BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease with variable response to biologic therapy. Tissue-based predictors of treatment response are limited, and conventional eosinophil-focused histopathology has shown inconsistent predictive value.ObjectiveTo assess whether artificial intelligence (AI)-derived baseline histopathology of nasal polyps contains information associated with clinical response to mepolizumab in CRSwNP.MethodsThis hypothesis-generating substudy included patients with severe CRSwNP enrolled in a randomized controlled trial. Baseline biopsies were analysed using an AI-driven spatial histopathology pipeline extracting 84 morphological features per cell. Features were evaluated in eosinophil-only, noneosinophil, and all-cell configurations. Treatment response at 6 and 12 months was defined using EUFOREA criteria. Linear discriminant analysis and partial least squares regression were applied.ResultsFifty-eight patients were included. At 12 months, the eosinophil-only model showed limited discrimination (AUC ≈ 0.43), the noneosinophil model moderate discrimination (AUC ≈ 0.62), and the all-cell model the highest performance (AUC ≈ 0.75). At 6 months, all models showed limited discrimination (AUC ≈ 0.49). For continuous outcomes, noneosinophil models explained the greatest variance (R2 up to ≈ 0.34).ConclusionAI-derived baseline histopathology contains information associated with clinical response to mepolizumab in CRSwNP. Models incorporating the broader tissue microenvironment outperformed eosinophil-focused approaches, supporting the potential of computational pathology for pretreatment stratification of biologic therapy in CRSwNP.

NSAID-exacerbated respiratory disease (N-ERD) is characterized by asthma, chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), and intolerance to NSAIDs (including aspirin). In N-ERD, CRSwNP often remains refractory to standard medical and surgical treatment, necessitating escalation. Aspirin therapy after desensitization (ATAD) is an established option for CRSwNP in N-ERD, but its use is limited by adverse effects, non-response, and safety issues associated with aspirin desensitization. This narrative review focuses on newer developments in ATAD for N-ERD, including shortened desensitization schedules, lower aspirin maintenance doses, and use of intranasal preparations of aspirin such as intranasal lysine-aspirin. The developments in use of biomarkers for distinguishing the different underlying endotypes and phenotypes of N-ERD, and subsequent potential for individualization of treatment are also discussed. The availability of biologics for the treatment of CRSwNP may provide further treatment escalation options in N-ERD patients who do not tolerate or respond to ATAD; however, there is an absence of direct comparative evidence for ATAD versus biologics. Further, the conjunctive use of ATAD and biologics provides an interesting avenue of research. Finally, following a discussion of the recent advancements in ATAD and biologics in N-ERD, clinical recommendations for treatment options and pathways are made.

The repetition of a condition following endoscopic sinus surgery (ESS) poses an important difficulty in type 2 chronic rhinosinusitis with nasal polyps (CRSwNP) therapy. The recurrent nature of the disease is probably linked to the dynamic interplay of the enduring type 2 inflammatory microenvironment and the imbalanced sinonasal microbiome. The microbiomic characteristics and pathogenic mechanisms of postoperative recurrence are systematically elaborated in this paper, indicating that recurrent CRSwNP is characterized by microbial dysbiosis featured by enrichment of Staphylococcus aureus, depletion of Corynebacterium, and reduction in α-diversity. Its core mechanisms involve superantigen-mediated immune hijacking, epithelial barrier collapse caused by microbial metabolic imbalance, and physiological tolerance mediated by biofilms. On this basis, as a scoping review, this paper further reviews the shift of intervention strategies from "broad-spectrum bactericidal" to "precise ecological restoration", including narrow-spectrum antibacterial and phage therapies targeting Staphylococcus aureus, ecological replacement therapy by supplementing nasal-specific commensal bacteria (such as Corynebacterium), and synergistic regulation strategies using biological agents such as dupilumab to indirectly reshape the microecology by inhibiting type 2 inflammation. In addition, the paper also discusses the potential of constructing postoperative recurrence prediction models based on microbial biomarkers, aiming to provide a theoretical basis for the precise and dynamic management of CRSwNP.

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is a highly heterogeneous inflammatory disease with distinct inflammatory endotypes. This study aimed to identify reliable biomarkers for precise discrimination of eosinophilic CRSwNP (eCRSwNP), and to explore their potential roles in the pathological progression of CRSwNP.MethodsA total of 107 patients with CRS (including 22 CRSsNP and 85 CRSwNP) and 40 healthy controls were enrolled. Differentially expressed proteins related to eCRSwNP were screened via protein microarray combined with the random forest algorithm. The expression of candidate proteins was validated in clinical tissues and serum. Correlation analysis and receiver operating characteristic (ROC) curves were applied to evaluate the association of candidate molecules with eosinophilic inflammation and disease prognosis. Hematoxylin and eosin (HE) staining was performed to assess histopathological changes. Human umbilical vein endothelial cells (HUVECs) were used to explore the regulatory effects of IL-13 on VCAM-1 expression and angiogenesis. siRNA knockdown and tube formation assays were further adopted to verify the functional mechanism.ResultsProtein chip and machine learning analysis identified VCAM-1 as a major molecule associated with CRSwNP endotype. VCAM-1 expression was significantly elevated in both tissue and serum of CRSwNP patients, particularly in eosinophil CRSwNP (eCRSwNP) group. HE staining showed a significant increase in neovascularization in the CRSwNP group compared to the control and CRSsNP groups, especially in the eCRSwNP. Multiplex immunofluorescence revealed increased VCAM-1/CD31 co-expression in vascular regions of eCRSwNP tissues. In vitro, IL-13 induced VCAM-1 expression in HUVECs in a time and dose-dependent manner, while VCAM-1 knockdown reduced CD31 levels and impaired angiogenesis, indicating its functional role in pathological neovascularization.ConclusionVCAM-1 is significantly upregulated in eCRSwNP and closely correlated with eosinophilic inflammation. VCAM-1 may facilitate eosinophil infiltration by participating in IL-13-mediated angiogenesis and vascular remodeling in eCRSwNP.

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) is a distinct clinical syndrome characterised by moderate-to-severe asthma and a high prevalence of chronic rhinosinusitis with nasal polyps and aspirin/NSAID intolerance. The primary pathogenesis of N-ERD includes the dysregulation of arachidonic acid metabolism with subsequent cysteinyl leukotriene overproduction and persistent type 2/eosinophilic inflammation in the upper and lower airways. N-ERD has considerably heterogeneous clinical features and courses, emphasising the necessity for classifying its phenotypes and/or endotypes to enable early diagnosis and individualised treatment approaches. However, the lack of reliable and standardised tests and biomarkers can cause diagnostic delays, leading to inadequate management and more severe disease progression in affected individuals. Current treatments for N-ERD include NSAID avoidance, aspirin desensitisation, and the use of leukotriene modifiers and corticosteroids. Recently, biologics targeting interleukin (IL)-4, IL-5, IL-13 and IgE have been suggested as treatment options, particularly for patients with high type 2 inflammatory burden. However, the treatment responses in this patient population remain variable, highlighting the need for individualised therapeutic strategies. In this review, we summarise recent insights into the pathogenic mechanisms, clinical manifestations, and phenotype classification of N-ERD, evaluate emerging biomarkers, and explore the potential of targeted therapies within the framework of precision medicine.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly debilitating airway disease primarily characterized by type 2 inflammation and eosinophilic infiltration. Among the key cytokines involved, Interleukin-5 (IL-5) plays a relevant role in eosinophil biology and contributes, together with other mediators of type 2 inflammation, to epithelial barrier dysfunction, immune dysregulation, mucus hypersecretion, and tissue remodeling. Therapies targeting this cytokine have demonstrated both efficacy and safety in patients with CRSwNP. This narrative commentary summarizes current evidence in understanding IL-5's role in CRSwNP, integrating insights from an Italian otolaryngology expert panel, with a particular focus on the patient journey in Italy. Available evidence suggests that IL-5 is associated with disease severity and may contribute to multiple aspects of CRSwNP pathophysiology beyond eosinophilia. Targeting the IL-5 pathway has been shown to improve clinical outcomes, including nasal polyp burden, symptom control, olfactory function, and quality of life, in selected patients. From a clinical perspective, the expert panel highlighted several critical unmet needs in the Italian setting, including diagnostic delay, heterogeneous implementation of care pathways, suboptimal patient selection, and limited adherence to long-term management strategies. The importance of structured diagnostic work-up, endotyping, multidisciplinary management, and patient awareness was emphasized. The implementation of shared Diagnostic and Therapeutic Care Pathways (PDTA) and network-based models may support more standardized and timely management, although further evidence is needed to define their impact on clinical outcomes. Overall, improving the understanding of IL-5-driven mechanisms and addressing organizational gaps may contribute to optimizing the management of CRSwNP in clinical practice.

BackgroundAlthough several reports suggest that antidiabetic agents may exert anti-inflammatory effects, the influence of glycemic status and antidiabetic agents on chronic rhinosinusitis remains unexplored.ObjectiveThis study aimed to assess the impact of glycemic status and antidiabetic agents on postoperative recurrence of chronic rhinosinusitis with nasal polyps (CRSwNP).MethodsWe conducted a retrospective review of records from six medical centers, including patients who underwent endoscopic sinus surgery for bilateral CRSwNP, with a minimum follow-up duration of 3 years. Patients were stratified into normoglycemic patients, dysglycemic patients without antidiabetic agent use, and dysglycemic patients receiving antidiabetic agents. Clinical characteristics were compared both across these groups and between patients with and without postoperative rhinosinusitis recurrence. Binary logistic regression analysis was used to identify independent predictors of recurrence and analyze medication-specific effects. Cumulative hazard of rhinosinusitis recurrence according to perioperative glycemic status and antidiabetic agent use were analyzed.ResultsA total of 503 patients were analyzed. During the postoperative follow-up period, rhinosinusitis recurrence occurred least frequently among dysglycemic patients receiving antidiabetic agents (P = .008). Antidiabetic agent users had a significantly reduced cumulative hazard of recurrence compared with nonusers (P < .001). Consistently, the proportion of antidiabetic agent users was significantly higher in the nonrecurrence group than in the recurrence group (P = 0.008). In contrast, perioperative fasting blood glucose and glycated hemoglobin levels were not significantly associated with postoperative recurrence. Binary logistic regression analysis identified younger age, absence of antidiabetic agent use, and poorer preoperative olfactory identification scores as independent predictors of recurrence.ConclusionPerioperative antidiabetic agent use was associated with a significantly reduced risk of postoperative recurrence in CRSwNP patients. The lack of significant association between glycemic status and recurrence further suggests that antidiabetic agents themselves, distinct from glycemic control, may exert a modulatory effect on the CRSwNP disease course.

Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) in their non-polypous (CRS without nasal polyps - CRSsNP) and polypous (CRS with nasal polyps - CRSwNP) main phenotypes are chronic inflammatory diseases of the nasal mucosa and/or paranasal sinuses with a whole series of unknowns regarding etiology, pathogenesis, clinical manifestations, and therapeutic modalities. Although intranasal and oral antihistamines and intranasal corticosteroids are the main drugs in AR therapy, emerging evidence on the effects of herbal and biological drugs may add a new dimension to the treatment of these patients. CRS is a far more heterogeneous disease with numerous clinical phenotypes that require completely different approaches. In addition to endoscopic sinus surgery (ESS), which remains the mainstay of treatment, intranasal and systemic corticosteroids, macrolide antibiotics, and tetracyclines, as well as nasal irrigation with saline solutions, are the main modalities, especially in the period after surgical treatment. Recently, there has been increasing evidence for the beneficial effects of herbal medicines and biological therapy. However, to assess how well conservative treatment of AR and CRS keeps chronic inflammation under control, numerical parameters derived from cytological findings, biochemical analysis of nasal secretions by enzyme-linked immunoassay (ELISA), flow cytometry, and pathohistological and immunohistochemical analyses of tissue samples are necessary. This narrative review of the literature was done through a critical approach, which included our long-term experience in researching the effects of various drugs, as well as the results of other authors. The results of numerous studies have shown that the application of these drugs can significantly change the profile of inflammatory mediators (cytokines, chemokines, enzymes, growth factors) and thus direct the course of inflammation to a less intense form. Nevertheless, in spite of everything, the control of AR and CRS is still not at a satisfactory level, which directs us towards finding new modalities of conservative therapy, especially in the field of application of biological drugs and plant extracts.