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Previous studies have indicated that oridonin is a promising candidate for therapeutic intervention in a range of inflammatory diseases. The objective of this study was to investigate the protective mechanism of oridonin in chronic rhinosinusitis with nasal polyp (CRSwNP). In nasal polyp (NP) mice model, cigarette smoke (CS) induced polypoid changes compared to previous modeling methods. Compared with CS-treated mice, oridonin reduced polypoid changes, goblet cell count, and promoted the expression of tight junction proteins (ZO-1, occludin, claudin-1) and production of autophagosomes. Following treatment with oridonin, the levels of OVA-specific IgE, IL-6, IFN-γ, IL-5, IL-13 and IL-17A in serum were observed to decrease; the levels of TGF-β1, matrix metalloproteinase 2 (MMP2), MMP7, MMP9 and MMP12 levels in nasal lavage fluid were reduced, while tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were increased. Furthermore, the aforementioned alterations in the mouse model were reversed by 3-methyladenine (3-MA), an autophagy inhibitor. In vitro, cigarette smoke extract (CSE) was observed to decrease the expression of tight junction proteins, the production of autophagosomes, and to reduce the expression of LC3-II and Beclin-1, accompanied by an increase in P62 expression. In addition, oridonin was observed to reverse CSE-induced epithelial barrier damage, and was associated with autophagy and the PI3K/AKT/mTOR pathway. In conclusion, oridonin was demonstrated to improve the damage of the nasal epithelial barrier induced by CS through the promotion of autophagy, which may represent a novel therapeutic option for the treatment of CRSwNP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Chronic rhinosinusitis (CRS) is categorized phenotypically into CRS with and without nasal polyps (CRSwNP, CRSsNP). Endotyping categorizes the disease based on immune cell activity and inflammatory mechanisms into Type 1, Type 2, and Type 3. The Type 2 endotype is the most researched and associated with asthma, atopic disease, and severe CRSwNP. For patients with poorly controlled CRSwNP, there are 3 approved biologic treatments: omalizumab, dupilumab, and mepolizumab. Many other biologics are being tested in Type 2, non-Type 2, and mixed endotypes in CRSwNP and CRSsNP. These studies will play a significant role in shaping the future of CRS management., Competing Interests: Disclosure The authors have no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD), the clinical triad of chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and respiratory reactions to cyclooxygenase 1 inhibitors, is often challenging to manage, with many patients failing first-line therapies for CRSwNP and asthma. There are now 6 biologic medications approved for asthma and/or severe CRSwNP: omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab, and tezepelumab. With the availability of respiratory biologic treatment for both asthma and CRSwNP, clinicians now have a multitude of additional management options for patients with NSAID-ERD. Herein, we review the currently available clinical trial and real-world evidence for biologic efficacy and safety in patients with NSAID-ERD, discuss the mechanisms of biologic therapy specific to NSAID-ERD, and review evidence regarding the use of biologic therapy versus endoscopic sinus surgery for CRSwNP in patients with NSAID-ERD. We propose a management approach for choosing biologic therapy or endoscopic sinus surgery paired with aspirin therapy after desensitization for patients with NSAID-ERD., (Copyright © 2024. Published by Elsevier Inc.)

The classic approach of nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NSAID-ERD) includes pharmaceutical and surgical treatments, as well as avoidance of cyclooxygenase 1-inhibitor NSAIDs. The introduction of biologics in the treatment of severe asthma and chronic rhinosinusitis with nasal polyps represents an alternative therapeutic approach to the classical aspirin therapy after desensitization (ATAD) in some regions, and with convincing results. However, their use is limited due to approval and/or high-cost restrictions. NSAID-ERD is a mainly type 2 and highly eosinophilic disease, and mAbs targeting IgE or IL-5, IL-4, and IL-13 have been shown to be effective for both severe asthma and severe chronic rhinosinusitis with nasal polyps. So far, dupilumab demonstrated greater efficacy in patients with NSAID-ERD than in aspirin-tolerant patients with regard to several clinical outcomes. Patients with NSAID-ERD respond very rapidly to omalizumab also, with reduction in the release of prostaglandin D 2 and cysteinyl leukotrienes. Patients favored biologic treatment over ATAD in multiple retrospective analyses, which must be acknowledged when choosing one or the other option. Although this review will summarize ATAD in general, it will more prominently focus on when ATAD should be considered, even when type 2 biologics are available. In addition, there are conflicting studies as to whether patients on a type 2 biologic become desensitized to NSAIDs, because omalizumab proved to restore tolerance to aspirin in only two-third of patients. This goal of NSAID tolerance should be considered as part of disease control future approaches, representing one of many aspects in a patient-centered care approach., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Acute rhinosinusitis (ARS) is one of the most encountered conditions in primary care and otolaryngology clinics. However, little is known about how antibiotic prescription practices following a diagnosis of ARS compare to guidelines set forth by the American Academy of Otolaryngology in 2015., Objective: To investigate the epidemiology of ARS and the corresponding antibiotic prescribing practices by physicians and compare to published guidelines., Methods: Using the TriNetX Live database, we identified all patients diagnosed with ARS using the ICD10 code J01 between April 2015 and December 2022 across the state of Tennessee. After investigating the demographics of this cohort, we compared the first prescribed antibiotic within one day of ARS diagnosis to published guidelines. Antibiotics were grouped into their respective classes., Results: Of 81 310 patients diagnosed with ARS identified in the specified time frame, 66% were Female, 49% were African American, 44% were White, and the mean age was 47 ± 20 years. The six most common initial antibiotics prescribed for ARS were erythromycins/macrolides [14 609 (25.8%)], amoxicillin/clavulanate [14 322 (25.3%)], amoxicillin [9300 (16.4%)], third generation cephalosporins [7733 (13.6%)], quinolones [3648 (6.4%)] and tetracyclines [2235 (3.9%)]. Of this cohort, 56 719 patients (69.8%) of patients were prescribed an antibiotic within one day of diagnosis., Conclusion: Despite published guidelines recommending amoxicillin with or without clavulanic acid as first-line treatment for ARS, only 42.2% of prescribed antibiotics followed this guideline in our cohort. While accounting for patients with penicillin allergy, the second-most represented antibiotics were erythromycins/macrolides, which are specifically recommended against due to high rates of S. Pneumonia e resistance. Our results suggest that further investigation into the causes of erythromycin/macrolide prescriptions as first line treatment for ARS and practices at other institutions should be conducted. In addition, building awareness around published ARS guidelines for physicians may be useful in improving antibiotic stewardship in treatment of ARS., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Key Points: Data on current practice patterns for the management of chronic rhinosinusitis with nasal polyps, including which medications are deemed by otolaryngologists to better manage patient symptoms, are limited. This study demonstrated that contemporary practice patterns are largely consistent with published clinical consensus statements. Off-label nasal steroid irrigations and dupilumab are the most commonly used topical and systemic therapies for chronic rhinosinusitis with nasal polyps, respectively., (© 2024 ARS‐AAOA, LLC.)

Purpose: Antibody therapy for chronic rhinosinusitis with nasal polyps (CRSwNP) has been established in Germany since 2019. With limited long-term data on biologic treatment for CRSwNP, we conducted a comprehensive evaluation of our 4-year data. This monocentric study aims to assess the real-world effects of this treatment on clinical course, quality of life, treatment adherence, biologic switching, dual therapy, and comorbidities., Methods: We retrospectively analysed biologic therapy data in patients with severe chronic rhinosinusitis with nasal polyps. 191 patients with CRSwNP treated with Dupilumab, Mepolizumab, or Omalizumab were observed for up to 4 years in a real-life setting., Results: We observed clear symptom improvements with few side effects. No loss of efficacy or tolerability was noted during the 4-year period. Patients reported high satisfaction compared to previous therapies, with overall improved quality of life. Revision surgery or oral steroid use during biologic therapy was rare. Some patients prolonged injection intervals or discontinued steroid nasal spray. Biologic switching occurred infrequently due to side effects or inadequate response and was generally well tolerated. Many patients reported additional positive effects such as asthma or allergy symptom improvement and reduced medication intake., Conclusion: In summary, this study confirms the potency and tolerability of biologics for CRSwNP treatment, with sustained efficacy over 4 years. Biologic switching is a viable option for inadequate response or intolerable side effects. Therapy positively impacts Th2 comorbidities, corticosteroid requirements, surgery need, and overall compliance remains high., Clinical Trial Registration: Project No.: 22-0802. Registry name: Biologika bei Patient*innen mit chronischer Sinusitis mit Nasenpolypen., (© 2024. The Author(s).)

Background: Current treatment paradigms recommend surgical intervention when conventional medical management proves ineffective in resolving chronic rhinosinusitis with nasal polyposis., Objectives: To assess and compare the efficacy of dupilumab and functional endoscopic sinus surgery (FESS) for the treatment of chronic rhinosinusitis with nasal polyp (CRSwNP) over time., Methods: Studies comparing CRSwNP patients who received dupilumab with those who underwent FESS were included. Outcome measures included the nasal congestion score (NCS), Sino-nasal Outcome Test-22 (SNOT-22), University of Pennsylvania Smell Identification Test-40 (UPSIT-40), and nasal polyp score (NPS). The risk of bias was evaluated using the Newcastle-Ottawa Scale., Results: A total of 4 studies with 724 participants were included. The dupilumab group had a superior NCS, but an inferior NPS, compared to the FESS group during the follow-up period. The SNOT-22 score of the dupilumab group was inferior to that of the FESS group until 6 months posttreatment, but the scores were similar at around 1 year. A similar trend was observed for the UPSIT-40 score, but the score of the dupilumab group was higher at around 1 year., Conclusion: Functional endoscopic sinus surgery was more effective than dupilumab for several months after treatment. However, at 1 year after treatment, the effects of the 2 treatments became similar, with greater olfactory improvement seen in the dupilumab group., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent chronic inflammatory condition affecting the nose and paranasal sinuses, posing a significant socio-economic impact with substantial challenges in management. Biologics targeting type 2 inflammation such as dupilumab, have emerged as promising options. This study addresses a critical knowledge gap by comprehensively evaluating the 3-year impact of sustained dupilumab therapy in CRSwNP., Methods: A multicentric, retrospective collection of real-world data from five tertiary referral centers in Germany was conducted, enrolling 150 adult patients. The study investigated patient-reported outcomes, disease-specific indices and clinical measures, focusing on therapeutic response persistence, adverse events, and factors influencing treatment continuity., Results: Results indicate significant improvements in clinical parameters from baseline (n = 150) with sustained effectiveness after 36 months (n = 138) as indicated in mean score ± standard deviation. Dupilumab treatment significantly improved overall disease-related impairment (VAS score: 7.5 ± 2.5 to 1.6 ± 1.3) and rhinosinusitis symptoms (SNOT-22: 59.4 ± 19.4 to 18.0 ± 15.0). Nasal Polyp Scores (NPS) decreased (5.3 ± 1.8 to 0.7 ± 1.1), and olfactory function improved (3.2 ± 2.5 to 8.4 ± 2.8), with three out of four patients achieving normosmia or hyposmia after 36 months. An "Excellent" treatment response according to EUFOREA23 criteria was observed in 76.5% of patients after 36 months. Sixteen patients discontinued Dupilumab, 12 permanently. Adverse events totaled 69 in 48 patients, commonly self-limiting., Conclusion: The study highlights the enduring effectiveness and lack of habituation to dupilumab after a sustained therapy of 3 years, providing valuable insights into its long-term therapeutic implications for CRSwNP patients., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Dupilumab exerts clinical effects, including improved sinus opacification, olfactory function, and quality of life, in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNPs). 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: To assess the comprehensive efficacy and therapeutic response to dupilumab in patients with severe CRSwNP with comorbid asthma., Methods: In 16 adult patients with severe CRSwNP 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, 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, Lund-Mackay computed tomography score, and SNOT-22 scores improved significantly. Regarding comorbid asthma, the annualized rate of exacerbations decreased, and ACQ-7 scores and lung function improved significantly. According to the European Position Paper on Rhinosinusitis and Nasal Polyps 2020/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, the rate of asthma exacerbations in the previous year, and blood eosinophil counts benefited more from the treatment., Conclusion: Dupilumab improved upper and lower airway outcomes especially in patients with severe CRSwNP with comorbid, poorly controlled asthma., Trial Registration: UMIN Clinical Trials Registry: UMIN000038669., Competing Interests: Disclosures The authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Elexacaftor/tezacaftor/ivacaftor (ETI), a combination cystic fibrosis transmembrane receptor (CFTR) modulator, has demonstrated improved pulmonary outcomes in individuals with cystic fibrosis (CF). However, ETI's impact on functional endoscopic sinus surgery (FESS) remains unclear., Methods: The TriNetX Analytics Research Network, consisting of 120 million global de-identified electronic medical records, was queried from 2012 to 2023 for subjects with CF who underwent sinus surgery. 1 Patients on ETI prior to FESS (n = 6,056) were propensity score matched to control individuals with CF not on CFTR modulators (n = 37,906) and those on other FDA-approved CFTR modulators (tezacaftor/ivacaftor, lumacaftor/ivacaftor, and ivacaftor) (n = 2437) based on relevant factors. The primary outcome was the absolute risk reduction (ARR) of undergoing FESS. Secondary outcomes included ARR of CF-related pulmonary exacerbations and hospital admission from 0 to 6, 6 to 12, and 12 to 24 months following FESS., Results: ETI use demonstrated a significant ARR for FESS when compared to CF patients not on CFTR modulators (2.12%; 95% confidence interval [CI] 1.5-2.75; p-value < 0.0001) and those on other CFTR modulators (4.7%; 95% CI 3.54-5.85; p-value < 0.0001). No significant differences occurred in secondary outcomes between ETI and non-CFTR modulator groups, except for reduced CF-related pulmonary exacerbations from 0 to 6 months post-FESS. Additionally, a significant reduction in pulmonary exacerbations was observed at all time points and hospital admissions within 6 months following FESS compared to those using other CFTR modulators., Conclusions: In a large dataset, CF patients on ETI demonstrated significantly reduced risk of FESS, pulmonary exacerbations, and hospital admission compared to patients not on CFTR modulators or those on other CFTR modulators, suggesting improved sinonasal disease and overall health status in CF., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Key Points: Chitosan is a promising drug delivery vector for therapeutics owing to its biocompatibility. Once crosslinked with chitosan, prolonged drug release was noted regardless of hydrophilicity. Hydrophilic drugs may require different strategies to obtain a sustained release profile., (© 2024 ARS‐AAOA, LLC.)

Acute rhinosinusitis is one of the most common diseases in the population, both in primary and specialist otolaryngological care. It is also responsible for a disturbingly high percentage of prescribed antibiotic therapy, regardless of the etiology of the disease. Despite the fact that acute viral and acute postviral rhinosinusitis dominate among the phenotypes of acute rhinosinusitis, and the development of acute bacterial rhinosinusitis occurs in only 0.5-2% of all cases in adults and 5-10% in children, antibiotics still remain an important element of treatment, despite alarming data on the growing antibiotic resistance and the adverse effect of antibiotics on the human microbiome, leading to dysbiosis. The discovery of antibiotics was one of the greatest achievements of modern medicine, but their inappropriate use leads to the gradual increase in the phenomenon of antibiotic resistance, considered one of the most serious public health problems, recognized by the WHO as one of the 10 greatest threats to human health in the 21&lt;sup&gt;st&lt;/sup&gt; century. The unjustified use of antibiotics in outpatient care is the key to the growth of this problem, in parallel with the lack of patient compliance. The COVID pandemic has intensified this unfavourable trend. That is why the knowledge of antibiotic stewardship is so important. According to the guidelines, in the therapy of acute rhinosinusitis, symptomatic and anti-inflammatory treatment dominates, and antibiotic therapy has very strictly defined and limited indications. The latest guidelines also recommend herbal medicines, including BNO 1016, in the treatment of acute viral and postviral rhinosinusitis. Available studies indicate that it has a beneficial effect not only on shortening the duration of the disease and reducing symptoms, but also reduces the need for antibiotic treatment in acute rhinosinusitis. Complications of acute rhinosinusitis are relatively rare and are not related to taking antibiotics.

Objective: The objectives of this study were to characterize the endotypes of different chronic rhinosinusitis without nasal polyps (CRSsNP) samples, to investigate the effects of certain anti-inflammatory drugs on these endotypes, and to investigate the effect of the same drugs on recently identified CRSsNP marker proteins., Patients and Methods: Initially, ethmoid tissues (ETs) from CRSsNP patients (n=12) were dissected into sections and incubated with the addition of mometasone, verapamil, cenicriviroc, and dupilumab. Cell culture media were collected after 24 hours, and the contents of the secreted proteins interferon-gamma (IFN-γ), interleukin (IL)-5, IL-17A, macrophage inflammatory protein-1 beta (MIP-1β), resistin and platelet (P)-selectin were measured using enzyme-linked immunosorbent assay (ELISA). The endotypes were characterized using the unstimulated samples. The fold changes of protein secretion caused by the analyzed substances were calculated. For each protein, the samples of the distinct endotypes were compared with the remaining samples., Results: Both single and mixed endotypes were identified within the CRSsNP samples, whereas none of the typical endotype-defining cytokines were elevated in a significant portion of the samples. All of the incubated medicaments greatly reduced the tissue secretions of IFN-γ and IL-5 in type 1 CRS while causing a lower secretion of IL-17A in all endotypes compared to the remaining samples. Among the analyzed CRSsNP marker proteins, the distinct endotypes revealed different reactions to the drugs. Dupilumab induced more effects among the examined cytokines than the marker proteins but did not stand out from the other substances overall., Conclusions: Medications used to treat CRS may have different effects on distinct CRS endotypes.

Background: Anti-IL-4 receptor α antibody (dupilumab) has demonstrated favorable sinonasal outcomes for chronic rhinosinusitis with nasal polyps (CRSwNP), which is mainly caused by type 2 inflammation. Although increased blood eosinophil levels and injection site symptoms are frequently observed as acute adverse events (AEs) of dupilumab, limited knowledge is available regarding the late AEs of dupilumab for CRSwNP., Objectives: We investigated the late AEs following the initiation of dupilumab treatment for CRSwNP., Material and Methods: Fifty-one patients with CRSwNP treated with dupilumab for > 3 months were enrolled, and their clinical data were collected from their medical records., Results: Six (11.8%) patients experienced late AEs. One case of eczema with pruritus, one case of psoriasis-like dermatitis, two cases of severe rash, one case of malignant lymphoma, and one case of alopecia areata were observed. Skin disorders were the most common late AEs in this study. It is a Th1-inflammatory disease, and its mechanism is thought to be due to the immune imbalance caused by dupilumab. We could not confirm whether malignant lymphoma in our case was caused by dupilumab use., Conclusions and Significance: Skin disorders are often late AEs associated with dupilumab; therefore, careful monitoring after dupilumab initiation should be considered.

Background: Biologic therapies approved for treating chronic rhinosinusitis with nasal polyps (CRSwNP) have well-established safety profiles but reports of rheumatic adverse events (AEs) are increasing and not well defined. This review aims to assess the risk and incidence of rheumatic AEs associated with biologic therapy in CRSwNP and summarize current reported management strategies., Methods: A protocol was registered in PROSPERO [CRD42024525663]. A search was conducted in four electronic databases: Medline (Ovid), Embase, Scopus, and Cochrane CENTRAL from inception until January 4, 2024. Two reviewers independently screened citations and extracted data. Methodological quality was assessed using the Joanna Briggs Institute's critical appraisal tool. Data were pooled using a random effects model to calculate overall incidence and relative risk., Results: Twenty-one studies met the final inclusion criteria, totaling 3434 patients of which 2763 (80%) received either dupilumab (n = 2257; 82%), mepolizumab (n = 372; 13%), or omalizumab (n = 134; 5%) for treatment of CRSwNP. The overall incidence rate for any on-treatment rheumatic AE was 0.05 per person-year (95% CI, 0.03-0.09, I 2  = 75%). Biologic therapy increased the risk of developing a rheumatic AE (RR = 2.53; 95% CI, 1.29-4.94) compared with placebo. The most frequently reported rheumatic AE was arthralgia or joint pain (n = 94; 95%), followed by lupus-like syndrome or lupus erythematosus-like reaction (n = 2; 2.5%). Discontinuation of treatment was the most common intervention (n = 21, 39%)., Conclusion: Biologic therapy increases the risk of rheumatic AEs in CRSwNP patients by over twofold. Healthcare providers should remain vigilant in monitoring rheumatic AEs and apply appropriate management strategies on a case-by-case basis., (© 2024 The Author(s). International Forum of Allergy & Rhinology published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngic Allergy and American Rhinologic Society.)

Key Points: A persistent type 2 endotype signature exists in recalcitrant chronic rhinosinusitis with nasal polyps mucosa on dupilumab. Revision sinus surgery immediately prior to dupilumab reduces long-term interleukin (IL)-4/IL-13 tissue mRNA. Pre-dupilumab revision surgery is associated with reduced tissue eosinophils and GATA-3+ cells., (© 2024 ARS‐AAOA, LLC.)

Key Points: Unilateral or destructive sinonasal disease should raise suspicion for tumor. Patients receiving biologic therapy for CRSwNP should be carefully selected. Tissue diagnosis should be considered prior to starting biologics for nasal polyposis., (© 2024 ARS‐AAOA, LLC.)

Background: Nasal polyps (NPs) are commonly associated with chronic rhinosinusitis (CRS). In keeping with the unified airway hypothesis, asthma and CRS with NP (CRSwNP) frequently co-occur, share a similar pathophysiology, and are often treated with oral corticosteroids (OCS); however, a need for alternative treatment options for patients with comorbid asthma and CRSwNP remains., Objective: To characterize the short- and long-term dual airway effectiveness of the anti-interleukin-5 monoclonal antibody, mepolizumab, in real-world patients with asthma and comorbid NP., Methods: Adult patients with CRSwNP who initiated mepolizumab from November 1, 2014, to September 30, 2021, were identified from 2 Merative MarketScan Research Databases. Outcomes were compared for the 12 months pre- and post-mepolizumab initiation and a variable follow-up period. Primary outcomes included the following: annual rate and proportion of patients with NP- and asthma-related exacerbations; NP surgery occurrences; all-cause OCS claims, number of OCS bursts, and daily OCS dose; all-cause and NP-related health care resource utilization., Results: During the 12 months post-index, patients experienced fewer NP- and asthma-related exacerbations, required fewer sinus surgeries, and reduced use of OCS, with fewer all-cause OCS claims and OCS bursts. Significant reductions in asthma exacerbation-related and NP-related health care resource utilization were also observed., Conclusion: This study illustrated the near- and long-term real-world effectiveness of mepolizumab treatment, with a focus on dual lower and upper airway benefit from single-agent add-on therapy. These results may aid physicians in clinical decision-making for patients with asthma and comorbid CRSwNP with complex care needs., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The recent approval of Dupilumab has profoundly revolutionized the management of patients affected by severe and recalcitrant Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). However, a review that summarizes the results of real-life studies and compares them to phase 3 studies SINUS-24 and 52 is still lacking., Materials and Methods: A search of all real-life studies published from 2019 to 2023 was performed. Patients characteristics at baseline and 6 and 12 months after starting Dupilumab were extracted and compared to those from phase 3 trials: age, sex, smoking habits, comorbid asthma and aspirin-exacerbated respiratory disease (AERD), previous endoscopic sinus surgery (ESS), hematic eosinophils and total IgE, NasalAQ2 Polyps Score (NPS), smell, SNOT-22, adverse events (AEs), and response to treatment., Results: 15 papers were included with an overall number of 1658 patients. A higher rate of comorbidities and previous ESS was found in patients from real-life studies. In addition, they had worse smell and SNOT-22 at baseline compared to patients from SINUS-24 and 52. Comorbid and post-ESS patients tended to have a faster NPS and SNOT-22 improvement, although the absolute values were not clinically relevant. A more extensive surgery and a number of ESS ≥ 2 were related to worse olfactory outcomes, probably due to iatrogenic damage. No correlation was found between hematic eosinophils and outcomes. AEs were reported by 12.4% of patients and 2.2% had to discontinue dupilumab. Weight gain was an emergent AE (0.8%), probably related to the restored sense of smell and taste. Non-responders were 3.5% and they were switched to systemic steroid, ESS, or another biologic., Conclusion: Despite some differences in prescription criteria between countries, dupilumab was demonstrated to be effective even in the real-life scenario. However, emerging AEs and possible unknown long-term AEs of a likely lifelong therapy should be considered., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysine residues of histones and other proteins, generally leading to a closed chromosomal configuration and transcriptional repression. Different HDACs have distinct substrate specificities and functions in different biological processes. Accumulating evidence indicates that HDACs play a key role in the pathogenesis of multiple respiratory diseases., Areas Covered: After an extensive search of the PubMed database, Web of Science and ClinicalTrials.gov, covering the period from 1992 to 2024, this review summarizes recent advances in understanding the role of HDACs in inflammatory respiratory diseases, including allergic rhinitis (AR), chronic rhinosinusitis (CRS), asthma and chronic obstructive pulmonary disease (COPD). We also examine recent progress on the efficacy and potential use of histone deacetylase inhibitors (HDACi) for the treatment of these diseases., Expert Opinion: Available data indicate that HDACs play an important role in the development of common inflammatory respiratory diseases, and HDACi have shown promise as treatments for these diseases. However, the exact roles and underlying mechanisms of specific HDACs in disease pathogenesis require further study. Additional work is necessary to develop novel potent HDACi with high isoform selectivity.

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., (© 2024. The Author(s).)

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 FEV 1 ≥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., (© 2024 The Author(s). Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Key Points: CRSwNP-specific mean total annual spending ranged from $5,837 (EDS-FLU) to $28,058 (dupilumab). Most CRSwNP patients receiving biologics had comorbid asthma and did not undergo sinus surgery. While biologics were covered by most Medicare Part D plans, only 37% of plans covered EDS-FLU., (© 2024 ARS‐AAOA, LLC.)

Background: Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of oncologic therapies whose mechanism of action can result in unique immune-related adverse events (irAEs) not seen in other cancer therapeutics. The objective of this study was to determine the presence of sinonasal irAEs with these medications., Methods: A case report of chronic rhinosinusitis with nasal polyps (CRSwNP) caused by an ICI is presented and was the impetus for this review. Review of the literature using Pubmed and Cochrane Database of Systematic Reviews was performed. Additionally, we searched the FDA adverse event reporting system (FAERS) database for sinonasal AEs in the 7 FDA-approved ICIs., Results: We demonstrate an emerging scientific literature describing cases of CRS associated with multiple ICIs with a particular predilection toward TH2 driven phenotypes. Review of the FAERS also demonstrates a small percentage of patients who report sinonasal complaints after initiating ICI therapy., Conclusion: Sinonasal symptoms and the development of CRS, in particular, are not currently well recognized as potential irAEs for ICIs. Increased awareness and further study may help to elucidate if these are more common than currently reported and if irAE-related CRS is a unique phenotype., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: This randomised, double-blind, placebo-controlled, parallel-group, 52-week Phase III study (MERIT; NCT04607005) assessed mepolizumab efficacy and safety in patients with chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS (ECRS) in Japan, Russia, and China, for which data are limited., Methodology: Eligible patients (enrolled at 60 centres) had blood eosinophil count >2%, endoscopic bilateral NP score ≥5, nasal obstruction visual analogue scale (VAS) score >5, ≥2 sinonasal symptoms, and either previous sinus surgery or systemic corticosteroid use/intolerance. Patients were randomised (1:1) to receive mepolizumab 100 mg subcutaneously or placebo every 4 weeks, plus standard of care. Co-primary endpoints: change from baseline in total endoscopic NP score (ENPS) (Week 52) and nasal obstruction VAS score (Weeks 49-52). Post hoc analyses conducted in a modified intent-to-treat (mITT) population excluded patients from two study sites, related to Good Clinical Practice violations by the Site Management Organisation overseeing these sites. These were considered the primary efficacy analyses., Results: In the mITT population, mepolizumab (n=80) versus placebo (n=83) significantly improved nasal obstruction VAS score from baseline to Week 49-52 and was associated with a trend of total ENPS improvements at Week 52. Mepolizumab/placebo on-treatment adverse events (AEs) occurred in 68/84 and 65/85 patients in the safety population (treatment-related AEs: 2/84 and 5/85, respectively), and on-treatment serious AEs in 0/84 and 4/85 patients, respectively (no fatalities reported)., Conclusions: Mepolizumab was effective and well-tolerated in patients with CRSwNP/ECRS from Japan, Russia, and China.

Topical delivery to paranasal sinuses through sustained-release stents is one of the new horizons in treating chronic rhinosinusitis (CRS). This study aims to introduce and evaluate sustained co-release of encapsulated ciprofloxacin (CIP) and dexamethasone (DEX) in polyvinyl alcohol-based carriers within the maxillary sinus of rabbit animals. DEX and CIP were loaded in a tyramine-substituted polyvinyl alcohol microparticle (PVATyr MP). The mechanical stability, degradability, and sustained-release patterns of both drugs as well as cellular cytocompatibility were assessed in vitro. The PVATyr MPs were then injected into the maxillary sinus of rabbits and they were monitored weekly for 21 days. Nasal endoscopy, MRI imaging, and tissue microscopy were used to follow the changes and compared them with the control condition. Also, the concentrations of drugs were evaluated in the maxillary sinus and blood samples over the study period. Produced PVA-based MPs possessed a relatively narrow particle size distribution (CV 7.7%) with proper physical stability until 30 days of incubation. The uniform-sized PVATyr MPs and their surrounding hydrogel showed sustained-release profiles for DEX and CIP for up to 32 days in vitro. The injected drugs-loaded hydrogel showed complete clearance from the maxillary sinus of rabbits within 28 days. The concentrations of DEX and CIP in mucosal remained within the therapeutic window when measured on days 7, 14, and 21, which were well above the plasma concentrations without any pathological changes in endoscopy, MRI imaging, and histological examinations. DEX/CIP loaded PVATyr MPs provided an effective, controlled, and safe sustained-drug delivery in both in vitro and in vivo analyses at therapeutic concentrations with minimal systemic absorption, suggesting a promising treatment approach for CRS., (© 2024. The Author(s).)

Some cases of chronic rhinosinusitis (CRS) require surgical treatment and postoperative nasal packing, but bleeding and adhesion are common complications after nasal surgery. Biodegradable drug-loaded implants hold great therapeutic options for the treatment of CRS, but little data are available regarding the safety and efficacy of a novel drug-loaded haemostatic sponge (DLHS) in the sinus. The aim of this study was to investigate the safety and efficacy of DLHS in the sinus. We conducted a prospective, randomized, controlled, double-blind clinical trial. In this clinical trial, 49 patients were enrolled and randomly divided into 2 groups: group A (n = 25) had the DLHS containing 1 mg budesonide and 0.67 mg sodium hyaluronate placed into the sinus, and group B (n = 24) had the Nasopore placed after ESS. Endoscopic follow-up was performed for 12 weeks, and the findings were classified using the discharge, inflammation, polyps/oedema (DIP) endoscopic appearance scores. All patients completed questionnaires to evaluate their sinonasal symptoms by using the sinonasal outcome test-22 (SNOT-22) Chinese version and visual analogue scale (VAS). Serum cortisol concentration in group A was measured prior to surgery and at days 1, 3, 7, and 14 after nasal surgery. Comparing group A and group B, at 2 weeks, no significant differences were observed in either objective or subjective parameters. The mean value of VAS for rhinorrhoea and DIP for oedema and the mean value of nasal adhesion were significantly lower in Group A than in Group B at 6 and 12 weeks, but a significant difference did not occur in SNOT-22 and VAS for dysosmia between the two groups at 6 and 12 weeks. The mean serum cortisol concentrations in group A at the follow-up were within normal limits without remarkable fluctuations. This study demonstrates the safety and efficacy of a novel biodegradable DLHS with the possibility of being used in CRS patients, and this sponge may reduce inflammation and minimize adhesions via controlled local drug delivery without measurable systemic exposure., (© 2024. The Author(s).)

Primary ciliary dyskinesia (PCD) is a heterogeneous genetic disorder associated with abnormalities in ciliary structure and function. Here, we report A 22-year-old non-smoking Chinese man with recurrent episodes of respiratory tract infections and sinusitis since high school period. The diagnosis is more complicated by the atypical symptoms and the late age of onset. We summarized the clinical characteristics of this case and literature review. This report aimed to improve the clinical understanding of primary ciliary dyskinesia.

Objective: Several monoclonal antibodies (MoAbs) targeting specific type 2 immune reactions have been developed as innovative therapeutic approaches for chronic inflammatory airway diseases, such as chronic sinusitis with nasal polyps (CRSwNP) and asthma. However, the clinical safety of these MoAbs and how to choose them are not clear. Therefore, we aimed to assess the systemic drug- and dose-based safety of MoAbs in chronic airway inflammation using network meta-analysis (NMA)., Methods: Electronic databases were systematically searched for relevant studies published in English between January 2009 and December 2022. Eligible studies must have clearly reported adverse events (AEs) among the MoAbs' safety data., Results: 1). Regarding serious AEs, mepolizumab was significantly safer than placebo; in terms of permanent treatment discontinuation, reslizumab and dupilumab were significantly safer than benralizumab. 2). Regarding asthma worsening, dupilumab was associated with the best safety profile; was safer than dupilumab/300 mg/q2-4w. 3). In terms of injection-site reactions, dupilumab posed a higher risk than placebo; dupilumab/300 mg/qw posed a higher risk than dupilumab/300 mg/q2w and dupilumab/300 mg/q2-4w; lebrikizumab/250 mg/q4w posed a higher risk than lebrikizumab/37.5 mg/q4w; mepolizumab/100 mg/q4w posed a higher risk than mepolizumab/75 mg/q4w; benralizumab/30 mg/q4-8w posed a higher risk than benralizumab/20 mg/q4-8w. 4) In CRSwNP patients combined with asthma, the risks of experiencing AEs were not increased., Conclusion: Overall, biologics are safe and well tolerated in chronic inflammatory airway disease. This drug- and dose-based NMA provides further evidence on the different safety profiles of different emerging MoAbs. This information may help guide rational drug use and provide clinical recommendations for choosing MoAbs., Trial Registration: SYSTEMATIC REVIEW REGISTRATION (PROSPERO #CRD42023387610)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chronic rhinosinusitis with nasal polyps (CRSwNP) significantly impacts quality of life and often presents therapeutic challenges, with biologics like dupilumab showing promise in managing severe, uncontrolled cases. The aim of this study was to assess the influence of overweight on the effectiveness of dupilumab in patients with uncontrolled CRSwNP. This retrospective study analyzed treatment outcomes of 75 CRSwNP patients receiving dupilumab, categorizing them into underweight/normal-weight (BMI ≤ 24.9 kg/m 2 ) and overweight/obese (BMI ≥ 25 kg/m 2 ) groups. Outcome measures included changes in nasal polyp score (NPS) and sinonasal outcome test (SNOT-22) scores. Results demonstrated that the underweight/normal-weight group experienced significantly greater improvements in NPS and a higher rate of total NPS improvement compared to the overweight/obese group. While SNOT-22 scores improved in both groups, no significant differences were observed. Among patients with comorbid asthma, the underweight/normal-weight subgroup also showed significantly better outcomes, including greater reductions in both NPS and SNOT-22 scores. Multiple regression analysis identified BMI as an independent prognostic factor for NPS outcomes. The findings suggest that overweight/obesity adversely affects the response to dupilumab in CRSwNP, emphasizing the need for personalized treatment strategies considering BMI.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent medical condition. Type 2 inflammation signs CRSwNP in western countries. Type 2 inflammation leads to nasal airflow limitation. Budesonide aqueous nasal spray (BANS) is an intranasal corticosteroid (INCS); it has been launched in the early 1980s. BANS is indicated for treating allergic rhinitis, nonallergic rhinitis, and nasal polyps (both as treatment and prevention after surgery). Consolidated evidence documented its efficacy in treating CRSwNP. In addition, BANS is safe with negligible local and systemic side effects. Recent guidelines for patients with CRSwNP recommend using INCS as the first line in many situations. In particular, patients may assess the perception of symptoms' severity using the Visual Analog Scale (VAS). A score >5/10 means uncontrolled symptoms in both diseases and requires adequate treatment. BANS could appropriately be used in patients with uncontrolled symptoms and/or moderate/severe nasal obstruction. In addition, BANS may adequately integrate surgery and biologics for CRSwNP management. In conclusion, BANS represents a valuable option in managing patients with type 2-mediated CRSwNP.

Purpose: Since its release, Dupilumab has shown great results in treating severe uncontrolled CRSwNP. However, there is a lack of real-world data beyond 12 months of follow-up, and it is not clear to what extent biomarkers are appropriate for monitoring and predicting the Dupilumab therapy success. Hence, this study aims to analyze biomarkers for monitoring therapy, predicting therapy success and assess the effect of Dupilumab in real-world settings., Methods: The follow-up was performed with 104 patients retrospectively up to 22 months, assessing SNOT-22, NPS, olfactometry, ACS, FEV-1, and blood biomarkers (total serum IgE, Eosinophils, ECP). Patients were divided into subgroups depending on their pretherapeutic biomarker levels and subsequent development was analyzed., Results: There was substantially improvement in all clinical parameters up to 1 year and then continuously up to month 22. Patients with initially elevated baseline blood eosinophil counts (> 0.5 billion/L) had a trend of better SNOT-22 development after 1 year (- 12.19 points, p = 0.03). The course of total serum IgE showed moderate correlation with almost all clinical variables obtained. Therapy was well tolerated with only mild and transient adverse events., Conclusion: Dupilumab has considerably reduced symptoms and disease severity even beyond 1 year of treatment, supporting its role as targeted and effective treatment option for CRSwNP. Our data shows that total serum IgE is a promising biomarker for the monitoring during the treatment with Dupilumab. Elevated pre-therapeutic serum eosinophil counts may be a predictor of good subjective response to therapy. Larger cohorts and a long-term-follow-up over years are needed to further consolidate these findings., (© 2024. The Author(s).)

Background: Dupilumab, a monoclonal antibody targeting IL-4 and IL-13, has demonstrated its efficacy in several clinical trials. However, to date, real-life data remains limited., Objective: The aim of our study was to assess the real-life impact of dupilumab on patients with severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) quality of life., Materials and Methods: This was a retrospective, monocentric, observational, real-life study, conducted in accordance with the STROBE guidelines. The following parameters were collected before treatment and at 1, 4, and 12 months: Sino-Nasal Outcome Test-22 (SNOT-22), nasal polyp score (NPS), Sniffin' Sticks-16 (SST-16), visual analog scale (VAS) for loss of smell, nasal congestion score (NCS), gustatory VAS, asthma control, oral corticosteroid usage, surgery rates, and occurrence of side effects., Results: The study included 47 patients. SNOT-22 scores decreased from 52.4 ± 24.3 to 12.7 ± 10.5 at 12 months (p < 0.001). NPS decreased from 6.15 ± 1.71 to 1.57 ± 1.40 at 12 months (p < 0.001). SST-16 scores increased from 1.6 ± 2.83 to 9.1 ± 5.4 at 12 months (p < 0.001). NCS decreased from 2.45 ± 0.72 to 0.38 ± 0.63 at 12 months (p < 0.001). Prior to treatment, 72.3% were using oral corticosteroids, compared to 17.0% at 12 months (p < 0.01). Two patients required additional surgery, and 17% reported completely uncontrolled asthma, compared to 0% at 12 months (p < 0.01)., Conclusion: Our real-life results confirm the efficacy of Dupilumab in the treatment of severe and uncontrolled CRSwNP., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Evidence supporting topical steroids for the treatment of chronic rhinosinusitis without nasal polyposis (CRSsNP) is unclear. Recent trials describe alternative topical steroid delivery modalities, including rinses and exhalation delivery system (EDS), necessitating a re-examination of the current literature., Methods: Cochrane Library, CINAHL, PubMed, and Scopus databases were searched from inception to February 13, 2024 for placebo-controlled randomized control trials on topical steroids used to treat CRSsNP, including topical spray, nasal irrigation, sinonasal catheter, and EDS modalities. Primary outcome measures included total symptom scores (TSS) (Δ) and response rates (odds ratio)., Results: Ten trials (N = 751) were included for meta-analysis, with a mean age of 47.5 years (range: 18-80 years; 95% confidence interval [CI]: 43.9-51.2 years). Topical steroids delivered by any method significantly improved TSS in CRSsNP patients (Δ0.4; 95% CI: 0.3-0.6; p < 0.0001). When stratified by allergy status, CRSsNP patients without allergy had significantly improved TSS when treated with EDS (Δ0.4; 95% CI: 0.1-0.7; p = 0.01), but not with topical spray (Δ0.04; 95% CI: -0.9 to 1.0; p = 0.94). Patients treated with EDS or sinonasal catheter responded significantly better compared to placebo (odds ratio [OR]: 3.4; 95% CI: 1.9-6.0; p < 0.0001; OR: 12.4; 95% CI: 1.8-83.8; p < 0.01), whereas patients treated with topical spray had no significant difference (OR: 1.8; 95% CI: 0.9-4.0; p = 0.12)., Conclusions: Topical steroids are effective in treating CRSsNP, especially when delivered via EDS or sinonasal catheter. Future trials comparing steroid delivery mechanisms using validated outcome measures in CRSsNP populations are needed., (© 2024 ARS‐AAOA, LLC.)

Background: Orbital involvement of invasive fungal sinusitis (IFS) is an ominous prognostic marker that should prompt rapid intervention. Transcutaneous retrobulbar administration of amphotericin B (TRAMB) is an off-label adjunctive treatment that can increase drug penetrance into diseased orbital tissue. To date, there is a lack of consensus regarding the use of TRAMB for treatment of IFS with orbital involvement., Objective: This systematic review aims to synthesize the indications, efficacy, and potential complications of TRAMB., Methods: PubMed, EMBASE, and Web of Science databases were probed for systematic review. Article search was conducted through June 2023 using the keywords "invasive fungal sinusitis," "invasive fungal rhinosinusitis," "rhino-orbital mucormycosis," "rhinosinusitis," "orbital," "retrobulbar," and "amphotericin.", Results: In suitable cases as determined by radiologic and clinical evaluation, TRAMB administration has the potential to improve orbital salvage rates and improve versus stabilize visual acuity. Treatment complications are more likely with deoxycholate than with liposomal amphotericin formulations. The existing literature describing use of TRAMB is limited due to its retrospective nature, but the increase in IFS cases since 2020 due to the COVID pandemic has broadened the literature., Conclusions: TRAMB is an effective adjunctive treatment in IFS with mild-to-moderate orbital involvement when used in combination with standard of care debridement, systemic antifungal therapy, and immunosuppression reversal. Prospective longitudinal studies and multi-institutional randomized trials are necessary to determine the definitive utility of TRAMB.

Objectives: The 22-question SinoNasal Outcome Test (SNOT-22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT-22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT-22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF)., Methods: Prospective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT-22 scores were obtained at baseline and after 3-6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution-based methods were used to assess internal consistency and calculate the MCID of the SNOT-22., Results: A total of 184 PwCF participated with mean baseline SNOT-22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre- and post-HEMT data reported improvement in SNOT-22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT-22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02-1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14-18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39-20.11) were associated with greater SNOT-22 improvement. The mean MCID calculated via distribution-based methods was 8.5., Conclusion: Worse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT-22 in PwCF is 8.5 points, similar to non-CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT-22 has strong internal consistency in PwCF., Level of Evidence: 3 Laryngoscope, 134:3965-3973, 2024., (© 2024 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

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., Competing Interests: Disclosure Statement This study was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Disclosure of potential conflict of interest: K. Gayvert, J. Horowitz, J. D. Hamilton, and W. K. Lim are employees of Regeneron Pharmaceuticals Inc, and may hold stock and/or stock options in the company. M. Desrosiers reports clinical trial funding from AstraZeneca, GlaxoSmithKline, Probionase Therapies, and Sanofi; is an advisory board member of Regeneron Pharmaceuticals Inc and Sanofi; and is an equity holder in Probionase Therapies. T. M. Laidlaw is an advisory board member for GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc, and Sanofi. L. P. Mannent, K. Patel, and A. Jagerschmidt are employees of Sanofi and may hold stock and/or stock options in the company. N. Amin and S. Harel are former employees of Regeneron Pharmaceuticals Inc and may hold stock and/or stock options in the company., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In health, nitric oxide (NO) shows high concentrations in the upper airways, while nasal NO (nNO) is significantly lower in patients with sinonasal inflammation, such as people with cystic fibrosis (PwCF). In PwCF treated with elexacaftor/tezacaftor/ivacaftor (ETI; PwCF-ETI), clinical improvement of sinonasal symptoms and inflammation was observed. We therefore hypothesised that ETI may increase nNO in PwCF., Methods: 25 PwCF-ETI underwent nNO measurement at baseline and after 3 to 24 months of ETI treatment. NNO was measured using velum closure (VC) techniques in cooperative patients and tidal breathing (TB) for all patients. As controls, 7 CF patients not eligible for ETI (PwCF-non ETI) and 32 healthy controls (HC) were also repeatedly investigated., Results: In PwCF-ETI, sinonasal symptoms, lung function parameters and sweat chloride levels improved from baseline to follow-up whereas there was no change in PwCF-non ETI and HC. NNO increased from a median (IQR) value at baseline to follow-up from 348.2 (274.4) ppb to 779.6 (364.7) ppb for VC (P < 0.001) and from 198.2 (107.0) ppb to 408.3 (236.1) ppb for TB (P < 0.001). At follow-up, PwCF-ETI reached nNO values in the normal range. In PwCF-non ETI as well as HC, nNO did not change between baseline and follow-up., Conclusions: In PwCF-ETI, the nNO values significantly increased after several months of ETI treatment in comparison to baseline and reached values in the normal range. This suggests that nNO is a potential non-invasive biomarker to examine sinonasal inflammatory disease in PwCF and supports the observation of clinical improvement in these patients., Competing Interests: Declaration of competing interest Z.S. reports payments for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Vertex Pharmaceuticals Incorporated, outside the submitted work. S.G. reports grants with payments made to the institution from Mukoviszidose e.V. (German CF foundation) and Vertex Pharmaceuticals Incorporated, outside the submitted work and personal payments for presentations and advisory boards from Chiesi GmbH and Vertex Pharmaceuticals Incorporated, outside the submitted work. E.S. reports a grant for attending meetings and/or travel from the European Cystic Fibrosis Society, outside of the submitted work. J.R. reports payment for presentations among educational events and attending meetings from Vertex Pharmaceuticals Incorporated, outside the submitted word. Additionally, he is work package leader in BEAT-PCD (ERS-CRC). M.A.M. reports grants from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and German Innovation Fund with payments to the institution and grants, consulting fees, lecture fees, fees for participation in advisory board and travel reimbursement from Vertex Pharmaceuticals Incorporated, outside the submitted work. Additionally, he reports consulting fees, fees for participation in advisory board and travel reimbursement from Boehringer Ingelheim, outside the submitted work. Further, he reports consulting fees and fees for participation in advisory board from Abbvie, Antabio, Arrowhead, Enterprise Therapeutics and Kither Biotec, outside the submitted work. Furthermore, he reports consulting fees from Prieris, Recode, Santhera, Splisense, outside the submitted work. He further reports personal fees for participation in advisory board from Pari, outside the submitted work. He is a Fellow of ERS (FERS). M.S. reports grants from the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG; STA 1685/1–1). She is Chairman of the German CF Research Council (FGM) and Treasurer of the German Society of Paediatric Pulmonology (GPP). All other authors have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background: Patients with severe asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, that can increase the symptom burden and complicate treatment. Real-life clinical data on the impact of biologic treatments on CRS-specific quality-of-life questionnaires are still lacking., Materials and Methods: In this retrospective real-life study, we collected data from patients with severe asthma with comorbid CRS with/without nasal polyposis at baseline, and after 3, 6 and 12 months of treatment with omalizumab, mepolizumab, benralizumab or dupilumab. In particular, we evaluated improvements in HRQoL as measured by SinoNasal Outcome Test-22 (SNOT-22, 0 - 110), Visual Analog Scale symptom scores (VAS, 0-10), and Asthma Control Test (ACT, 5-25) and the proportion of patients meeting the minimal clinically important difference (MCID)., Results: Disease-specific HRQoL, as measured by SNOT 22 and VAS score improved in all patients at 3, 6, and 12 months of treatment compared with baseline (SNOT-22: 14, IQR: 0-52 vs 10, IQR:0-30 vs 0, IQR:0-15 vs 0, IQR:0-12, p  < 0.001, VAS score: 1, IQR: 0-5 vs 0, IQR:0-3 vs 0, IQR:0-2 vs 0, IQR 0-1, p  < 0.001). After 3 months of treatment >80% of patients reached the MCID for ACT, while only patients on dupilumab showed to reach a MCID in 100% of cases. The effect size depended upon the symptom burden at baseline., Conclusions: The study confirms the efficacy of omalizumab, mepolizumab, benralizumab, and dupilumab in a real-life setting, with a rapid improvement in CRS-specific HRQoL and general health status. These data highlight the importance of targeting type 2 inflammation in asthmatic patients with co-existing upper and lower airways disease.The Authors disclose that preliminary data and analysis of the present study have been presented in abstract form during the "X International Workshop on Lung Health - Respiratory Disease and Immune Response", held in Nice on 19-21 January 2023.

Objectives: Dupilumab, an anti-IL-4 receptor monoclonal antibody (mAb), was recently approved for the treatment of severe chronic rhinosinusitis with nasal polyps (CRSwNP). The main objective of this study was to assess whether previous exposure to biological treatment affected the clinical outcomes in CRSwNP and asthma patients, treated with dupilumab over time. A collateral secondary objective was to analyse the effects over time of dupilumab in patients with and without aeroallergen sensitization., Methods: Single-centre retrospective observational study on severe CRSwNP patients treated with dupilumab. Nasal polyp score (NPS), visual analogue scale (VAS) symptom score, sinonasal outcome test (SNOT-22), aeroallergen sensitization, total serum IgE levels, and blood eosinophil counts were assessed at baseline and after 4, 6 and 12 months., Results: 42 patients were included, 40 (95.2%) had asthma. Twenty-one (50%) patients received dupilumab without prior biological treatment (Group A: naive) and 50% switched to dupilumab from previous biological treatment (Group B: pre-treated). NPS, VAS symptoms, SNOT-22 improved significantly after 12 months treatment in both groups of patients ( p  < 0.001). After 12 months, VAS overall symptom score showed a significant reduction from 6 (IQR, 4.6-8.6) and 6 (IQR, 3.8-7.1) for Group A and Group B patients respectively, to 1.2 (IQR, 0.8-2.7) and 1.2 (IQR, 0.2-2.5); NPS from 6 (IQR, 4.0-7.0) and 5 (IQR, 3.5-6.0), respectively, to 1 (IQR, 0.0-2.0) and 0 (IQR, 0.0-3.0) and SNOT-22 from 64 (IQR, 56-78) and 71 (IQR, 47.5-76.0) respectively, to 5.5 (IQR, 4-21) and 6 (IQR, 4-15). IgE reduced from 57 to 22.1 and from 46.9 to 30.2 in Group A and Group B respectively ( p  < 0.001)., Conclusions: Dupilumab improves symptom severity, polyp size, and health-related quality of life, regardless of the presence or absence of comorbid aeroallergen sensitization and previous administration of biologic therapy.

Background: Yujiang Paidu Decoction (YJPD) has demonstrated clinical efficacy in the treatment of chronic rhinosinusitis. However, the effects and mechanisms of the YJPD on chronic rhinosinusitis with nasal polyps (CRSwNP) remain unclear., Purpose: This study aimed to elucidate the potential mechanism of action of YJPD in the treatment of CRSwNP based on network pharmacology, transcriptomics and experiments., Methods: A CRSwNP mouse model was established using ovalbumin (OVA) and staphylococcus aureus enterotoxin B (SEB) for 12 weeks and the human nasal epithelial cell (HNEpC) model was induced with IL-13 in vitro. Behavioral tests, scanning electron microscopy (SEM), micro-CT and pathological change of nasal tissues were observed to investigate the therapeutic effects of YJPD. Network pharmacology and transcriptomics were launched to explore the pharmacological mechanisms of YJPD in CRSwNP treatment. Finally, an ELISA, immunofluorescence, RT-qPCR, Western blotting and Tunel were performed for validation., Results: Different doses of YJPD intervention effectively alleviated rubbing and sneezing symptoms in CRSwNP mice. Additionally, YJPD significantly reduced abnormal serological markers, structural damage of the nasal mucosa, inflammatory cell infiltration, goblet cell increases, and inhibited OVA-specific IgE levels and the secretion of Th2 cytokines such as IL-4, IL-5, and IL-13. Moreover, transcriptomics and network pharmacology analyses indicated that YJPD may exert anti-inflammatory and anti-apoptotic effects by inhibiting the MAPK/AP-1 signaling pathway. The experimental findings supported this conclusion, which was further corroborated by similar results observed in IL13-induced HNEpCs in vitro., Conclusion: YJPD could alleviate inflammatory status and epithelial apoptosis by inhibiting aberrant activation of MAPK/AP-1 signaling pathway. This finding provides a strong basis for using YJPD as a potential treatment in CRSwNP., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Li et al.)

Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has revolutionized the treatment of cystic fibrosis (CF) for most affected individuals but the effects of treatment on sinus microbiota are still unknown. Changes to the airway microbiota in CF are associated with disease state and alterations to the bacterial community after ETI initiation may require changes to clinical management regimens. We collected sinus swab samples from the middle meatus in an observational study of 38 adults with CF and chronic rhinosinusitis (CRS) from 2017 to 2021 and captured the initiation of ETI therapy. We performed 16S and custom amplicon sequencing to characterize the sinus microbiota pre- and post-ETI. Real-time quantitative PCR (RT-qPCR) was performed to estimate total bacterial abundance. Sinus samples from people with CF (pwCF) clustered into three community types, dependent on the dominant bacterial organism: a Pseudomonas -dominant, Staphylococcus -dominant, and mixed dominance cluster. Shannon's diversity index was low and not significantly altered post-ETI. Total bacterial load was not significantly lowered post-ETI. Pseudomonas spp. abundance was significantly reduced post-ETI, but eradication was not observed. Staphylococcus spp. became the dominant organism in most individuals post-ETI and we showed the presence of methicillin-resistant Staphylococcus aureus (MRSA) in the sinus both pre- and post-ETI. We also demonstrated that the sinus microbiome is predictive of the presence of Pseudomonas spp., Staphylococcus spp., and Serratia spp. in the sputum. Pseudomonas spp. and Staphylococcus spp., including MRSA, persist in the sinuses of pwCF after ETI therapy, indicating that these pathogens will continue to be important in CF airway disease management in the era of highly effective modulator therapies (HEMT).IMPORTANCEHighly effective modulator therapies (HEMT), such as elexacaftor/tezacaftor/ivacaftor (ETI), for cystic fibrosis (CF) have revolutionized patient care and quality of life for most affected individuals. The effects of these therapies on the microbiota of the airways are still unclear, though work has already been published on changes to microbiota in the sputum. Our study presents evidence for reduced relative abundance of Pseudomonas spp. in the sinuses following ETI therapy. We also show that Staphylococcus spp. becomes the dominant organism in the sinus communities of most individuals in this cohort after ETI therapy. We identified methicillin-resistant Staphylococcus aureus (MRSA) in the sinus microbiota both pre- and post-therapy. These findings demonstrate that pathogen monitoring and treatment will remain a vital part of airway disease management for people with cystic fibrosis (pwCF) in the era of HEMT., Competing Interests: The authors declare no conflict of interest.

This study aimed to clarify other diseases claimed simultaneously with acute upper respiratory infection (URI), antibiotic prescriptions, and examinations associated with infectious diseases in pediatric patients with acute URI insurance claims at otorhinolaryngology outpatient visits. Pediatric patients who visited an otolaryngology department between 2019 and 2021 and were definitively diagnosed with URI were selected using a large Japanese medical claims database. Patient backgrounds, antibiotic use, and examinations were descriptively evaluated. In total, 8010 patients were included in the analysis. The median number (interquartile range) of diseases claimed in the same month as acute URI was 4 (3-6). Only 519 (6.5 %) patients were claimed as acute URI alone. Regardless of the prescription of antibiotics, the most commonly redundantly claimed disease in these patients was allergic rhinitis, followed by acute bronchitis, acute sinusitis, and earwax impaction. The frequently prescribed antibiotics were third-generation cephalosporins, macrolides, and penicillins with extended-spectrum, including amoxicillin which was recommended by the Japanese manual; the proportion of patients with examinations was low (2.9-21.7 %). Among patients with acute URI, diagnoses requiring antibiotics were also claimed; therefore, when evaluating acute URI using the Japanese medical claims database, care must be taken in patient selection. Moreover, the implementation rate of examinations necessary for diagnosis was low, so there is an urgent need to develop an environment where examinations can be conducted in outpatient settings., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: There is no known predictor for olfactory function recovery with dupilumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP). This study assessed whether patient-reported recovery of olfactory function on oral corticosteroids (OCS) is a prognostic factor., Methods: Retrospective analysis of pre-biological OCS-responsiveness on olfactory functioning (OCS-responsive or OCS-unresponsive; OCS-r and OCR-u, respectively) as predictor for olfactory functioning after 6 months of dupilumab therapy for severe CRSwNP., Results: 212 CRSwNP patients treated with dupilumab were divided between OCS-r (reported improvement of olfactory function with OCS before dupilumab treatment, n = 152), and OCS-u (OCS-unresponsive; no such improvement, n = 60). Olfactory function was tested with Sniffin's Sticks Identification Test (12 pens; SSIT-12). At baseline, both groups had a median SSIT-12 score of 3 / 12 indicating anosmia. Hyposmia and normosmia rates were also comparable (5.9% and 3.3% in OCS-r, respectively; 5.0% and 1.7% in OCS-u, respectively). After 6 months of dupilumab treatment, OCS-r showed higher olfactory scores (median SSIT-12: 8/12; 52.6% hyposmia and 17.8% normosmia) than OCS-u (median SSIT-12: 5/12; 31.7% hyposmia and 3.3% normosmia). The positive predictive value of OCS-responsiveness on scoring <7 (normosmia/hyposmia) on the SSIT-12 after 6 months of dupilumab treatment was 70.4%. Conversely, the negative predictive value of OCS-unresponsiveness on scoring <7 (anosmia) on the SSIT-12 after 6 months of dupilumab treatment was 65.0%., Conclusion: Patients who report olfactory function improvement on OCS have a higher chance of recovery of olfactory function during the first six months of treatment with dupilumab than patients who do not.

Purpose: To compare the effects of doxycycline (DOX) and conventional management in patients with refractory chronic rhinosinusitis and nasal polyps (CRSwNP)., Methods: Six databases were searched to September 2023. We retrieved studies that compared improvements in refractory chronic sinusitis-related symptoms between DOX-treated and control groups., Results: DOX significantly reduced the Lund-Kennedy (LK) score [- 0.3670 (range - 0.6173; - 0.1166); I 2  = 92.8%], the nasal polyposis score [- 0.9484 (- 1.2287; - 0.6680); I 2  = 92.5%], the patient-reported Sinonasal Outcome Test (SNOT) score [- 0.3141 (- 0.4622; - 0.1660); I 2  = 91.2%], and the nasal obstruction score [- 0.1813 (- 0.3382; - 0.0243); I 2  = 86.2%]. On subgroup analyses by the measurement timepoints, the extent of nasal polyposis was significantly lower in the DOX group during treatment, at the end of treatment, and 4 and 8 weeks later. The LK scores also indicated improvements during treatment and at the end of treatment. The SNOT score tended to decrease with time in the treatment group. Nasal obstruction symptoms improved during treatment and 4 weeks later., Conclusion: DOX enhances the postoperative endoscopic outcomes of refractory CRSwNP patients by reducing recurrent polyposis and inflammation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2024 AstraZeneca. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)