokines) profile alterations in airways microenvironment and in systemic circulation in response to therapy 4. What are the associations between host and microbiome variables for building up diagnostic and predictive biomarker classifiers of responsive disease endotypes

Chronic rhinosinusitis (CRS) has been divided into two subtypes: CRS with (CRSwNP) and without nasal polyps (CRSsNP), which not only differ in terms of presence of polyps, but also appear to have distinct pathogenesis and clinical presentations. It is known that CRSwNP patients have a greater disease burden compared with those suffering from CRSsNP with respect to disease severity and poor treatment. More specifically, approximately 85% of CRSwNP patients are characterized by severe symptoms, recurrent disease and a dominant Th2 endotype associated with a marked infiltration of eosinophils and mast cells, goblet hyperplasia and increased levels of Th2 inflammatory cytokines including Interleukin IL-4, IL-5, and IL-13. An additional hallmark of CRSwNP is the loss of healthy barrier function in sinonasal epithelial cells, increased permeability, decreased epithelial resistance, and a high degree of tissue remodeling compared with cells from CRSsNP patients and control individuals. This loss of barrier function is reflective of a general inflammatory process, though it is unclear if the epithelial cells are inherently abnormal or if the state is induced. Treatment for CRS is most frequently glucocorticoid-based, but response is quite variable in patients with nasal polyps and side-effects from oral steroids limit their long-term efficacy. An inverse relationship between glucocorticoid receptor β expression in nasal polyp tissue and steroid efficacy has been observed. Furthermore, neutrophil accumulation in nasal polyp tissue has been related to corticosteroid insensitivity. Some individuals exhibit a very high level of resistance to steroid therapy thus underscoring the need for therapeutics targeting non-steroid-responsive pathophysiologic mechanisms involved in sinus polyp formation. Asthma is frequently a comorbid condition sharing similar pathophysiology in CRSwNP patients, which affects 20-60% of diseased individuals. Yet, specific subsets of patients such as those with IL-5-enriched nasal polyps are characterized by a greater percentage of asthma and revision surgery. Clinically, CRSwNP with comorbid asthma (CRSwNP + AS) is associated with even more severe sinonasal symptoms and worse quality of life, and it is more difficult to treat both medically and surgically. Correspondingly, asthma in the presence of nasal polyposis is harder to control, being more exacerbation prone, with increased airway obstruction and more extensive eosinophilic inflammation. Although a clear correlation apparently exists between sinonasal and lower airway inflammation in patients with CRSwNP+AS, the definitive underlying mechanism(s) remains poorly elucidated. The airways microbiota, i.e. the niche-specific communities of microbes including bacteria, fungi, archaea and viruses that inhabit the respiratory tract, has been proved to play a critical role in airway health and immune cells homeostasis -including eosinophils regulation- through its constant interaction trial.show_full_description

Inclusion Criteria: * Eligible for inclusion will be patients diagnosed with CRSwNP according to the European Position Paper on Rhinosinusitis and Nasal Polyps that fulfill the criteria for initiating treatment with biologics as standard of care \[49\], suffering or not from comorbid severe asthma (CRSwNP + AS, CRSwNP - AS, respectively) who will consent to participate in the study. The study will not influence prescribing of mepolizumab to patients. Eligible to treatment women in childbearing potential will be informed before consent that they must take care of contraception and potential pregnancy during therapy as there is not enough data regarding the use of mepolizumab during pregnancy. All patients with severe asthma will be qualified for treatment with mepolizumab in accordance with GINA guidelines. Exclusion Criteria: * Patients less than 18 years of age, subjects suffering from COPD, known or suspected immunodeficiency or autoimmune disease, chronic interstitial lung diseases, cystic fibrosis, individuals exposed to systemic corticosteroid/immunosuppressive treatments, biologics for asthma care or antibiotics within the previous 3 months before mepolizumab administration, active smokers and obese individuals will be excluded from this study. Pregnant women will not be included into the study because of the potential changes that their microbiome and other host parameters could undergo during pregnancy. The control group will comprise healthy volunteers who will be free from CRS, asthma, and atopy.