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BACKGROUND: Chronic rhinosinusitis and asthma frequently coexist, yet the morphological relationship between paranasal sinus and lower airway in asthma remains unclear. We hypothesized that paranasal sinus opacification is closely associated with lower airway structural abnormalities in asthma. METHODS: We analyzed two independent asthma cohorts: the Kyoto asthma cohort (discovery) and the Hi-CARAT study (validation). Paranasal sinus opacification was identified as the Lund-Mackay score (LMS) ≥ 6 on paranasal sinus CT. Mucus plugs score in upper-middle lobe airways and lower lobe airways, wall area percentage (WA%) of the right apical (RB1) and posterior basal (RB10) bronchi, and total airway count on inspiratory CT were compared between those with LMS ≥ 6 and LMS < 6. Small airway dysfunction (SAD%) was measured on registered inspiratory and expiratory CT in the discovery cohort. RESULTS: Of 96 and 180 patients in the discovery and validation cohorts, 21 and 75 had LMS ≥ 6. Patients with an LMS ≥ 6 had higher mucus plugs scores in both upper-middle and lower lobe airways. WA% was also increased, particularly in RB10. In multivariable analyses, LMS ≥ 6 was independently associated with greater mucus plugs and increased WA% in the subsegmental RB10 airways independent of oral corticosteroid use, biologics use, blood eosinophil counts, and fractional exhaled nitric oxide. LMS ≥ 6 was also associated with greater SAD%. CONCLUSIONS: Paranasal sinus opacification on CT was associated with lower airway mucus plugs and wall thickening in asthma, independent of type 2 inflammation, supporting the unified airway concept.

Severe eosinophilic asthma (SEA) is a type-2 inflammatory phenotype driven by persistent eosinophilia, characterized by frequent exacerbations, progressive lung function decline, and substantial oral corticosteroid (OCS) dependence, for which conventional therapies remain insufficient in a significant minority of patients. Benralizumab-a humanized, afucosylated anti-interleukin-5 receptor alpha (IL-5Rα) monoclonal antibody-achieves near-complete depletion of eosinophils and basophils through dual receptor blockade and afucosylation-enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), producing one of the most extensive anti-eosinophilic effects among currently approved biologics. Pivotal Phase 3 trials (SIROCCO, CALIMA, ZONDA) demonstrated annual exacerbation rate reductions of up to 51%, robust OCS-sparing with complete elimination in 52.7% of OCS-dependent patients, and significant improvements in forced expiratory volume in 1 second (FEV1). Long-term extension data over five years (MELTEMI) confirmed sustained efficacy and safety, without evidence of adverse consequences attributable to chronic eosinophil depletion. Landmark studies including PONENTE, SHAMAL, and ABRA have further extended benralizumab's clinical impact: enabling structured OCS elimination, demonstrating that well-controlled patients can reduce inhaled corticosteroids to as-needed therapy, and establishing biologic-based treatment of acute eosinophilic exacerbations as a viable new approach. Real-world evidence consistently corroborates trial findings, with clinical remission-defined as the composite achievement of exacerbation freedom, OCS independence, symptom control, and preserved lung function-reported in 17-44% of patients at 12 months and up to 91% in selected longer-term cohorts. Beyond asthma, benralizumab demonstrates meaningful activity in comorbid chronic rhinosinusitis with nasal polyps, eosinophilic granulomatosis with polyangiitis, and eosinophilic esophagitis. This review comprehensively examines benralizumab's molecular pharmacology, pivotal and real-world clinical evidence, comorbidity management, and its central role in driving the paradigm shift from symptom control toward clinical remission in severe eosinophilic airway disease.

Allergic fungal rhinosinusitis (AFRS) is a clinically distinct subset of type 2 chronic rhinosinusitis with nasal polyps (CRSwNP), characterized by markedly elevated total IgE, fungal sensitization, and expansile disease with bony remodeling. Definitive diagnosis requires all five Bent and Kuhn criteria, including histopathological demonstration of eosinophilic mucin without tissue invasion and a positive fungal stain. Tezepelumab, a monoclonal antibody against thymic stromal lymphopoietin (anti-TSLP), has phase 3 evidence in severe CRSwNP but has not been evaluated specifically in AFRS. We report a 32-year-old woman with an AFRS-like CRSwNP phenotype, clinically and radiologically suspected but not histologically confirmed (total serum IgE 1,330 IU/mL; fungal polysensitization to Aspergillus, Alternaria, Penicillium and Candida) and severe asthma. During 11 months of tezepelumab prescribed for severe asthma rather than initiated for sinonasal disease, sinonasal disease was not controlled: the 22-item Sino-Nasal Outcome Test (SNOT-22) score remained severe (85→89/110) and imaging showed interval progression of maxillary disease, with persistence of a left posterior ethmoidal mucocele encroaching on the optic canal and orbit that had already been present on pre-biologic imaging. Revision endoscopic sinus surgery (FESS) was required; two months postoperatively the SNOT-22 improved markedly to 48/110 and asthma control improved partially (Asthma Control Test [ACT] 8→15/25). The temporal pattern is compatible with improvement following surgery rather than anti-TSLP therapy, although perioperative corticosteroids, continued medical treatment, changes in adherence and the natural course of disease may also have contributed. A single, uncontrolled observation with only two months of postoperative follow-up cannot establish that TSLP blockade is ineffective in AFRS; it does illustrate that fixed structural disease may not be addressed by biologic therapy alone. Dedicated prospective studies of anti-TSLP therapy in histologically confirmed AFRS are needed.

OBJECTIVE: Severe eosinophilic asthma (SEA) is often associated with chronic rhinosinusitis with nasal polyps (CRSwNP) characterized by type 2-driven eosinophilic inflammation. We sought to investigate the effect of mepolizumab on relevant clinical, functional, and inflammatory endpoints in naïve SEA patients with or without nasal polyps evaluated through induced sputum and followed for 12 months. METHODS: We conducted an exploratory observational real-world cohort study including biologic-naïve SEA patients who initiated treatment with mepolizumab at an asthma referral center in Tradate, Italy. Clinical, functional, and inflammatory parameters were assessed at baseline and after 12 months. Induced sputum was used to evaluate airway inflammation. Patients were stratified by presence or absence of CRSwNP. RESULTS: Forty patients were included, 27/40 (67.5%) had CRSwNP. After 12 months, significant reductions were observed in annual exacerbations (median, 2.0 vs. 0.0; adjusted p value [p-adj] < 0.001), maintenance oral corticosteroid use (5.0 vs. 0.0 mg; p-adj = 0.004), blood eosinophil count (543 vs. 55 cells/µL; p-adj < 0.001), and sputum eosinophil % (39.0% vs. 1.3%; p = 0.004). Asthma control and FEV1 improved significantly. In patients with CRSwNP, sinonasal symptoms markedly improved (p-adj = 0.004). No post-treatment differences in airway eosinophilia were detected between the groups. Overall, 77.5% achieved clinical remission in accordance with Severe Asthma Network Italy Delphi consensus criteria. CONCLUSIONS: Mepolizumab provided substantial clinical, functional, and anti-inflammatory benefits in SEA, regardless of CRSwNP status. Despite higher baseline eosinophilia, patients with CRSwNP showed no clear differences in outcomes when compared with those without CRSwNP, supporting the concept of united airway disease. These findings highlight the value of induced sputum as a noninvasive tool and support integrated, comorbidity-driven approaches in severe asthma management.

Nasal polyposis is a multifactorial disorder arising from complex interactions among cellular, molecular, and inflammatory mechanisms. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and other ion channels are essential for epithelial ion transport, mucosal hydration, and barrier integrity in the nasal airway. Prostaglandin E2 (PGE2) acts not only as an inflammatory mediator but also as a regulator of ion exchange through CFTR-dependent and CFTR-independent pathways. Ionocytes, specialized epithelial cells that regulate ion balance and fluid secretion in the respiratory tract, are closely associated with CFTR function. Both eosinophilic and non-eosinophilic inflammation may alter ionocyte abundance and function, thereby reducing normal CFTR activity. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also characterized by diminished PGE2 production. The I3PGE2 hypothesis proposes that CRSwNP results from the combined effects of ion channel dysfunction, persistent inflammation, altered ionocyte number and function, and impaired PGE2 synthesis. Together, these abnormalities disrupt nasal physiology and promote polyp formation. We hypothesize that corticosteroids and biologic therapies may improve CRSwNP by reducing inflammation, restoring ion channel activity, improving ionocyte function, and recovering PGE2 production. These effects enhance hydration and mucociliary clearance, limit mucus accumulation, restore epithelial homeostasis and mucosal host defense, and ultimately contribute to the reduction or resolution of nasal polyps.