Efficacy of dupilumab for severe chronic rhinosinusitis with nasal polyps and asthma: A prospective study.

BACKGROUND: Dupilumab exerts clinical effects, including improved sinus opacification, olfactory function, and quality of life, in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). Meanwhile, only a few studies have reported its effects on nasal airway resistance and olfactory function, particularly in the Japanese population. Predictors of response remain unclear. OBJECTIVE: In this prospective, observational study, we assessed the comprehensive efficacy and therapeutic response to dupilumab in severe CRSwNP patients with comorbid asthma. METHODS: In 16 adult severe CRSwNP patients with comorbid asthma, the efficacy of 48-week dupilumab treatment, including olfactory function measured by a T&T olfactometer, nasal airway resistance measured by rhinomanometry, nasal polyp score, Lund-Mackay computed tomography score (LMS), and 22-item Sinonasal Outcome Test (SNOT-22), was assessed. Regarding asthma, the annualized rate of exacerbations, 7-item Asthma Control Questionnaire (ACQ-7), and spirometry were assessed. Treatment responsiveness was analyzed. RESULTS: With 48-week dupilumab treatment, olfactory function, nasal airway resistance, nasal polyp score, LMS, and SNOT-22 scores improved significantly. Regarding comorbid asthma, the rate of exacerbations decreased, and ACQ-7 scores and lung function improved significantly. According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2022/European Forum for Research and Education in Allergy and Airway Diseases criteria, 15 patients (94%) were moderate-to-excellent responders at 48 weeks of treatment. Patients with higher SNOT-22 scores, ACQ-7 scores, rates of asthma exacerbation in the previous year, and blood eosinophil counts benefited more from treatment. CONCLUSION: Dupilumab improved upper and lower airway outcomes especially in severe CRSwNP patients with comorbid, poorly controlled asthma.

Quality of Life in Symptomatic Septal Perforation.

OBJECTIVE: The aim of this study is to investigate the impact of septal perforation (SP) on quality of life (QoL). SP is compared to the general population and patients with chronic rhinosinusitis with nasal polyposis (CRSwNP) using the Sino-Nasal Outcome Test 22 (SNOT-22). METHODS: Prospective single-center study in a referral Rhinology Unit from January 2014 to March 2023. RESULTS: A total of 392 patients were included in three groups: controls (n = 141), CRSwNP (n = 118), and SP (n = 133). The mean score of the SNOT-22 was significantly higher in the CRSwNP group (42.4, SD = 24.4) and SP (46.5, SD = 22) compared to the control group (6.2, SD = 8.4). Scores by either items or domains were significantly higher in the CRSwNP and SP groups compared to the control group. There were no significant differences in the mean SNOT-22 between the CRSwNP and SP groups (p = 0.26; 95% CI -1.68-9.99). Domain-specific analysis of overall SNOT-22 scores revealed that patients with SP experienced higher levels of disturbances in sleep, function, and psychological domains (p ≤ 0.001). CONCLUSION: SP produces a negative impact on QoL similar to CRSwNP. Moreover, sleep, psychological, and function domains are significantly worse in SP. Etiology and area of SP influence nasal and emotion domain, though more studies on SP using SNOT-22 and specific questionnaires are needed. LEVEL OF EVIDENCE: Level III Laryngoscope, 2024.

Dupilumab: a delayed response in asthmatic and atopic patients treated for chronic rhinosinusitis with nasal polyps.

PURPOSE: Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) is a common disease, which was previously approached with sinus surgery or systemic corticosteroids. The advent of biological therapies radically changed the approach to this disease. On the other hand, there is scarce scientific evidence of how specific subsets of patients respond to this treatment. METHODS: this is a monocentric, prospective study investigating the long-term efficacy on biweekly 300 mg dupilumab therapy in CRSwNP, prescribed to 61 patients. Patients were evaluated at baseline and every 2 months for the first 6 months, then at 9, 12, 16, 20 and 24 months. RESULTS: dupilumab proved to be an effective treatment, neatly improving both subjective and objective measurements in CRSwNP. The main finding of the study is the difference between specific subgroups of patients: while the overall response is similar, patients with Th2 comorbidities such as asthma and atopy tend to reach a stable response later, with the improvement ongoing even after 6 months of therapy, while non-asthmatic, non-atopic patients attain an earlier stability in response. CONCLUSIONS: dupilumab provides an excellent long-term control of CRSwNP, but the response in asthmatic and atopic patients appears to be different and delayed when compared to non asthmatic and non atopic ones.

Real-Life Evidence of Mepolizumab Treatment in Chronic Rhinosinusitis with Nasal Polyps: A Multicentric Study.

Background: The introduction of biological drugs in the management of chronic rhinosinusitis with nasal polyps (CRSwNP) is allowing new and increasingly promising therapeutic options. This manuscript aims to provide a multicenter trial in a real-life setting on Mepolizumab treatment for severe uncontrolled CRSwNP with or without comorbid asthma. Methods: A retrospective data analysis was jointly conducted at the Otolaryngology-Head and Neck Surgery departments of La Sapienza University and San Camillo Forlanini Hospital in Rome. Both institutions participated by sharing clinical information on patients with CRSwNP treated with Mepolizumab. Patients were evaluated before starting Mepolizumab, at six months and at twelve months from the first drug administration. During follow-up visits, patients underwent endoscopic evaluation, quality of life assessment, nasal symptoms assessment, and blood tests to monitor mainly neutrophils, basophils, eosinophils, and IgG, IgA, and IgE assay. Results: Twenty patients affected by CRSwNP and treated with Mepolizumab were enrolled (12 females and 8 males with a mean age of 63.7 years). Sixteen patients (80%) had concomitant asthma. During follow-up, a gradual improvement in nasal polyp score, quality of life and nasal symptoms, assessed by SNOT-22 and VAS and loss of smell measured by olfactory VAS, was found. Regarding blood tests, eosinophils decreased gradually, while other blood parameters showed no statistically significant changes. Conclusions: Mepolizumab has been shown to be effective in the therapeutic management of patients with CRSwNP. Further studies are needed to support our findings and better understand the underlying immune pathways to predict patients' response to biological treatment in CRSwNP.

Antibody-based therapeutics for chronic rhinosinusitis with nasal polyps.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent inflammatory condition with heterogenous underlying endotypes, the most common being type 2 mediated inflammation. Several biologics have been developed to target specific pro-inflammatory cytokines and their receptors with proven efficacy in both quantitative and qualitative outcomes in patients with severe uncontrolled disease. However, there is an ongoing debate on the role of biologics relative to conventional therapies for CRSwNP and their efficacy in patient subgroups with non-polyp type 2 disease. AREAS COVERED: This review examines the evidence on the efficacy and safety of biologics in CRSwNP, recommendations for their use, and discusses the broader economic factors influencing their application in clinical practice. EXPERT OPINION: Emerging real-life data demonstrating the variable efficacy of the available biologics for patients with CRSwNP, coupled with the high cost compared to conventional therapies such as surgery, renders biologics to be considered as an add-on therapy in the majority of cases. However, ongoing research into increasing biologic dose intervals and novel therapies targeting alternative pathways may offer a more cost-effective and sustainable option in future.

Sustained remission induced by 2 years of treatment with benralizumab in patients with severe eosinophilic asthma and nasal polyposis.

BACKGROUND AND OBJECTIVE: Several randomized controlled trials (RCTs) have shown that benralizumab is characterized by a good profile of efficacy and safety, thereby being potentially able to elicit clinical remission on-treatment of severe eosinophilic asthma (SEA). The main goal of this multicentre observational study was to verify the effectiveness of benralizumab in inducing a sustained remission on-treatment of SEA in patients with or without comorbid chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Throughout 2 years of treatment with benralizumab, a four-component evaluation of sustained remission of SEA was performed, including the assessment of SEA exacerbations, use of oral corticosteroids (OCSs), symptom control and lung function. RESULTS: The present study recruited 164 patients suffering from SEA. After 24 months of add-on biological therapy with benralizumab, 69 (42.1%) achieved the important target of sustained remission on-treatment (exacerbation rate = 0, OCS dose = 0, pre-bronchodilator FEV1 ≥80% pred., ACT score ≥ 20). During the same period, a persistent improvement of CRSwNP (SNOT-22 < 30, NP recurrence = 0) was observed in 33 (40.2%) out of 82 subjects with concomitant NP. The latter comorbidity and post-bronchodilator reversibility of airflow limitation were two independent predictors of sustained remission on-treatment (OR = 2.32, p < 0.05 and OR = 5.59, p < 0.01, respectively). CONCLUSION: Taken together, the results of this real-life clinical investigation indicate that benralizumab can induce a sustained remission on-treatment of SEA, especially in those patients with comorbid CRSwNP and reversible airflow limitation.

Nasal brushing molecular endotyping distinguishes patients with chronic rhinosinusitis with nasal polyps with better response to dupilumab.

BACKGROUND: There is evidence of pathophysiologic diversity in chronic rhinosinusitis with nasal polyps (CRSwNP), but data characterizing the molecular endotypes of CRSwNP and their association with treatment are lacking. OBJECTIVE: This study aimed to identify gene signatures associated with CRSwNP endotypes, clinical features, and dupilumab treatment response. METHODS: Nasal brushing samples were collected from 89 patients randomized to dupilumab 300 mg every 2 weeks or placebo in the SINUS-52 trial (NCT02898454). Microarrays were used to identify transcriptional clusters and assess the relationship between gene expression and baseline clinical features and clinical response to dupilumab. Endotype signatures were determined using differential expression analysis. RESULTS: Two distinct transcriptional clusters (C1 and C2) were identified, both with elevated type 2 biomarkers. At baseline, C2 patients had higher mean Nasal Polyp Score and higher type 2 biomarker levels than C1 patients. At week 24, significant improvements in clinical outcomes (dupilumab vs placebo) were observed in both clusters, although the magnitude of improvements was significantly greater in C2 than in C1, and more C2 patients demonstrated clinically meaningful responses. Gene set enrichment analysis supported the existence of 2 molecular endotypes: C2 was enriched in genes associated with type 2 inflammation (including periostin, cadherin-26, and type 2 cysteine protease inhibitors), while C1 was enriched in genes associated with T cell activation and IL-12 production. CONCLUSIONS: Two distinct gene signatures associated with CRSwNP clinical features were identified; the endotype signatures were associated with clinical outcome measures and magnitude of dupilumab response.

Tezepelumab improved chronic rhinosinusitis with nasal polyps in a Patient with aspirin exacerbated respiratory disease.

Introduction: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and aspirin-exacerbated respiratory disease (AERD) have more severe sinus disease than those without AERD. CRSwNP associated with type 2 inflammation and AERD can be difficult to control with standard medical therapy and sinus surgery. Case study: 74-year-old Japanese woman with chronic sinusitis since age 50 and asthma since age 60. At age 64, she began to experience asthma exacerbations and was started on short-term corticosteroid therapy with prednisolone. At age 70, she experienced urticaria, nasal congestion, and wheezing after taking an NSAID; based on an NSAID provocation test, we diagnosed the patient with AERD and CRSwNP. A diagnosis of severe eosinophilic chronic rhinosinusitis was also made based on the scoring system and algorithm used in the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis. Results: Treatment with benralizumab (30 mg), formoterol-fluticasone combination via pressurized metered inhaler (1000 µg), and leukotriene receptor antagonist improved the asthma symptoms and exacerbations so the short-term prednisolone was stopped; however, nasal congestion and olfactory dysfunction (hyposmia) persisted, and peripheral blood eosinophil count (peak, 1500 cells/µL) and fractional exhaled nitric oxide (peak, 42 ppb) became elevated. Swapping the benralizumab for monthly tezepelumab (210 mg) improved not only the asthma symptoms but also the nasal congestion, olfactory dysfunction, eosinophil count (<300 cells/µL), and fractional exhaled nitric oxide level [8ppb]. Conclusion: Changing from benralizumab to tezepelumab improved asthma symptoms, nasal obstruction, and olfactory dysfunction in elderly, female, Japanese patient with AERD and CRSwNP.

Preoperative laboratory measurements as a predictor for nasal steroid irrigations after sinus surgery for chronic rhinosinusitis with nasal polyps.

PURPOSE: To assess whether preoperative C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), immunoglobulin E (IgE), and blood eosinophil percentage (EOS) can predict need for steroid irrigations after FESS. MATERIALS AND METHODS: Adult patients at BIDMC from inception until September 8, 2023 with chronic rhinosinusitis with nasal polyps who underwent FESS and had preoperative CRP (n = 129), ESR (n = 79), IgE (n = 107), or EOS (n = 125) were included. Labs were divided into normal (CRP: 0-5.0 mg/L; ESR: 0-15 mm/h; IgE: 150-300Ul/mL; EOS: 1-7 %) and high groups (CRP: >5.0 mg/L; ESR: >15 mm/h; IgE: >300Ul/mL; EOS: >7 %). The primary outcome was need for intranasal steroid irrigations after FESS (≤4 weeks, 4-12 weeks, 12-26 weeks, 26-52 weeks, 1-3 years, 3-5 years, and > 5 years). Receiver operating characteristic curves were created to determine thresholds for predicting postoperative steroid irrigations. RESULTS: Elevated IgE required intranasal steroid irrigation at 1-3 years (normal 34 %, high 62 %, p = 0.02), 3-5 years (normal 24 %, high 48 %, p = 0.04), and > 5 years (normal 19 %, high 43 %, p = 0.02). Elevated EOS required intranasal steroid irrigation at 26-52 weeks (normal 7 %, high 25 %, p = 0.009) and > 5 years (normal 19 %, high 46 %, p = 0.005). The area under the curve for IgE at 1-3 years was 0.696 (95 % CI: 0.597-0.795) with cutoff at 144-148 Ul/mL. CRP and ESR were not predictive of postoperative intranasal steroid treatment. CONCLUSIONS: Elevated IgE and EOS (but not CRP or ESR) may predict need for intranasal steroid treatment after FESS.

Pre-asthma: a useful concept? A EUFOREA paper. Part 2-late onset eosinophilic asthma.

The concept of pre-diabetes has led to provision of measures to reduce disease progression through identification of subjects at risk of diabetes. We previously considered the idea of pre-asthma in relation to allergic asthma and considered that, in addition to the need to improve population health via multiple measures, including reduction of exposure to allergens and pollutants and avoidance of obesity, there are several possible specific means to reduce asthma development in those most at risk (pre- asthma). The most obvious is allergen immunotherapy (AIT), which when given for allergic rhinitis (AR) has reasonable evidence to support asthma prevention in children (2) but also needs further study as primary prevention. In this second paper we explore the possibilities for similar actions in late onset eosinophilic asthma.

Effectiveness and safety profile of mepolizumab in chronic rhinosinusitis with nasal polyps: Real life data in a tertiary care.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation. Mepolizumab was approved for the treatment of CRSwNP in 2021, it may be useful to evaluate its safety profile in a real-world setting. AIM: This work aimed to prospectively highlight the effectiveness and safety profile of Mepolizumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina. METHODS: An observational cohort study was carried out considering all patients treated with Mepolizumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions. RESULTS: A total of 30 patients were treated with Mepolizumab, one patient discontinued the treatment. A statistically significant reduction in the Sino-Nasal Outcome Tests-22 (SNOT-22) and nasal polyp score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, -33 and - 43, p < 0.001 for both comparisons; NPS, 0 and - 1, p < 0.001 for both comparisons). The median (Q1-Q3) sniffin' sticks test score increased from 7 (6-8) at the 6th month to 11 (10-13) at the 12th month. Seven patients (24.1 %) reported pain at the injection site, accompanied by redness, warmth, and tenderness within the first 24 h post-injection with a median duration of three days from the onset. CONCLUSIONS: Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider Mepolizumab a safe and effective treatment in CRSwNP patients. Further studies in real-life setting are necessary to better understand the long-term effects.

The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.

Pharmacokinetics/pharmacodynamics of benralizumab in chronic rhinosinusitis with nasal polyps: Phase III, randomized, placebo-controlled OSTRO trial.

AIMS: Benralizumab, a humanized, afucosylated monoclonal antibody against the interleukin 5 receptor, α subunit, causes rapid depletion of eosinophils by antibody-dependent cellular cytotoxicity. We investigated the pharmacokinetic and pharmacodynamic effects of benralizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) from the phase III OSTRO trial. METHODS: Patients received a placebo or 30 mg of benralizumab by subcutaneous injection every 8 weeks (first three doses every 4 weeks) to week 48; a subset of patients continued in an extended follow-up period to assess treatment durability to week 80. Serum benralizumab concentrations and blood eosinophil and basophil counts were assessed to week 80. Biomarker assessments were performed on nasal polyp tissue biopsies at week 56 and nasal lining fluid at weeks 24 and 56 to examine changes in immune cells and inflammatory mediators. RESULTS: Among 185 patients in this analysis, 93 received benralizumab. Serum benralizumab concentrations reached a steady state by week 24 (median concentration 385.52 ng mL-1); blood eosinophils were almost fully depleted and blood basophils were reduced between weeks 16 and 56. Nasal polyp tissue eosinophils decreased with benralizumab from 57.6 cells mm-2 at baseline to 0 cells mm-2 at week 56 (P < .001 vs placebo), and tissue mast cells were numerically reduced. In nasal lining fluid, eosinophil-derived neurotoxin was significantly reduced at weeks 24 and 56 (P < .001) and interleukin-17 at week 56 (P < .05) with benralizumab. CONCLUSION: Benralizumab treatment led to rapid, sustained, nearly complete depletion of eosinophils from blood and nasal polyp tissue in patients with CRSwNP.

Biologics Reduce Symptoms of Alcohol Intolerance Better than Aspirin Desensitization in Patients with N-ERD and Nasal Polyps.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory disease (N-ERD) is associated with chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and NSAID hypersensitivity. An overproduction of leukotrienes characterizes the pathomechanism of the disease. N-ERD patients often report breathing difficulties after consuming alcohol. These symptoms have been observed in patients receiving either aspirin therapy after desensitization (ATAD), therapy with the biologics dupilumab (anti-IL-4Ra antibody) and omalizumab (anti-IgE antibody), or intranasal corticosteroid treatment (INCS). METHODS: This retrospective, real-world study assessed the severity of alcohol-related and non-alcohol-related respiratory symptoms in CRSwNP/N-ERD patients 3-6 months after ATAD, biologic (dupilumab or omalizumab), or INCS therapy. A total of 171 patients (98 women and 73 men) were enrolled in the study. All groups received standard INCS therapy. Sixty-three patients were treated with ATAD; 48 received biologics (dupilumab n = 31; omalizumab n = 17); and 60 received INCS only and served as a control group. Alcohol-dependent symptoms and typical CRS symptoms (alcohol-independent) were quantified using visual analog scales (VAS). RESULTS: ATAD and biological therapy significantly reduced VAS scores for alcohol dependence and CRS symptoms. In the control group receiving INCS, only non-alcohol dependent CRS symptoms improved significantly (p < 0.05). The most significant differences in pre/post scores were observed in patients receiving dupilumab, with the most significant improvement in alcohol-dependent and CRS symptoms (dupilumab > omalizumab > ATAD). CONCLUSIONS: This real-world study shows that alcohol-related respiratory symptoms are a relevant parameter in CRSwNP/N-ERD patients. Patients benefit more from biologic therapy than from ATAD in terms of their alcohol-related symptoms and other CRS symptoms. Future studies should include placebo-controlled oral alcohol challenge.

Severe hypereosinophilia in a patient treated with dupilumab and shift to mepolizumab: the importance of multidisciplinary management. A case report and literature review.

Type 2 inflammation is a heterogeneous condition due to the complex activation of different immunological pathways. Rapid progress in research to evaluate the efficacy of biologics for chronic rhinosinusitis with nasal polyps and asthma has led to the availability of effective therapeutic options. These drugs are safe, but temporary iatrogenic hypereosinophilia may sometimes be associated with clinical symptoms or organ damage. Here, we describe a case of severe hypereosinophilia in a patient with chronic rhinosinusitis with nasal polyps and asthma treated with dupilumab and a subsequent therapeutic shift to mepolizumab that led to maintenance of symptom control and concomitant normalization of blood eosinophil count.

Chemokine CCL19 and Its Receptors CCR7 and CCRL1 in Chronic Rhinosinusitis.

Background: CCL19 has been shown to predict disease severity in COVID-19 and treatment response in rheumatoid arthritis. CCL19 can exert both pro- and anti-inflammatory effects and is elevated in chronic rhinosinusitis (CRS). However, its role in CRS remains unknown. This study sought to determine the transcriptional changes in CCL19, its receptors, and associated cytokines and their association with disease severity in CRS. Methods: A clinical database of control subjects and patients with CRS was examined. Lund-Kennedy, Lund-Mackay, Sinonasal Outcomes Test 22 (SNOT-22), and rhinosinusitis disability index (RSDI) scores were collected at enrollment. mRNA was extracted from sinonasal tissues and subjected to multiplex gene expression analysis. Gene transcript differences between patients with CRS and controls were compared and correlated with disease severity metrics. Immunohistochemical analyses of CCL19, CCR7, and CCRL1 were conducted to compare differences in protein expression between cohorts. A subgroup analysis was performed to compare transcriptional and protein expression difference between patients with (CRSwNP) and without (CRSsNP) nasal polyps and controls. Results: Thirty-eight subjects (control group, n=7; CRS group, n=31) were included in this study. CCRL1 (p=0.0093) and CCR7 (p=0.017) levels were significantly elevated in CRS compared to those in controls. CCL19 (p=0.038) and CCR7 (p=0.0097) levels were elevated in CRSwNP and CCRL1 was elevated in CRSsNP (p=0.0004). CCR7 expression was significantly elevated in sinonasal epithelial cells in CRSwNP (p=0.04). CCL19 expression was positively correlated with TNFA expression (p<0.0002). CCL19 and CCR7 expression was positively correlated with SNOT-22 and RSDI scores (p<0.05). Conclusion: CCL19 and CCR7 may modulate TNF-α-driven pro-inflammatory signaling and contribute to increased disease severity in CRS. Mechanistic studies are required to further elucidate the role of CCRL1 in CRS.

[Correlation study of NCF2 in chronic rhinosinusitis with nasal polyps].

Objective:After selecting NCF2 based on bioinformatics, clinical experiments were conducted to verify the expression of NCF2 in chronic rhinosinusitis with nasal polyps to study its correlation. Methods:The differentially expressed genes（DEGs） between CRSwNP and non-CRS patients were explored using the CRS-related dataset from the gene expression omnibus GEO database. The weighted gene co-expression network（WGCNA） was used for cluster analysis. The expression and cell distribution of NCF2 in the tissues were determined by single gene enrichment analysis（GSEA）, immune inflammatory infiltration analysis, and principal component（PCA） analysis. The expression degree of NCF2 in the tissues of the subjects was determined by immunohistochemistry, and the percentage of EOS in the peripheral blood of the subjects was detected and the correlation was analyzed. EOS in the tissues of the subjects were counted under a microscope and compared. Results:①The Venn diagram was obtained by crossing the module with the highest correlation between DEGs and WGCNA to determine the core gene NCF2. ②GSEA analysis showed that NCF2 was significantly related to the immunological processes such as allogeneic rejection and asthma. ③The area under the ROC curve was 1, indicating that NCF2 had diagnostic value for CRSwNP. ④NCF2 was highly expressed in nasal polyps, mainly distributed in monocytes and eosinophils. ⑤HE staining showed that the number of EOS in ECRSwNP tissues and the percentage of eosinophils in peripheral blood were higher than those in nonECRSwNP and control groups. ⑥The immunohistochemistry results showed that NCF2 was significantly expressed in the nasal polyps of ECRSwNP patients, which was higher than that in the nasal mucosa of nonECRSwNP group and control group. ⑦The expression of NCF2 in tissues was positively correlated with EOS count in ECRSwNP group and EOS expression in peripheral blood. Conclusion:The expression of NCF2 is increased in eosinophilic chronic rhinosinusitis with nasal polyps, and it is significantly correlated with the expression of eosinophils in peripheral blood and tissues, suggesting that NCF2 may be used as a basis for the intrinsic classification of ECRSwNP and a reference index for clinical diagnosis and treatment.

Anti-thymic stromal lymphopoietin monoclonal antibody in patients with chronic rhinosinusitis with nasal polyps (DUBHE): Rationale and design of a multicenter, randomized, double-blind, placebo-controlled study.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) has a complex pathogenesis and is difficult to treat, which brings a huge economic burden to society. Despite all the progress in the treatment of CRSwNP, some patients with CRSwNP still experience recurrence. Therefore, there is an urgent need to develop novel drugs and treatments for CRSwNP. Thymic stromal lymphopoietin (TSLP) is produced by epithelial cells and mediates type 2 and nontype 2 inflammation through various downstream cellular immune and inflammatory pathways. Anti-TSLP treatment with tezepelumab has been proven to be effective in treating patients with uncontrolled asthma, regardless of their peripheral blood eosinophil levels being low or high. However, there is no relevant research on the usage of anti-TSLP monoclonal antibodies for the treatment of uncontrolled CRSwNP. Objective: This is the first phase Ib/IIa study for subjects with uncontrolled CRSwNP, aiming to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of multiple ascending doses (MAD) of anti-TSLP monoclonal antibody. Methods: The DUBHE is a multicenter, randomized, double-blind, placebo-controlled, phase Ib/IIa clinical study. The study will be composed of 3 periods: a screening/run-in period of 4 weeks, a treatment period of 52 weeks (16 weeks of double-blind treatment period +36 weeks of open-label treatment period), and a safety follow-up period of 12 weeks. No more than 113 subjects with uncontrolled CRSwNP will be divided into 4 groups to receive different doses of CM326 or placebo treatments (55 mg every two weeks [Q2W] group, 110 mg Q2W group, 220 mg Q2W group, and 220 mg every four weeks [Q4W] group). Enrolled patients will be stratified by tissue eosinophil count (TEC). Results: The safety of the monoclonal antibody that targets TSLP in uncontrolled CRSwNP and its preliminary efficacy at 16 weeks of treatment. Conclusion: In this study, for the first time, the safety and preliminary efficacy of MAD of CM326 will be verified. The efficacy of CM326 in patients with eosinophilic CRSwNP (TEC ≥55/high power field [HPF]), as well as noneosinophilic CRSwNP (TEC <55/HPF) will be testified. Trial registration: NCT05324137.

Multidisciplinary Decision-Making-ITAlian Consensus After Two Years of Real Practice on the Management of Severe Uncontrolled CRSwNP by Biologics (ITACA Study).

PURPOSE OF REVIEW: We aimed to reach an Italian multidisciplinary consensus on some crucial aspects of treatment decision making in CRSwNP, following 2 years of clinical experience in order to support specialists in the management of CRSwNP in clinical practice. We addressed issues relating to therapeutic decision-making and shared criteria for the treatment choice, as well as appropriate timing and criteria for evaluating treatment response, and highlighted the need for repeated multidisciplinary assessments. RECENT FINDINGS: A national survey has been conducted recently to understand how rhinology practice has changed in Italy with the advent of biologics and how this affects patients with uncontrolled, severe CRSwNP. Despite the many published consensus documents, practical recommendations, and protocols on the use of biologics in CRSwNP, heterogenous behaviors in practice are still observed mainly conditioned by the novelty of the topic. The consensus procedure followed a modified Delphi approach. The scientific board included 18 otorhinolaryngologists and 8 allergists, who selected the 4 main topics to be addressed and developed overall 20 statements. Consensus on these statements was sought by a larger group of 48 additional experts, through two rounds of voting, the first web-based, the second in presence with discussion and possible refinement of the statements. The statements reaching an average score ≥ 7 at the second voting round were approved. Five statements were proposed for each of the following topics: baseline evaluation of patients eligible for biologic therapy; choice between different therapeutic options; assessment of the response to biologic treatment; multidisciplinary management. At the first voting round, 19 out of the 20 statements reached a mean score ≥ 7. Following the discussion and a few consequent amendments, at the second round of voting all the 20 statements were approved.

Interleukin-19 enhances eosinophil infiltration through upregulation of epithelium-derived RANTES expression via the ERK/NF-κB signalling pathway in patients with eosinophilic CRSwNP.

BACKGROUD: The recurrence rate of chronic rhinosinusitis with nasal polyps (CRSwNP) is positively correlated with eosinophil infiltration. Increased interleukin (IL)-19 and eosinophil chemokine RANTES levels have been reported in patients with CRSwNP. This study aimed to clarify the role of IL-19 in mediating RANTES expression and eosinophilic infiltration in eosinophilic CRSwNP (Eos CRSwNP). METHODS: Nasal tissue samples were obtained from patients with CRSwNP and controls. The expression of IL-19, its receptors, ECP, and RANTES in tissues was investigated. Primary human nasal epithelial cells (HNECs) and nasal polyp tissue blocks were cultured, then stimulated by IL-19; ERK phosphorylation, NF-κB pathway activation, RANTES level, eosinophils migration and infiltration were detected using RT-qPCR, ELISA, western blotting, HE, immunohistochemistry, immunofluorescence staining, confocal microscopy, and transwell migration assay. RESULTS: The expression of IL-19 and its receptors (IL-20R1/IL-20R2), eosinophil cationic protein, and RANTES in nasal tissues from patients with Eos CRSwNP was significantly increased compared to that in non-Eos CRSwNP and control subjects. IL-19 co-localized with RANTES in nasal tissues and significantly elevated RANTES expression in HNECs. IL-19-blocking antibody and siRNA knockdown of IL-20R1 ameliorated the effect of IL-19 on RANTES secretion in HNECs. Moreover, IL-19-induced RANTES upregulation was associated with the activation of the ERK and NF-κB pathways. NF-κB activation was mediated by the ERK pathway in IL-19-treated HNECs, and IL-19 enhanced eosinophil infiltration in nasal polyp tissue blocks. CONCLUSIONS: Our findings indicate that IL-19 promotes RANTES expression via the ERK/NF-κB pathway in HNECs and is implicated in eosinophil infiltration in patients with Eos CRSwNP.